Azvudine and nirmatrelvir/ritonavir (Paxlovid) are recommended for COVID-19 treatment in China, but their safety and efficacy in the elderly population are not fully known. In this multicenter, retrospective, cohort study, we identified 5131 elderly hospitalized COVID-19 patients from 32,864 COVID-19 patients admitted to nine hospitals in Henan Province, China, from December 5, 2022, to January 31, 2023. The primary outcome was all-cause death, and the secondary outcome was composite disease progression. Propensity score matching (PSM) was performed to control for confounding factors, including demographics, vaccination status, comorbidities, and laboratory tests. After 2:1 PSM, 1786 elderly patients receiving azvudine and 893 elderly patients receiving Paxlovid were included. Kaplan-Meier and Cox regression analyses revealed that compared with Paxlovid group, azvudine could significantly reduce the risk of all-cause death (log-rank P = 0.002; HR: 0.71, 95% CI: 0.573-0.883, P = 0.002), but there was no difference in composite disease progression (log-rank P = 0.52; HR: 1.05, 95% CI: 0.877-1.260, P = 0.588). Four sensitivity analyses verified the robustness of above results. Subgroup analysis suggested that a greater benefit of azvudine over Paxlovid was observed in elderly patients with primary malignant tumors (P for interaction = 0.005, HR: 0.32, 95% CI: 0.18-0.57) compared to patients without primary malignant tumors. Safety analysis revealed that azvudine treatment had a lower incidence of adverse events and higher lymphocyte levels than Paxlovid treatment. In conclusion, azvudine treatment is not inferior to Paxlovid treatment in terms of all-cause death, composite disease progression and adverse events in elderly hospitalized COVID-19 patients.

Peptide-drug conjugates (PDCs) have emerged as a promising modality in precision oncology, enabling targeted delivery of cytotoxic payloads while minimizing off-target toxicity. The integration of covalent warheads, such as those based on sulfur(VI) fluoride exchange (SuFEx) chemistry, enhances drug-target residence time and tumor accumulation. However, existing screening methods for covalent peptide (CP) libraries require post-translational warhead conjugation, limiting throughput. Here, we present an integrated mRNA display platform that incorporates covalent warheads during ribosomal synthesis, enabling efficient screening of ultra-diverse covalent macrocyclic peptide libraries (>10¹³ variants). This approach, using site-specific incorporation of N-chloroacetyl-d-phenylalanine and fluorosulfate-l-tyrosine, accelerated the discovery of irreversibly binding (K _i = 3.58 μmol/L) Nectin-4-targeting peptide CP-N1-N₃ via proximity-triggered SuFEx. The peptide was further conjugated to cytotoxic payloads, yielding the covalent PDC CP-N1-MMAE with potent cytotoxicity (IC₅₀ ≈ 43 nmol/L) against MDA-MB-468 cells. This platform establishes a new paradigm for precision covalent drug discovery.

Oroxylin A (OA) is a natural flavonoid primarily derived from the plants Oroxylum indicum and Scutellaria baicalensis. Currently, OA is obtainable through chemical synthesis and exhibits polypharmacological properties, including anti-cancer, anti-inflammatory, anti-microbial, and multi-organ protective effects. The first-in-class drug OA tablets are presently undergoing phase Ib/IIa clinical trials for hepatocellular carcinoma (HCC) treatment. Substantial evidence suggests that OA demonstrates therapeutic potential against various hepatic and gastrointestinal (GI) disorders, including HCC, hepatic fibrosis, fatty liver disease, hepatitis, liver injury, colitis, and colorectal cancer (CRC). OA exerts its therapeutic effects primarily by modulating several crucial signaling pathways, including those associated with apoptosis, oxidative stress, inflammation, glucolipid metabolism, and fibrosis activation. The oral pharmacokinetics of OA is characterized by phase II metabolism, hydrolysis, and enterohepatic recycling. This review provides a comprehensive overview of the critical stages involved in the development of OA tablets, presenting a holistic perspective on the progression of this first-in-class drug from preclinical to clinical phases. It encompasses the synthesis of active pharmaceutical ingredients, pharmacokinetics, pharmacological efficacy, toxicology, drug delivery, and recent advancements in clinical trials. Importantly, this review examines the potential mechanisms by which OA may influence the gut-liver axis, hypothesizing that these interactions may confer health benefits associated with OA that transcend the limitations posed by its poor bioavailability.
Humans ; Flavonoids/pharmacokinetics* ; Tablets ; Animals ; Gastrointestinal Diseases/drug therapy* ; Liver Diseases/drug therapy* ; Drug Development ; Clinical Trials as Topic ; Scutellaria baicalensis/chemistry*

Objective To investigate an automated pretreatment technology for detecting levels of free silica in workplace dust. Methods An fully automated pretreatment workstation for detecting free silica levels in workplace dust was developed by integrating graphite-controlled digestion temperature, online-controlled dilution of digestion solutions, and filtration endpoint recognition based on monitoring technology, combined with multi-channel synchronous measurements. Results The fully automatic pretreatment workstation was used to digest and filter 14 standard samples of free silica produced by three institutions, and then detected by pyrophosphate method. The result range of high-, medium-, and low-level free silica standard samples detection was 66.5%-84.8%, 40.0%-44.5%, and 2.1%-24.8%, respectively. The mean relative standard deviations were 3.9%, 1.4% and 1.5%. Conclusion The fully automated pretreatment workstation produced results that met relevant requirements. It can effectively replace the manual digestion and filtration steps of the pyrophosphate method to measure free silica levels in workplace dust and enable rapid detection of free silica in dust samples.

Objective:To investigate the clinical effects of combined tissue flap transplantation in repairing giant chest wall defects.Methods:This study was a retrospective observational study. From August 2013 to December 2020, 31 patients with chest wall tumor or radiation ulcer after radical resection of chest wall tumor and conformed to the inclusion criteria were admitted to the Department of Breast Oncoplastic Surgery of Hunan Cancer Hospital, including 12 males and 19 females, aged 25-71 years. After resection of tumor or ulcer and wound debridement, the area of secondary chest wall defect was 300-600 cm 2 with length of 16-35 cm and width of 16-32 cm. According to the actual situation of the patients and the preoperative design, the chest wall defects were repaired with the flexible combination of perforator flaps and myocutaneous flaps from different donor sites, and the area of the combined tissue flap was 260-540 cm 2 with length of 20-30 cm and width of 13-20 cm. Free posteromedial thigh perforator flap+free anterolateral thigh myocutaneous flap were used in 2 patients, free deep inferior epigastric artery perforator flap+free anterolateral thigh myocutaneous flap were used in 5 patients, free deep inferior epigastric artery perforator flap+pedicled rectus abdominis myocutaneous flap+free anterolateral thigh myocutaneous flap were used in 7 patients, free deep inferior epigastric artery perforator flap+pedicled rectus abdominis myocutaneous flap+pedicled latissimus dorsi myocutaneous flap were used in 2 patients, and bilateral free anterolateral thigh myocutaneous flaps were used in 15 patients. For the remaining small area of superficial tissue defect after being repaired by combined tissue flaps, skin graft was used to repair or delayed local flap transfering was performed after the tissue flaps survived and edema subsided. The appropriate blood vessels in the donor and recipient sites were selected for anastomosis to reconstruct the blood supply of tissue flaps. The wounds in the donor sites of tissue flaps that can be directly sutured were sutured directly; for those that cannot be sutured directly, the skin grafting or delayed suture was performed. The anastomosis of blood vessels in the recipient sites, operation length, and postoperative hospital stay were recorded. The survivals of tissue flaps and skin grafts, the shape and texture of reconstructed chest wall, the wound healing, scar formation, and function of donor sites of tissue flaps, and the scar formation of the donor sites of skin grafts were observed after operation. Tumor recurrence and death of recurrent patients were followed up after operation. Results:The blood vessels in the recipient sites were anastomosed as follows: proximal internal thoracic vessels for 24 times, distal internal thoracic vessels for 12 times, trunk of thoracodorsal vessels for 4 times, anterior serratus branches of thoracodorsal vessels for 8 times, and thoracoacromial vessels for 12 times. The operation length was 6.0 to 8.5 hours, and the postoperative hospital stay was 9 to 21 days. Necrosis at the edge of partial tissue flaps occurred in 4 patients after operation, which healed after dressing change, and the tissue flaps and skin grafts of the other patients survived completely. The shape and texture of the reconstructed chest wall were good. Four patients had poor wound healing in the donor sites of abdominal tissue flaps, which healed after dressing change and local drainage. Only linear scar was left in the donor sites of all tissue flaps, and there was no obvious dysfunction in the donor sites of tissue flaps. Mild hypertrophic scar was left in the donor sites of skin grafts. During follow-up of 9 to 36 months after operation, 6 patients had tumor recurrence, and the recurrence time was 5 to 20 months after operation. After comprehensive treatment for patients with tumor recurrence, 3 patients died.Conclusions:Transplantation of combined tissue flaps in repairing the giant chest wall defects can shorten the time of total operation and hospital stay, and avoid multiple operations. After operation, patients had good chest wall appearance, with reduced tumor recurrence in patients with chest wall tumor.

This experiment aims to investigate the effects of a dietary supplement of herbal tea resi-due on white feather broilers in the prospectives of growth performance,serum indexes and intesti-nal immune indexes.A total of 280 1-day-old white feather broilers with similar body mass and good health were randomly divided into 4 groups with 5 replicates per group and 14 birds per repli-cate.Group Ⅰ(control group)was fed a basal diet.Groups Ⅱ,Ⅲ and Ⅳ were fed a diet supple-mented with 2％,4％and 6％herbal tea residue powder,respectively.The feeding lasted for 49 days,and was divided into 2 phases from 1 to 21 days of age and 22 to 49 days of age.Blood,tissue and mucosa of the duodenum and jejunum were collected on 21 d and 49 d.Total cholesterol(T-CHO),triglyceride(TG),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C)and the activities of aspartate aminotransferase(AST)and alanine amin-otransferase(ALT)in the serum were examined.The villus height and crypt depth of the jejunum were observed and measured by morphology.The mRNA expression levels of intestinal interleukin-1β(IL-1β),interleukin-2(IL-2),interleukin-4(IL-4),interleukin-10(IL-10)and tumor necrosis factor-α(TNF-α)were determined by qPCR.The results showed that compared with group Ⅰ,the mass of group Ⅲ on 21 d and 49 d significantly increased(P＜0.05).The average daily feed intake of 22-49 d and 1-49 d significantly increased(P＜0.05).The average daily mass gain of 1-21 d,22-49 d and 1-49 d significantly increased(P＜0.05).In the serum of 21 d,compared with group Ⅰ,T-CHO in group Ⅱ significantly decreased(P＜0.05).TG in groups Ⅱ,m and Ⅳ significantly de-creased(P＜0.05).LDL-C and AST activity in group Ⅳ significantly decreased(P＜0.05).In the serum of 49 d,T-CHO in group Ⅲ,LDL-C in group Ⅳ,HDL-C of groups Ⅲ and Ⅳ significantly increased(P＜0.05),and the ALT activity of these two groups decreased(P＜0.05).AST activity in group Ⅱ significantly decreased(P＜0.05).In the duodenum of 21 d,compared with group Ⅰ,the expressions of TNF-α in group Ⅱ was significantly decreased(P＜0.05).In the duodenum of 49 d,the expression of IL-10 in group Ⅱ was significantly increased(P＜0.05),and the expression of IL-2 in groups Ⅲ and Ⅳ was significantly decreased(P＜0.05).In the jejunum of 49 d,the ex-pression of IL-10 in group Ⅱ was increased(P＜0.05),and the expression of IL-2 in groups Ⅲand Ⅳ was significantly decreased(P＜0.05).In conclusion,dietary herbal tea residue can regulate circulating lipid level and enhance intestinal immunity of white feather broilers without affecting their normal growth performance.This experiment also suggested that the a 2％-4％supplementa-tion of herbal tea residues to white feather broilers was of good effect.

The study adopted muscle injection of pVAX1-SP-GHRH(1-44)expression plasmid and electrostimulation to determine its effects on mouse growth and sow production performance.One hundred and fifty four-week-old C57 BL/6 female mice were randomly divided into 6 groups of 5 replicates each.Muscle single-injection followed by electrostimulation was performed.The con-trol group received an empty plasmid injection(80 μg/kg),while the treatment groups received pVAX1-SP-GHRH(1-44)plasmid injections(20,40,80,120,160 μg/kg).Twenty healthy preg-nant sows were randomly divided into 2 groups,each with 10 sows.Electrostimulation treatment was applied to the semimembranosus muscle of the pregnant sows after a single injection.The con-trol group received physiological saline injection,while the plasmid group received a 2 mg pVAX1-SP-GHRH(1-44)expression plasmid injection.Mouse weight,feed intake,and serum GHRH and IGF-1 levels were measured at days 0,7,14,21,and 28 after injection.Pregnant sows were bled via the tail vein at days 0,14,28,and 42 after injection,and their serum was separated to measure serum GHRH and IGF-1 levels.The birth weight,placental weight,number of piglets born,number of healthy piglets,number of weak piglets,number of deformed piglets,number of stillborn piglets,and number of mummified piglets were recorded at day 14.The mouse study re-sults showed that muscle injection of pVAX1-SP-GHRH(1-44)plasmid followed by electrostim-ulation could promote mouse feeding and increase weight gain(P＜0.05),significantly increase mouse serum GHRH and IGF-1 levels(P＜0.05),and maintain its effects until day 21.The results of the pregnant sow study showed that the average birth weight of the piglets in the plasmid group was significantly increased(P＜0.01),and the placenta weight was significantly increased(P＜0.05).The serum GHRH and IGF-1 concentrations in the plasmid group sows were significantly increased(P＜0.01).The study results showed that muscle injection of pVAX1-SP-GHRH(1-44)expression plasmid followed by electrostimulation could promote mouse feeding and increase weight gain,and also significantly improve the average birth weight and placental weight of the piglets in pregnant sows.

Objective To evaluate the value of rs61330082 and rs4730153 polymorphisms of Visfatin locus for the diagnosis of type 2 diabetes mellitus(T2DM)in a high-risk population.Methods SNPscanTM high-throughput single nucleotide polymorphism typing technique was used to genotype Visfatin gene loci rs61330082 and rs4730153 in 346 T2DM patients(T2DM group)and 1426 normal controls(NC group).Logistic regression analysis was used to analyze T2DM risk factors.ROC curves were used to analyze the optimal cut-off values of Visfatin gene rs61330082 and rs4730153 for the diagnosis of T2DM.Results The proportion of women,age,obesity,smoking,hypertension,FPG,HbA1c and TG were higher in T2DM group than those in NC group(P<0.01)and HDL-C was lower than in NC group(P<0.01).The frequency of G allele and GG genotype was higher in T2DM group compared with NC group(P<0.05).Logistic regression analysis showed that age,female,obesity,hypertension,TG,and GG genotype at rs4730153 locus were risk factors for T2DM,HDL-C was a protective factor for T2DM.The area under the ROC curve of GG genotype at Visfatin rs4730153 mutation for diagnosis of T2DM was 0.668 and the optimal cut-off point for predicting T2DM was 20.04%,with sensitivity 60.1%and specificity 66.1%,respectively.Conclusion The GG genotype of Visfatin gene rs4730153 locus is associated with the risk of T2DM and can beused as a candidate gene for predicting phenotype of T2DM.

Aortic aneurysm and dissection are critical cardiovascular diseases that threaten human life and health seriously. No pharmacological treatment can effectively prevent disease progression. The imbalance of aortic wall cells and non-cellular components leads to structural or functional degeneration of the aorta, which is a prerequisite for disease occurrence. As the important non-cellular component, extracellular matrix (ECM) is crucial to maintain the aortic structure, function, and homeostasis. Abnormal production of elastin and collagen, destruction of cross-linking between elastic fibers and collagen fibers, and the imbalance of metalloproteinase and inhibitors leads to excessive degradation of ECM proteins, all of which have destroyed the structure and function of aorta. It will provide more ideas for disease prevention and treatment by learning ECM proteins and their metabolic mechanism. Here, we focus on the ECM proteins that have been reported to be involved in aortic aneurysm and dissection, and discuss the regulatory mechanism of metalloproteinase and inhibitors.

Background: Recent studies have reported that costoclavicular blocks (CCBs) can consistently block almost all branches of the brachial plexus while sparing the phrenic nerve and provide effective analgesia after shoulder surgery. We aimed to compare the efficacy of the CCB with that of the interscalene block (ISB) as the sole blocking technique for shoulder surgery. Methods: A total of 212 patients undergoing elective arthroscopic shoulder surgery were randomized to receive an ISB or CCB based on a non-inferiority design. All patients received titration sedation with propofol under monitored anesthesia during surgery. The primary outcomes were the proportion of patients with complete motor blockade of the suprascapular nerve (SSN) and incidence of hemidiaphragmatic paralysis (HDP). The secondary outcomes included block-related variables, complications, and postoperative pain scores. Results: The proportion of patients with complete motor blockade of the SSN at 20 min between the CCB and ISB groups (53% vs. 66%) exceeded the predefined non-inferiority margin of −5%, but was comparable at 30 min (87% vs. 91%). The CCB resulted in a significantly lower incidence of HDP (7.55% vs. 92.45%), Horner’s syndrome (0% vs. 18.87%), and dyspnea (0% vs. 10.38%) than the ISB. None of the patients experienced failed blocks or required conversion to general anesthesia. Pain scores were comparable between the groups. Conclusions Ultrasound-guided CCBs may be comparable to ISBs, with fewer unfavorable complications in patients with impaired lung function undergoing arthroscopic shoulder surgery.