OBJECTIVE To analyze the impact of intergenerational substitution effect of the drugs with the same indication on fund expenditures for national medical insurance for this indication in China， taking national medical insurance negotiated drugs for non-small cell lung cancer （hereinafter referred to as “NSCLC national negotiation drugs”） as an example. METHODS The sales amounts of 15 types of NSCLC national negotiated drugs in secondary and tertiary public hospitals across seven sample provinces from 2017 to 2023 were collected from the Pharmaceutical Drug Database of the China National Pharmaceutical Industry Information Center. A sliding t-test and Mann-Kendall trend test were used to evaluate the trends in sales amounts and DDDs. Taking epidermal growth factor receptor（EGFR）-tyrosine kinase inhibitors （TKIs） and anaplastic lymphoma kinase （ALK）-TKIs as examples， the generational substitution characteristics of these drugs were analyzed. RESULTS The change points of sales amounts and DDDs differed slightly across provinces； the change points of sales amount were mostly concentrated between the first quarter of 2019 and the second quarter of 2020， while those for DDDs were primarily concentrated in the first to second quarters of 2021. In five provinces， i.e. Beijing， Heilongjiang， Jiangsu， Sichuan and Shaanxi， sales amounts showed no significant upward trend after the breakpoints （P＞0.05）， whereas in Guangdong and Hubei， both sales amounts and DDDs continued to rise significantly following the breakpoints （P＜0.05）. Since 2020， the growth in sales amounts of EGFR-TKIs had slowed. After 2021， the sales amounts and DDDs of first- and second-generation EGFR-TKIs declined， while third-generation EGFR-TKIs showed clear substitution effects. The sales amounts of ALK-TKIs continuedto grow. However， the sales amounts and DDDs of first-generation ALK-TKIs had declined year by year， with second-generation ALK-TKIs demonstrating a significant substitution effect on first-generation ones， while third-generation ALK-TKIs had not yet shown a clear substitution trend. CONCLUSIONS With the annual access to and renewal of drugs in national medical insurance negotiations， the overall expenditure trend for NSCLC negotiated drugs comes to a plateau. The intergenerational substitution relationships of drugs with the same indication achieve a relative balance in fund expenditures for negotiated drugs with the same indication. It is recommended that pharmaceutical companies carefully consider their research pipelines， and that medical insurance authorities， during the renewal management process， pay attention to the impact of drug substitution effects on the overall actual expenditure of medical insurance funds for that specific target or the same indication， and scientifically evaluate the extent of price reductions during contract renewals.

Oligonucleotide drugs have experienced accelerated development in the past 10 years, and some of them have been used in clinical treatment. Because of its convenient design, flexible sequence, and high specificity, it is expected to solve the “undruggable” challenge of many targets which are difficult in drug development. Moreover, its clinical transformation period and cost are relatively low, which makes oligonucleotide drug become the frontier of emerging biotechnology drug discovery. Brain diseases include a series of incurable diseases, such as neurodegenerative diseases, glioma, and motor neuron diseases. Many of them are age-related and regarded as aging-associated brain diseases. Due to the complex etiology, many targets are difficult to be drugged. At the same time, the existence of the barrier system “blood-brain barrier” in the brain makes most drugs unable to achieve effective accumulation at brain lesions, and many small molecule drugs have failed in clinical transformation. The specificity and sequence flexibility of oligonucleotide acid drugs provide new possibilities for drug development, but they also face the challenge of brain delivery. Although a variety of oligonucleotide drugs have been used in the medical market, brain-targeted oligonucleotide drugs are still extremely rare. This article reviewed recent advances and discussed key topics and clinical transformation challenges in this field, such as clinical approval cases, bottlenecks of brain-targeted delivery and current strategies, as well as potential targets for aging-related brain diseases.

Objective To study the application effect of Glisson hepatic pedicle priority approach marked by APR triangle in laparoscopic anatomic right hemihepatectomy(LARH).Methods The clinical data of 66 patients underwent LARH in the Affiliated Hospital of Tangshan Vocational and Technical College were retrospectively analyzed.According to the surgical approaches,the patients were divided into the extrathecal group and the APR group.The 35 patients of the extrathecal group underwent LARH via Glisson hepatic pedicle extrathecal approach.The 31 patients of the APR group were treated with LARH through the Glisson hepatic pedicle priority approach marked by APR triangle.The clinical data including perioperative indexes,postoperative complications,oxidative stress and liver function indexes of patients in the two groups were statistically analyzed,and the differences between the two groups were compared.Results The operative time and intraoperative blood loss of patients in the APR group were significantly shorter/less than those in the extrathecal group,with statistically significant differences(P<0.05).There was no significant differences in the intraoperative blood transfusion ratio,drainage tube indwelling time,first exhaust time,postoperative hospitalization time or postoperative complications of patients between the two groups(P>0.05).The levels of malondialdehyde(MDA),cortisol(Cor)and superoxide dismutase(SOD)at each time point after surgery of patients in the two groups were significantly different from those before surgery(P<0.05),and the levels of MDA,Cor and SOD at each time point after surgery of patients in the APR group were significantly better than those in the extrathecal group(P<0.05).The levels of albumin(ALB),total bilirubin(TBil),aspartate aminotransferase(AST)and alanine aminotransferase(ALT)at each time point after surgery of patients in the two groups were significantly different from those before surgery(P<0.05).Moreover,the levels of ALB,TBil,AST and ALT at each time point after surgery of patients in the APR group were significantly better than those in the extrathecal group(P<0.05).Conclusion Compared with the Glisson hepatic pedicle extrathecal approach,the Glisson hepatic pedicle priority approach marked by APR triangle in LARH has shorter operation time,less bleeding and less oxidative stress reaction,which is beneficial to the recovery of liver function after surgery.

Autophagy is an essential cellular metabolic process that involves clearance of damaged organelles and protein aggregates in cells through lysosomes,providing energy for cells,and maintaining cellular tissue homeostasis.Impaired autophagy is closely related to the pathophysiology of a variety of diseases.In the pathogenesis of atherosclerosis(AS),the dysfunction of autophagy of vascular cells plays a crucial role in the formation and progression of AS.The functional status,survival or death of vascular cells,including endothelial cells,vascular smooth muscle cells and macrophages,can influence the formation and stability of plaques,thereby affecting the progression of AS.This review summarizes the relationship between autophagy and AS,and details the impact of autophagy dysfunction on vascular cell function in the process of AS,as well as the role of mitophagy and inflammasome in the development of AS,aiming to provide novel insights for the prevention and treatment of AS.

Aim To disclose the subcellular localiza-tion,expression pattern,cellular physiological function and possible molecular mechanism of C12ORF56,a novel gene located at q14.2 of chromosome 12,in the pathogenesis of lung cancer.Methods ONCOMINE database was applied to investigate the mRNA level dif-fering of C12ORF56 between normal and lung cancer tissues.Analysis based on LinkedOmics,Metascape,String and GSEA database or tools provided indication of potential cellular physiological functions of C12ORF56 in the developing of lung cancer.C12ORF56 was knocked down via siRNA and the pro-liferation of NCI-H1073 cells were observed by EdU and CCK-8 assay.RT-qPCR was used to detect the ex-pression level of C12ORF56 of lung cancer cells on dif-ferent cycle phases.The core sequence regions of pro-moter affecting the transcription of C12ORF56 gene were analyzed by Jaspar online-tools and verified by dual-luciferase assay.Results C12ORF56 was highly expressed in lung cancer cells,especially in squamous cell lung cancer.C12ORF56 correlated with cell cy-cle,cancer immune,DNA replication.Knockdown of C12ORF56 reduced NCI-H1703 cell proliferation.Conclusion The up-regulation of C12ORF56 is in-volved in the development of lung cancer by enhancing lung cancer cell proliferation.

OBJECTIVES: To observe the clinical efficacy of moxibustion combined with western medication on ureteral stent-related symptoms after ureteroscopic lithotripsy (URL). METHODS: One hundred and fifty patients with upper urinary tract calculus implanted with ureteral stents after URL were randomly divided into a moxibustion group (50 cases, 1 case dropped out), a placebo moxibustion group (50 cases, 3 cases dropped out) and a blank control group (50 cases). No intervention was performed in the blank control group. On the basis of oral administration with tamsulosin hydrochloride sustained release capsule (starting from the first day after surgery, once a day, 0.2 mg each time, continuously for 4 weeks), in the moxibustion group, moxibustion was operated at Guanyuan (CV 4) and bilateral Shenshu (BL 23); the sham-moxibustion was delivered at the same acupoints in the placebo moxibustion group, once daily, 6 times a week, for 15 min in each treatment. The duration of treatment was 4 weeks. Before treatment, and after 1, 2 and 4 weeks of treatment, the scores of lower urinary tract symptoms, body pain, general health, work performance and satisfaction of sexual matters were compared among the 3 groups. The tract calculus clearance rate, urinary infection and the oral administration of painkillers were compared after 4 weeks of treatment in the 3 groups. RESULTS: The scores of lower urinary tract symptoms, body pain and general health after 1 week of treatment, and the scores of lower urinary tract symptoms, body pain, general health and work performance after 2 and 4 weeks of treatment were lower than those before treatment in the 3 groups (P<0.01). The scores of lower urinary tract symptoms and body pain in the moxibustion group after 1, 2 and 4 weeks of treatment were lower than those in the blank control group and the placebo moxibustion group (P<0.01, P<0.05) respectively. The score of general health in the moxibustion group was lower than that in the blank control group after 1 week of treatment (P<0.01), and lower than those of the blank control group and the placebo moxibustion group after 2 and 4 weeks of treatment (P<0.01, P<0.05). Regarding the score of work performance, it was lower in the moxibustion group after 1 and 2 weeks of treatment compared with those in the blank control group (P<0.05, P<0.01), and lower than those of the blank control group and the placebo moxibustion group after 4 weeks of treatment (P<0.01, P<0.05). The tract calculus clearance rate in the moxibustion group was 95.9% (47/49), higher than that in the blank control group (80.0%, 40/50, P<0.05). The proportion of oral administration of painkillers in the moxibustion group (28.6%, 14/49) and the placebo moxibustion group (40.4%, 19/47) was lower than that in the blank control group (76.0%, 38/50, P<0.01) respectively. CONCLUSIONS Moxibustion combined with western medication relieves lower urinary tract symptoms and body pain, and accelerate the recovery of general health and work performance in the patients after URL.
Humans ; Ureteroscopy/adverse effects* ; Moxibustion ; Lithotripsy/adverse effects* ; Pain ; Lower Urinary Tract Symptoms ; Calculi ; Stents/adverse effects* ; Acupuncture Points

OBJECTIVE: To explore clinical effect of arthroscopy-assisted rotator cuff tendon transfer in treating irreparable rotator cuff tears (IRCT). METHODS: From May 2015 to May 2018, 23 patients with unrepairable rotator cuff tears were treated with arthroscopy-assisted rotator cuff tendon transfer, and 21 patients were followed up finally, including 8 males and 13 females, aged from 48 to 82 years old with an average of(64.3±9.1) years old;the courses of disease ranged from 6 to 36 months with an average of (14.0±6.4) months. American Rotator and Elbow Surgeons Score(ASES) and Constant-Murley score were used to evaluate clinical efficacy before surgery and at the latest follow-up. RESULTS: All 21 patients were followed up for 36 to 54 months with an average of (39.4±4.4) months. Axillary incision of 1 patient was redness, swelling and exudation after surgery, which healed after 3 weeks of dressing change, and exudate culture was negative. At the latest follow-up, MRI showed partial tearing of the metastatic tendon in 2 patients, but pain and movement of the affected shoulder were still better than before surgery. ASES increased from preoperative (41.0±9.6) scores to the latest follow-up (75.6±14.0) scores, and had statistical difference (t=10.50, P<0.01). Constant-Murley score increased from (49.8±7.1) scores before operation to (67.5±11.6) scores at the latest follow-up (t=11.27, P<0.01). CONCLUSION Arthroscopic assisted latissimus dorsalis tendon transposition restores physiological and anatomical structure of glenohumeral joint by reconstructing balance of horizontal and vertical couples of shoulder joint, thus achieving the stability of the shoulder joint, relieving shoulder pain and improving shoulder joint function.
Male ; Female ; Humans ; Middle Aged ; Aged ; Aged, 80 and over ; Rotator Cuff Injuries/surgery* ; Superficial Back Muscles ; Rotator Cuff ; Treatment Outcome ; Shoulder Joint/surgery* ; Tendon Transfer ; Arthroscopy ; Range of Motion, Articular/physiology*

OBJECTIVE: To develop and validate a user-friendly risk score for older mitral regurgitation (MR) patients, referred to as the Elder-MR score. METHODS: The China Senile Valvular Heart Disease (China-DVD) Cohort Study functioned as the development cohort, while the China Valvular Heart Disease (China-VHD) Study was employed for external validation. We included patients aged 60 years and above receiving medical treatment for moderate or severe MR (2274 patients in the development cohort and 1929 patients in the validation cohort). Candidate predictors were chosen using Cox's proportional hazards model and stepwise selection with Akaike's information criterion. RESULTS: Eight predictors were identified: age ≥ 75 years, body mass index < 20 kg/m², NYHA class III/IV, secondary MR, anemia, estimated glomerular filtration rate < 60 mL/min per 1.73 m², albumin < 35 g/L, and left ventricular ejection fraction < 60%. The model displayed satisfactory performance in predicting one-year mortality in both the development cohort (C-statistic = 0.73, 95% CI: 0.69-0.77, Brier score = 0.06) and the validation cohort (C-statistic = 0.73, 95% CI: 0.68-0.78, Brier score = 0.06). The Elder-MR score ranges from 0 to 15 points. At a one-year follow-up, each point increase in the Elder-MR score represents a 1.27-fold risk of death (HR = 1.27, 95% CI: 1.21-1.34, P < 0.001) in the development cohort and a 1.24-fold risk of death (HR = 1.24, 95% CI: 1.17-1.30, P < 0.001) in the validation cohort. Compared to EuroSCORE II, the Elder-MR score demonstrated superior predictive accuracy for one-year mortality in the validation cohort (C-statistic = 0.71 vs. 0.70, net reclassification improvement = 0.320, P < 0.01; integrated discrimination improvement = 0.029, P < 0.01). CONCLUSIONS The Elder-MR score may serve as an effective risk stratification tool to assist clinical decision-making in older MR patients.

In this study, the mechanism of Xiaoyan Lidan formula (XYLDF) against 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine (DDC)-induced chronic intrahepatic cholestasis (CIHC) in mice was investigated based on metabolomics, molecular docking and pharmacological methods. In the pharmacodynamics study, a dosage of 5 g·kg^-1 (clinical equivalent) XYLDF was administered in DDC-induced mice, then the effect of XYLDF against CIHC was evaluated by measuring the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP) as well as total bilirubin (TBIL) in serum and observing liver histopathological changes. All experiments were approved by the Ethical Committee Experimental Animal Center of Guangzhou University of Chinese Medicine (ZYD-2021-001). The serum metabolites of mice in each group were detected and identified based on ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry, and the relevant biological pathways and molecular key targets were further enriched. Molecular docking technology was used to further evaluate the binding activity of the main active ingredients of XYLDF with potential targets. Subsequently, the in vitro experiment was conducted for the validation of the vital target. The results showed that compared with the model group, XYLDF significantly decreased the levels of ALT, AST, AKP and TBIL in the serum of CIHC mice, as well as alleviated inflammatory infiltration and hepatocyte necrosis in liver tissue. According to the metabonomic study, a total of 35 differential metabolites was identified as biomarkers associated with cholestasis, 12 of which were significantly recovered by XYLDF treatment. These biomarkers were involved in the pathways of primary bile acid biosynthesis and linoleic metabolism, which are closely related to the mechanism of XYLDF against CIHC. Protein-protein interaction network indicated that cytochrome P450 3A4 (CYP3A4) and cytochrome P450 1A1 (CYP1A1) are significant potential targets with good binding properties with six major active ingredients of XYLDF. Furthermore, it was found that 4-methoxy-5-hydroxycanthin-6-one, dehydroandrographolide and isodocarpin, three of the main active components in XYLDF, markedly induced the expression of CYP3A4 mRNA in vitro. This study revealed that XYLDF mainly mediates the biosynthesis of bile acids in CIHC mice to improve liver tissue lesions and bile efflux disorders, among which, CYP3A4 is the key target in the protection of XYLDF against CIHC. This research provides a reference for further elucidation of the pharmacological mechanism of XYLDF.

AIM: To observe the clinical features of acute macular neuroretinopathy(AMN)induced by Omicron.METHODS: A retrospective study. A total of 9 patients(18 eyes)diagnosed with AMN from December 2022 to January 2023 in the Hospital of Chengdu University of Traditional Chinese Medicine were included. Patients underwent spectral-domain optical coherence tomography(SD-OCT), fundus fluorescein angiography(FFA), fundus photography, autofluorescence(AF), infrared reflectance(IR), optical coherence tomography angiography(OCTA)and multicolor, etc. Furthermore, they were followed up for 1～3mo and observed the prognosis.RESULTS: The initial symptom of the Omicron-induced AMN was the sudden onset of central/paracentral scotoma in the eyes with or without impaired vision and metamorphopsia, and the scotoma could persist for at least 3mo. The image features of AMN are as follows. First, the SD-OCT examination showed the rupture of outer retinal layers, scattered hyperreflective lesions, and atrophy of outer retinal layers. In severe cases, hyperreflective lesions were seen in the inner nuclear layer(INL)or with microcystic cavities under the retinal pigment epithelium(RPE). Second, the OCTA examination demonstrated the decreased blood flow density of the deep capillary plexus(DCP)of the macula. Third, the IR examination showed the weak reflection of lesion areas. Fourth, the fundus photography demonstrated the localized brown wedge-shaped lesion.CONCLUSIONS: The Omicron-induced AMN is mostly found in young females, and the characteristic manifestation of fundus is damage to the outer retinal layers. The extent of fundus lesions is related to the systemic inflammatory response and ocular microcirculatory changes after infection. The multimodal fundus image examination and a history of Omicron infection are helpful to diagnose the Omicron-induced AMN.