OBJECTIVE To systematically review the pharmacoeconomic evaluation literature about proprotein convertase subtilisin/kexin type 9 （PCSK9） inhibitors for the prevention of cardiovascular disease in patients with hypercholesterolemia， and to provide a reference for clinical treatment， health decision-making and future follow-up research. METHODS Retrieved from English and Chinese databases such as PubMed and CNKI， the pharmacoeconomic literature about PCSK9 inhibitors （evolocumab and alirocumab） for the prevention of cardiovascular disease in patients with hypercholesterolemia was collected from the establishment of the database to October 8， 2023. The quality of the included literature was assessed with Consolidated Health Economic Evaluation Reporting Standards 2022 （CHEERS 2022） scale. The descriptive analysis was performed for basic information， model structure， related parameters， sensitivity analysis and the results of included studies. RESULTS & CONCLUSIONS A total of 29 literature were included， with overall good quality. The evaluation mainly adopted the Markov model from the healthcare system， payer and societal perspective. The effectiveness and utility data mainly came from the previous studies； the direct cost was mainly considered with a discount rate of 1.5%-5.0% per year， while the willingness-to-pay threshold was often set at 1-3 times the gross domestic product per capita. Most health output indicators were measured in life years and quality-adjusted life years. The sensitivity analysis of most studies demonstrated the robustness and the main influential factor was the drug cost. Most Chinese studies showed that PCSK9 inhibitor was not cost-effective for the prevention of cardiovascular disease in patients with acute coronary syndrome， myocardial infarction and atherosclerotic cardiovascular disease. It was cost-effective to use PCSK9 inhibitors for the prevention of cardiovascular disease only in specific groups， such as patients with triple vessel disease， patients with newly diagnosed acute coronary syndrome and low-density lipoprotein cholesterol≥100 mg/dL. Future research should refer to the CHEERS 2022 scale to improve the design， and strive to select large-scale， high-quality data to enhance the quality of reports and the transparency of health decisions， so as to more accurately assess the cost-effectiveness of PCSK9 inhibitors.

BACKGROUND:Previous studies have shown that human beta-defensin 3 has significant antifungal,antibacterial,and antiviral activities and plays an important bridging role in linking innate and acquired immune responses. OBJECTIVE:To observe the effect of human beta-defensin 3 hydrogel on treatment of periodontitis in rats. METHODS:Using Poloxamer 188 and 407 as the matrix,a blank hydrogel was constructed by cold solution.Human beta-defensin 3 hydrogel was prepared by mixing human beta-defensin 3 with the hydrogel.Twenty-five SD rats were randomly divided into five groups with five rats in each group:No treatment was given in the healthy group.The periodontitis model was constructed by the orthodontic ligature wire method in the periodontitis group,blank hydrogel group,minocycline hydrochloride group,and human beta-defensin 3 hydrogel group.8 weeks after modeling,blank hydrogel,minocycline hydrochloride,and human β-defensin 3 hydrogel were injected into the buccal and palatal periodontal bags,once a week,and relevant tests were carried out after continuous administration for 4 weeks. RESULTS AND CONCLUSION:(1)Compared with the healthy group,periodontal plaque index,gingival bleeding index,and periodontal probing depth were increased in the periodontitis group(P<0.01).Compared with the periodontitis group,the periodontal plaque index,gingival bleeding index,and periodontal probing depth of rats were decreased in the minocycline hydrochloride group and the human beta-defensin 3 hydrogel group(P<0.05).(2)Hematoxylin-eosin staining proved that the hydrogel was not toxic to the rat organism.(3)Stereomicroscopy and Micro CT showed that compared with the healthy group,the root exposure and the distance between enamel cementum boundary and alveolar crest of the periodontitis group were increased(P<0.05).Compared with the periodontitis group,the root exposure and the distance between enamel cementum boundary and alveolar crest of rats were reduced in the minocycline hydrochloride group and human beta-defensin 3 hydrogel group(P<0.05).(4)Hematoxylin-eosin,Masson,and tartrate-resistant acid phosphatase staining showed that periodontal inflammation was obvious,fiber structure was disordered and osteoclasts were active in the periodontitis group and blank hydrogel group,while periodontal inflammation was decreased,fiber arrangement was more regular,and osteoclasts were reduced in the minocycline hydrochloride group and human beta-defensin 3 hydrogel group.(5)qRT-PCR showed that compared with the healthy group,the mRNA expressions of interleukin 1β,tumor necrosis factor α,interleukin 6,and inducible nitric oxide synthase were increased in the periodontitis group(P<0.05).Compared with the periodontitis group,the mRNA expressions of interleukin 1β,tumor necrosis factor α,interleukin 6,and inducible nitric oxide synthase in gingival tissue of rats were decreased in the minocycline hydrochloride group and human beta-defensin 3 hydrogel group(P<0.05).(6)The results showed that human beta-defensin 3 hydrogel was able to attenuate inflammation in rat periodontal tissues by decreasing the relative expression of inflammatory factors and inhibiting osteoblasts.

Based on the theoretical reflection on the reflective function of medical records,the important findings in the practice of medical records writing in the field of palliative care,and conceptual analysis of narrative medicine tools,combined with empirical investigation materials and analysis,this paper focused on the practice of medical records writing for reflection and research.The main contents include defining the concept of narrative medical records,which are medical records used in clinical practice that incorporate narrative content;clarifying their characteristics and functions at different levels;and exploring practical paths for their application in clinical practice.Based on an in-depth exploration of the uniqueness of narrative medicine practice at Peking Union Medical College,it also emphasized the necessity of writing medical records with narrative thinking.Specifically,it focused on using narrative thinking and forms to enhance the improvement of current medical records writing,and further sought a general framework and multiple possibilities for narrative medicine clinical pathways.

Objective:To investigate the prognosis and safety of ripretinib in the treatment of patients with advanced gastrointestinal mesenchymal stromal tumors (GISTs) and to analyze the relationship between blood concentrations of this drug and prognosis.Methods:In this retrospective study, we investigated the effects of ripretinib in patients with advanced GISTs. The inclusion criteria comprised: (1) daily oral administration of ripretinib scheduled; and (2) uninterrupted treatment for at least 1month, with a stable and relatively fixed daily dosage maintained for a minimum of 2 weeks. Exclusion criteria comprised concurrent use of other tyrosine kinase inhibitors and presence of significant organ dysfunction. We retrospectively identified 79 patients with advanced GISTs who had received ripretinib across seven medical centers, namely Jiangsu Provincial Hospital, Jiangsu Cancer Hospital, Nanjing Drum Tower Hospital Affiliated to Nanjing University, Sir Run Run Shaw Hospital of Zhejiang University, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and the General Hospital of the People's Liberation Army, from 1 June 2021 to 31 March 2024. The cohort included 48 men and 31 women, 19 of whom had received ripretinib as second-line, 13 as third-line, and 47 as fourth-line therapy. Two peripheral venous blood samples were obtained from each participant and high-performance liquid chromatography-tandem mass spectrometry used to determine peak (Cmax) and trough (Cmin) concentrations of ripretinib. Machine learning methodologies, specifically the K-nearest neighbor algorithm combined with the Gridsearch CV strategy, were employed to establish the threshold for Cmin. We analyzed adverse reactions, treatment efficacy, median progression-free survival (mPFS), and the relationship between drug blood concentration and selected clinical parameters.Results:In the entire cohort, the Cmin and Cmax of ripretinib were 467 ± 360 μg/L and 986 ± 493 μg/L, respectively. Notably, female patients and individuals in the high-dose group exhibited significantly higher values for both Cmin and Cmax (both P<0.05). However, variations in drug concentrations associated with the line of ripretinib therapy, treatment efficacy, disease progression, and presence of selected specific genetic mutations were not significantly associated with values of Cmin and Cmax ( P>0.05). Among the 79 patients with advanced GISTs receiving ripretinib, reported adverse reactions included alopecia (53, 67.09%), hand–foot syndrome (24, 30.38%), fatigue (22, 27.85%), and myalgia (21, 26.58%). Two patients (2.53%) had grade III complications, both classified as hand–foot syndrome. The correlation between Cmax and adverse reactions was not statistically significant ( P > 0.05). By the time of the latest follow-up, five deaths (6.3%) had occurred within the cohort. The mPFS for the group was 16.3 months, with a mPFS of 14.4 months for those receiving standard dosage and 7.0 months for those receiving escalating dosage. Among the 65 patients treated with standard doses of ripretinib, those with Cmin exceeding a threshold of 450 μg/L exhibited a significantly longer mPFS (18.0 months vs.13.7 months; P < 0.05). Conclusion:In China, patients with advanced GISTs exhibit a notable tolerance to ripretinib, with no evidence for a correlation between adverse reactions and Cmax for the drug. Additionally, a Cmin exceeding 450 μg/L may be associated with an extended mPFS.

Objective:To investigate the prognosis and safety of ripretinib in the treatment of patients with advanced gastrointestinal mesenchymal stromal tumors (GISTs) and to analyze the relationship between blood concentrations of this drug and prognosis.Methods:In this retrospective study, we investigated the effects of ripretinib in patients with advanced GISTs. The inclusion criteria comprised: (1) daily oral administration of ripretinib scheduled; and (2) uninterrupted treatment for at least 1month, with a stable and relatively fixed daily dosage maintained for a minimum of 2 weeks. Exclusion criteria comprised concurrent use of other tyrosine kinase inhibitors and presence of significant organ dysfunction. We retrospectively identified 79 patients with advanced GISTs who had received ripretinib across seven medical centers, namely Jiangsu Provincial Hospital, Jiangsu Cancer Hospital, Nanjing Drum Tower Hospital Affiliated to Nanjing University, Sir Run Run Shaw Hospital of Zhejiang University, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and the General Hospital of the People's Liberation Army, from 1 June 2021 to 31 March 2024. The cohort included 48 men and 31 women, 19 of whom had received ripretinib as second-line, 13 as third-line, and 47 as fourth-line therapy. Two peripheral venous blood samples were obtained from each participant and high-performance liquid chromatography-tandem mass spectrometry used to determine peak (Cmax) and trough (Cmin) concentrations of ripretinib. Machine learning methodologies, specifically the K-nearest neighbor algorithm combined with the Gridsearch CV strategy, were employed to establish the threshold for Cmin. We analyzed adverse reactions, treatment efficacy, median progression-free survival (mPFS), and the relationship between drug blood concentration and selected clinical parameters.Results:In the entire cohort, the Cmin and Cmax of ripretinib were 467 ± 360 μg/L and 986 ± 493 μg/L, respectively. Notably, female patients and individuals in the high-dose group exhibited significantly higher values for both Cmin and Cmax (both P<0.05). However, variations in drug concentrations associated with the line of ripretinib therapy, treatment efficacy, disease progression, and presence of selected specific genetic mutations were not significantly associated with values of Cmin and Cmax ( P>0.05). Among the 79 patients with advanced GISTs receiving ripretinib, reported adverse reactions included alopecia (53, 67.09%), hand–foot syndrome (24, 30.38%), fatigue (22, 27.85%), and myalgia (21, 26.58%). Two patients (2.53%) had grade III complications, both classified as hand–foot syndrome. The correlation between Cmax and adverse reactions was not statistically significant ( P > 0.05). By the time of the latest follow-up, five deaths (6.3%) had occurred within the cohort. The mPFS for the group was 16.3 months, with a mPFS of 14.4 months for those receiving standard dosage and 7.0 months for those receiving escalating dosage. Among the 65 patients treated with standard doses of ripretinib, those with Cmin exceeding a threshold of 450 μg/L exhibited a significantly longer mPFS (18.0 months vs.13.7 months; P < 0.05). Conclusion:In China, patients with advanced GISTs exhibit a notable tolerance to ripretinib, with no evidence for a correlation between adverse reactions and Cmax for the drug. Additionally, a Cmin exceeding 450 μg/L may be associated with an extended mPFS.

OBJECTIVE: To review the research progress in biotherapy of rotator cuff injury in recent years, in order to provide help for clinical decision-making of rotator cuff injury treatment. METHODS: The literature related to biotherapy of rotator cuff injury at home and abroad in recent years was widely reviewed, and the mechanism and efficacy of biotherapy for rotator cuff injury were summarized from the aspects of platelet-rich plasma (PRP), growth factors, stem cells, and exosomes. RESULTS: In order to relieve patients' pain, improve upper limb function, and improve quality of life, the treatment of rotator cuff injury experienced an important change from conservative treatment to open surgery to arthroscopic rotator cuff repair. Arthroscopic rotator cuff repair plus a variety of biotherapy methods have become the mainstream of clinical treatment. All kinds of biotherapy methods have ideal mid- and long-term effectiveness in the repair of rotator cuff injury. The biotherapy method to promote the healing of rotator cuff injury is controversial and needs to be further studied. CONCLUSION All kinds of biotherapy methods show a good effect on the repair of rotator cuff injury. It will be an important research direction to further develop new biotherapy technology and verify its effectiveness.
Humans ; Rotator Cuff Injuries/therapy* ; Quality of Life ; Arthroplasty ; Exosomes ; Neurosurgical Procedures

Bone defects caused by different causes such as trauma, severe bone infection and other factors are common in clinic and difficult to treat. Usually, bone substitutes are required for repair. Current bone grafting materials used clinically include autologous bones, allogeneic bones, xenografts, and synthetic materials, etc. Other than autologous bones, the major hurdles of rest bone grafts have various degrees of poor biological activity and lack of active ingredients to provide osteogenic impetus. Bone marrow contains various components such as stem cells and bioactive factors, which are contributive to osteogenesis. In response, the technique of bone marrow enrichment, based on the efficient utilization of components within bone marrow, has been risen, aiming to extract osteogenic cells and factors from bone marrow of patients and incorporate them into 3D scaffolds for fabricating bone grafts with high osteoinductivity. However, the scientific guidance and application specification are lacked with regard to the clinical scope, approach, safety and effectiveness. In this context, under the organization of Chinese Orthopedic Association, the Expert consensus for the clinical application of autologous bone marrow enrichment technique for bone repair ( version 2023) is formulated based on the evidence-based medicine. The consensus covers the topics of the characteristics, range of application, safety and application notes of the technique of autologous bone marrow enrichment and proposes corresponding recommendations, hoping to provide better guidance for clinical practice of the technique.

Infectious bone defect is bone defect with infection or as a result of treatment of bone infection. It requires surgical intervention, and the treatment processes are complex and long, which include bone infection control,bone defect repair and even complex soft tissue reconstructions in some cases. Failure to achieve the goals in any step may lead to the failure of the overall treatment. Therefore, infectious bone defect has been a worldwide challenge in the field of orthopedics. Conventionally, sequestrectomy, bone grafting, bone transport, and systemic/local antibiotic treatment are standard therapies. Radical debridement remains one of the cornerstones for the management of bone infection. However, the scale of debridement and the timing and method of bone defect reconstruction remain controversial. With the clinical application of induced membrane technique, effective infection control and rapid bone reconstruction have been achieved in the management of infectious bone defect. The induced membrane technique has attracted more interests and attention, but the lack of understanding the basic principles of infection control and technical details may hamper the clinical outcomes of induced membrane technique and complications can possibly occur. Therefore, the Chinese Orthopedic Association organized domestic orthopedic experts to formulate An evidence-based clinical guideline for the treatment of infectious bone defect with induced membrane technique ( version 2023) according to the evidence-based method and put forward recommendations on infectious bone defect from the aspects of precise diagnosis, preoperative evaluation, operation procedure, postoperative management and rehabilitation, so as to provide useful references for the treatment of infectious bone defect with induced membrane technique.

Objective: To compare the sealing performance of three kinds of sealers AH-Plus, iRoot SP and GuttaFlow2 combined with single cone obturation and warm gutta-percha root canal filling. Methods: Seventy premolars with single root canal were extracted recently and prepped to P# by Waveone gold system after truncating tooth crown. Then they were randomly divided into 6 experimental groups (10 premolars per group) and 2 control groups (5 premolars per group). Single tip filling and warm gutta-percha filling were performed, namely AH-Plus single tip filling group (A1), AH-Plus warm gutta-percha filling group (A2), iRoot SP single tip filling group (B1), iRoot SP warm gutta-percha filling group (B2), GuttaFlow2 single tip filling group (C1), GuttaFlow2 warm gutta-percha group (C2), positive control group (D group) and negative control group (E group). After dye penetration test was performed on the filled teeth, microleakage of root tip was detected by longitudinal section method. Results: A1 group had the largest microleakage value, while B2 group had the smallest microleakage value. There was no statistically significant difference in apical sealing between single-tip filling and hot dental glue filling with the same sealant (P>0.05), and also no statistically significant difference in apical sealing between the three kinds of sealant with the same filling technology (P>0.05). Conclusion None of the three root canal sealers can completely seal the root canal, and there is no significant difference in the sealing effect between single tip filling and warm gutta-percha filling.

Background: Domestic yaks are the most important livestock species on the Qinghai-Tibetan Plateau. Adult female yaks normally breed in the warm season (July to September) and enter anestrous in the cold season (November to April). Nevertheless, it is unclear how ovarian activity is regulated at the molecular level. Objectives: The peculiarities of yak reproduction were assessed to explore the molecular mechanism of postpartum anestrus ovaries in yaks after pregnancy and parturition. Methods: Sixty female yaks with calves were observed under natural grazing in Haiyan County, Qinghai Province. Three yak ovaries in pregnancy and postpartum anestrus were collected. RNA sequencing and quantitative proteomics were employed to analyze the pregnancy and postpartum ovaries after hypothermia to identify the genes and proteins related to the postpartum ovarian cycle. Results: The results revealed 841 differentially expressed genes during the postpartum hypoestrus cycle; 347 were up-regulated and 494 genes were down-regulated. Fifty-seven differential proteins were screened: 38 were up-regulated and 19 were down-regulated. The differential genes and proteins were related to the yak reproduction process, rhythm process, progesterone-mediated oocyte maturation, PI3K/AKT signaling pathway, and MAPK signaling pathway categories. Conclusions Transcriptome and proteomic sequencing approaches were used to investigate postpartum anestrus and pregnancy ovaries in yaks. The results confirmed that BHLHE40, SF1IX1, FBPX1, HSPCA, LHCGR, BMP15, and ET-1R could affect postpartum hypoestrus and control the state of estrus.