Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC_{50, SMS2} = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t _{1/2, cornea} = 1.11 h; t _{1/2, meibomian glands} = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.

Objective To analyze the characteristics of platelet changes and their influencing factors during postoperative hospitalization in patients who underwent transcatheter aortic valve implantation (TAVI). Methods The patients who underwent TAVI at Beijing Anzhen Hospital Valve Surgery Center between March 2017 and October 2021 were retrospectively selected. The patients were divided into a self-limiting group and a non-self-limiting group according to the characteristics of postoperative platelet decline. In addition, the general preoperative data, preoperative and postoperative ultrasound data, intraoperative data, and the use of anticoagulant drugs during the postoperative stay in the hospital were compared between the two groups. Results A total of 249 patients were enrolled in this study. There were 175 (70.3%) patients in the self-limiting group, including 100 males and 75 females, and there were 74 (29.7%) patients in the non-self-limiting group, including 43 males and 31 females, with no statistical difference between the two groups (P=0.863). The mean age of patients was 73.11±8.88 years in the self-limiting group and 71.54±10.39 years in the non-self-limiting group (P=0.231). The decline of platelets in the self-limiting group generally occurred on the postoperative day 2 and reached the lowest count on the postoperative day 4, and returned to the baseline level on the postoperative day 5-7, while the platelets in the non-self-limiting group changed by simple rise, fall or irregular fluctuation. Patients in the self-limiting group had severer preoperative aortic stenosis (P<0.001) and used more extracorporeal circulation assistance during surgery (P<0.001). Postoperatively, patients in the self-limiting group were more likely to have periaortic valve leakage than those in the non-self-limiting group (P=0.013). Conclusion Platelet changes in most patients after TAVI show a self-limiting decline, which may be related to the severity of patients’ preoperative aortic stenosis, intraoperative extracorporeal circulation device use, and postoperative perivalvular leakage.

Objective:To compare and discuss the mid-to-long-term outcomes of mitral valve repair (MVP) versus biological mitral valve replacement (bMVR) in patients aged 60 years and above with rheumatic mitral valve disease.Methods:This is a retrospective cohort study. A total of 765 patients aged 60 years and older, diagnosed with rheumatic mitral valve disease and who underwent MVP or bMVR at Beijing Anzhen Hospital from January 2010 to January 2023, were retrospectively included. Among them, 186 were male and 579 were female, with an age of (66.1±4.5) years (range: 60 to 82 years). Patients were divided into two groups based on the surgical method: the mitral valve repair group (MVP group, n=256) and the bioprosthetic mitral valve replacement group (bMVR group, n=509). A 1∶1 propensity score matching was performed using a caliper value of 0.2 based on preoperative data. Paired sample t-tests, χ2 tests, or Fisher′s exact tests were used for intergroup comparisons. Kaplan-Meier method was employed to plot survival curves and valve-related reoperation rate curves for both groups before and after matching, and Log-rank tests were used to compare the mid-to long-term survival rates and valve-related reoperation rates between the two groups. Results:A total of 765 patients who completed follow-up were ultimately included, with a follow-up period ( M(IQR)) of 5.1(5.0) years (range: 1.0 to 12.9 years). After matching, each group consisted of 256 patients. The incidence of early postoperative atrial fibrillation (39.1% vs. 49.2%, χ2=4.95, P=0.026) and early mortality rates (2.0% vs. 6.2%, χ2=4.97, P=0.026) were lower in the MVP group. Unadjusted Kaplan-Meier analysis showed significantly higher 5-year and 10-year survival rates for the MVP group (92.54% vs. 83.02%, 86.22% vs. 70.19%, Log-rank: P=0.001). After adjustment with propensity scores, the Kaplan-Meier analysis still indicated higher 5-year and 10-year survival rates in the MVP group compared to the bMVR group (92.54% vs. 85.89%, 86.22% vs. 74.83%, Log-rank: P=0.024). There were no significant differences in the rates of valve-related reoperation between the two groups before and after matching (5-year and 10-year reoperation rates pre-matching: 1.75% vs. 0.57%, 5.39% vs. 7.54%, Log-rank: P=0.207; post-matching: 1.75% vs. 0, 5.39% vs. 9.27%, Log-rank: P=0.157). Conclusion:For patients aged 60 years and above with rheumatic mitral valve disease, mitral valve repair offers better mid-to-long-term survival compared to biological valve replacement.

AIM:The effects and mechanisms of paeoniflorin(PF)on sepsis-associated acute kidney injury(SA-AKI)in mice were investigated based on cellular pyroptosis and the JNK/NEK7/NLRP3 pathway.METHODS:A murine SA-AKI model was established by intraperitoneal injection of lipopolysaccharide(LPS).Twenty-four male C57BL/6J mice aged 6～8 weeks were divided into four groups(n=6)using a randomized numerical table method:control(Con)group(an equal amount of DMSO-containing PBS was injected intraperitoneally at the same time);LPS group(LPS was injected intraperitoneally at 15 mg/kg);LPS+PF group(PF was injected intraperitoneally at 50 mg/kg for 30 min prior to modeling);and LPS+PF+anisomycin group(intraperitoneal injection of PF 50 mg/kg and JNK agonist anisomycin 20 mg/kg 30 min before modeling).Samples were taken 24 h after modeling.HE staining was used to observe the pathological changes in renal tissues,and Paller scoring of renal injury was performed.ELISA was used to detect the levels of renal in-jury markers:blood creatinine(Scr),kidney injury molecule 1(KIM-1),and the inflammatory factors interleukin 1β(IL-1β)and IL-18.Western blot was used to detect changes in phosphorylated c-Jun N-terminal kinase(p-JNK),NIMA-relat-ed expressed kinase 7(NEK7),nucleotide oligomerization domain(NOD)-like receptor protein 3(NLRP3),and N-ter-minal fragment of gasdermin D(GSDMD-N)protein levels.RESULTS:Compared with the Con group,HE staining in the LPS group showed congestion and edema in renal tissues,granular or cell-like tubular patterns in the dilated tubular lu-men of renal tubules,and congestion and edema in the renal interstitium.Paller scores,Scr,serum KIM-1,IL-1β,and IL-18 levels in renal tissues were elevated(P<0.05).The expression of p-JNK,NEK7,NLRP3,and GSDMD-N also in-creased(P<0.05).Compared with the LPS group,the LPS+PF group exhibited reduced renal histopathological injury,decreased Paller score,Scr,serum KIM-1,IL-1β,and IL-18 levels(P<0.05),and decreased protein expression of p-JNK,NEK7,NLRP3,and GSDMD-N(P<0.05).Compared with the LPS+PF group,the LPS+PF+anisomycin group showed increased renal histopathological injury,Paller score,Scr,serum KIM-1,IL-1β,and IL-18 levels(P<0.05),and increased expression of p-JNK,NEK7,NLRP3,and GSDMD-N(P<0.05).CONCLUSION:Paeoniflorin may at-tenuate SA-AKI by inhibiting the JNK/NEK7/NLRP3 signaling pathway and downregulating cellular pyroptosis.

Objective:To compare and discuss the mid-to-long-term outcomes of mitral valve repair (MVP) versus biological mitral valve replacement (bMVR) in patients aged 60 years and above with rheumatic mitral valve disease.Methods:This is a retrospective cohort study. A total of 765 patients aged 60 years and older, diagnosed with rheumatic mitral valve disease and who underwent MVP or bMVR at Beijing Anzhen Hospital from January 2010 to January 2023, were retrospectively included. Among them, 186 were male and 579 were female, with an age of (66.1±4.5) years (range: 60 to 82 years). Patients were divided into two groups based on the surgical method: the mitral valve repair group (MVP group, n=256) and the bioprosthetic mitral valve replacement group (bMVR group, n=509). A 1∶1 propensity score matching was performed using a caliper value of 0.2 based on preoperative data. Paired sample t-tests, χ2 tests, or Fisher′s exact tests were used for intergroup comparisons. Kaplan-Meier method was employed to plot survival curves and valve-related reoperation rate curves for both groups before and after matching, and Log-rank tests were used to compare the mid-to long-term survival rates and valve-related reoperation rates between the two groups. Results:A total of 765 patients who completed follow-up were ultimately included, with a follow-up period ( M(IQR)) of 5.1(5.0) years (range: 1.0 to 12.9 years). After matching, each group consisted of 256 patients. The incidence of early postoperative atrial fibrillation (39.1% vs. 49.2%, χ2=4.95, P=0.026) and early mortality rates (2.0% vs. 6.2%, χ2=4.97, P=0.026) were lower in the MVP group. Unadjusted Kaplan-Meier analysis showed significantly higher 5-year and 10-year survival rates for the MVP group (92.54% vs. 83.02%, 86.22% vs. 70.19%, Log-rank: P=0.001). After adjustment with propensity scores, the Kaplan-Meier analysis still indicated higher 5-year and 10-year survival rates in the MVP group compared to the bMVR group (92.54% vs. 85.89%, 86.22% vs. 74.83%, Log-rank: P=0.024). There were no significant differences in the rates of valve-related reoperation between the two groups before and after matching (5-year and 10-year reoperation rates pre-matching: 1.75% vs. 0.57%, 5.39% vs. 7.54%, Log-rank: P=0.207; post-matching: 1.75% vs. 0, 5.39% vs. 9.27%, Log-rank: P=0.157). Conclusion:For patients aged 60 years and above with rheumatic mitral valve disease, mitral valve repair offers better mid-to-long-term survival compared to biological valve replacement.

Objective    To summarize the clinical result of a combined technical system for bicuspid aortic valve (BAV) repair. Methods    Patients who diagnosed as BAV and sever aortic regurgitation (AR) underwent a strategy of combined repair technics including annuloplasty, sinus plasty, leaflet plasty, sinus-tubular junction (STJ) plasty depending on anatomy pathological characteristics between October 2019 and January 2021 were enrolled. The clinical data of the patients were analyzed. Results    A total of 17 patients were enrolled. There were 11 males and 6 females with an average age of 18-49 (32.4±13.6) years. Fifteen patients had typeⅠand 2 patients had typeⅡBAV according to Sievers classification. Annuloplasty was applicated in 13 patients, sinus plasty in 8 patients, leaflet plasty in 17 patients, and STJ plasty in 11 patients, respectively. The cardiopulmonary bypass (CPB) time was 95 (84, 135) min, aortic cross-clamping time was 68 (57, 112) min, and the ICU stay time was 17 (12, 25) h. After the operation, mild AR was presented in 14 patients, moderate AR in 1 patient and severe AR in 2 patients. The latter 3 patients underwent second operation under CPB, after then, 1 patient had mild AR and 2 patients had moderate AR. The follow-up time was 13.1±4.6 months. At the latest follow-up, 12 patients had mild AR and 5 patients had moderate AR, and no patient had reoperation. Conclusion    A combined technical system for BAV repair can be used effectively and safely with an acceptable short and middle-term result.

Conjunctival melanoma (CM) is a rare and fatal malignant eye tumor. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound named as cucurbitacin B (CuB). We found that CuB remarkably inhibited the proliferation of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1, without toxicity to normal cells. CuB can also induce CM cells G2/M cell cycle arrest. RNA-seq screening identified KIF20A, a key downstream effector of FOXM1 pathway, was abolished by CuB treatment. Further target identification by activity-based protein profiling chemoproteomic approach revealed that GRP78 is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a K _d value of 0.11 μmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in human recombinant GRP78 protein and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway proteins including KIF20A, underlying an interesting therapeutic perspective. Finally, CuB significantly inhibited tumor progression in NCG mice without causing obvious side effects in vivo. Taken together, our current work proved that GRP78-FOXM1-KIF20A as a promising pathway for CM therapy, and the traditional medicine CuB as a candidate drug to hinder this pathway.

Early childhood caries (ECC) is a significant chronic disease of childhood and a rising public health burden worldwide. ECC may cause a higher risk of new caries lesions in both primary and permanent dentition, affecting lifelong oral health. The occurrence of ECC has been closely related to the core microbiome change in the oral cavity, which may be influenced by diet habits, oral health management, fluoride use, and dental manipulations. So, it is essential to improve parental oral health and awareness of health care, to establish a dental home at the early stage of childhood, and make an individualized caries management plan. Dental interventions according to the minimally invasive concept should be carried out to treat dental caries. This expert consensus mainly discusses the etiology of ECC, caries-risk assessment of children, prevention and treatment plan of ECC, aiming to achieve lifelong oral health.
Child ; Child, Preschool ; Consensus ; Dental Caries/prevention & control* ; Dental Caries Susceptibility ; Humans ; Oral Health

【Objective】 To investigate the incidence and composition of adverse reactions to blood transfusion(ARBT) in Qingdao hospitals in recent years. 【Methods】 The "Statistical Table of Adverse Reactions to Blood Transfusion in Medical Institutions" issued by Qingdao Quality Control Center of Blood Transfusion throughout 2020 to 2021, involving 96 hospitals in the region, were collected and analyzed, including the number, proportion and types of ARBT, as well as the types of blood components transfused. 【Results】 From 2020 to 2021, 296 676 cases of blood transfusion in 96 hospitals occurred, and the incidence of ARBT was 0.27% (814/296 676), of which the incidence of ARBT involving plasma transfusion was 0.17% [accounting for 39.07% (318/814) of all transfusion reactions], involving platelet transfusion was 0.68% [31.08% (259/814)], involving erythrocyte transfusion was 0.11% [27.64% (225/814)] and cryoprecipitation transfusion 0.03% [1.47% (12/814)]. The types of ARBT were anaphylaxis 77.64% (632/814), fever 19.78% (161/814), transfusion-related dyspnea 1.47% (12/814), transfusion-related circulatory overload 0.37% (3/814), purpura 0.25% (2/814) and transfusion-related hypotension 0.25% (2/814), delayed hemolysis 0.12%(1/814) and acute hemolysis 0.12%(1/814), respectively. 【Conclusion】 In recent years, the incidence of ARBT in local medical institutions is lower than that of domestic general level, and the main reactions are anaphylaxis and fever following the transfusion of plasma or (and) platelets.The monitoring and control of ARBT should be strengthened in each hospital with accurate and timely report, and active preventive measures should be taken to control or reduce the incidence of ARBT effectively.

  Objective  To study the demographic and clinical characteristics, correlation of genotype and phenotype and treatment of Blau syndrome to facilitate early diagnosis and timely treatment of Blau syndrome.  Methods  Seventy-two patients with Blau syndrome from 11 centers from May 2006 to April 2022 were retrospectively analyzed, and their general information, clinical data, laboratory examination and treatment medication were collected.  Results  The distribution of patients with Blau syndrome was uniform in geographical north and south of China, and there was no obvious gender bias. The mean age of onset was (14.30±12.81) months, and the age of diagnosis was (55.18±36.22) months. 35% of patients with Blau syndrome happened before 1 year old, and all patients developed before 5 years old. 87.50% (63/72) had granulomatous arthritis, 65.28% (47/72) had rash, 36.11% (26/72) had ocular involvement, 27.78% (20/72) had fever, and 15.28% (11/72) had pulmonary involvement. Arthritic manifestations of Blau syndrome were most at risk, followed by rash, ocular involvement, and fever.The first 25 months of the disease, the risk of developing a rash was the greatest. The risk of developing arthritis was the greatest between 25 months and 84 months. The main mutations were p.R334Q and p.R334W, and patients with p.R334Q mutation had relatively high incidence of fever (35.71%[5/14] vs. 14.29%[1/7], P=0.43) and ocular involvement (42.86%[6/14]vs. 28.57%[2/7], P=0.51). There was a relatively high incidence of rash (85.71%[6/7] vs. 64.29%[9/14], P=0.59) in patients with the p.R334W mutation. Forty-five patients(62.50%)were treated with a combina-tion of glucocorticoid and methotrexate. Twenty-two patients were treated with tumor necrosis factor antagonist in addition to glucocorticoid and methotrexate.  Conclusions  The risk of different clinical manifestations of Blau syndrome from high to low was arthritis, followed by rash, ocular involvement and fever. The main treatment was glucocorticoid combined with methotrexate, to which biological agents could be added.