Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

Objective To investigate the molecular typing,virulence,and drug resistance features of bacterial strains in a simultane-ous outbreak of paratyphoid fever A and B,and then provide evidence for the prevention and treatment of the simultaneous transmission of different types of paratyphoid fever.Methods The clinical data of 31 patients confirmed as paratyphoid fever in the Hospital of Xin-jiang Production and Construction Corps from September 2018 to November 2018 were retrospectively analyzed.The isolated strains were performed serotyping and drug sensitivity tests.The molecular typing and the detection of virulence and drug resistance genes were carried out by multiplex PCR,pulsed-field gel electrophoresis(PFGE),and multilocus sequence typing(MLST).Results A total of 32 strains of Salmonella paratyphi were isolated from 31 patients,with 19 strains classified as type A and 13 as type B.The intermedi-ate rates of all strains against ciprofloxacin were 100%.The molecular typing and serotyping results of 11 representative strains were consistent.The PFGE fingerprints of Salmonella paratyphi A and B were also consistent.The MLST of Salmonella paratyphi A was ST85,and that of Salmonella paratyphi B was ST86.All strains carried virulence island SPI1-SPI5 representative genes such as invA,sitC,sseL,sifA,mgtC,siiE,and sopB,and regulatory gene phoP.Salmonella paratyphi A also carried cytolethal distending toxin(CDT)genes with trimeric structure such as cdtB,pltA,and pltB.The virulence plasmid genes such as pefA,prot6E,and spvB were all negative.Conclusion The simultaneous transmission of Salmonella paratyphi A and B has the characteristics of high pathogenicity and poor sensitivity to ciprofloxacin,which should be highly concerned by clinical and laboratory personnel.

In vivo confocal microscopy of the cornea is a non-invasive, rapid, and comprehensive technique for real-time, dynamic observation of all layers of the cornea. Confocal microscopy allows the examination of the morphology and cell density in the different layers of the cornea through direct visualization. With the increasing prevalence of diabetes, ocular complications have become common and have garnered more interest and in-depth research from clinical and scientific communities. This paper provides a comprehensive review of research progress made using in vivo confocal microscopy to observe various layers of cornea tissue in diabetic patients.

Objective:To retrospectively analyze the viral levels and associated factors in patients with hepatitis B virus (HBV)-related primary liver cancer (PHC) in real-world settings and further explore the correlation between low viral load (LVL) and/or low-level viremia (LLV) and PHC.Methods:Five hundred twenty-four cases with HBV-related PHC with complete pathologically confirmed data from 2013 to 2020 were included. Percentages (%) were used to express their viral load, antiviral (oral) status, patient compliance, presence or absence of cirrhosis, family history of liver cancer, and others. LVL definition: After excluding detection errors by PCR method, serum HBV DNA <50-2 000 IU/ml, and those who had received antiviral drug treatment were called LLV. Antiviral treatment (AVT) rate definition: As of the confirmed diagnosis of PHC, those who had been regularly treated using oral antiviral drugs for six months or more (≥6 months).Results:General situation: The ratio of male to female enrolled patients was 15.90:1 (493/31). Patients aged >40 years accounted for 91.98% (482 cases). Hepatitis B surface antigen (HBsAg) positivity condition: The ratio of HBsAg-positive to HBsAg-negative/anti-HBc-positive (HBsAg-/anti-HBc+) PHC patients was 5.89:1 (448/76). Among the 76 HBsAg-/anti-HBc+patients, the ratio of HBsAg-/anti-HBs+/anti-HBc+ to HBsAg-/anti-HBs-/anti-HBc+ patients was 0.95:1 (37/39). Hepatitis B e antigen (HBeA) positivity condition: The ratio of HBeAg-negative to HBeAg-positive cases was 3.23:1 (400/124). HBV DNA level condition: The medical history records of 75.00% of patients (393/524) had traceable HBV DNA test reports. Out of 393 patients, 45.04% (177/393) accounted for undetectable HBV DNA, 13.49% (53/393) accounted for LVL, 41.48% (163/393) accounted for HBV DNA exceeding the upper limit of LVL, and 4.07% (16/393) accounted for LLV. Among HBsAg-positive and HBsAg-/anti-HBc+ patients, the HBV DNA positivity rates were 59.12% (214/362) and 6.45% (2/31), respectively. Antiviral treatment condition: Among the 448 HBsAg-positive PHC patients, the total AVT rate was 18.08% (81/448), of which seven patients did not have their HBV DNA results traced back. Among them, the AVT rate of 148 patients with HBV DNA lower than the lowest detection value was 41.22% (61/148); the AVT rate of 53 patients with LVL was 18.87% (10/53); and the AVT rate of 163 patients with HBV DNA≥LVL upper limit was 1.84% (3/163). Liver cirrhosis and family history condition: 348 patients (66.41%) had liver cirrhosis. 67 patients (12.79%) had a distinct family history of HBV-related liver cirrhosis and liver cancer. Alpha-fetoprotein (AFP) condition: 514 patients underwent AFP testing, with 30.93% of the patients had normal AFP levels, and 69.07% had AFP levels exceeding the upper limit of normal values (355/514). Among them, 10 μg/L400 μg/L accounted for 34.44% (177/514) and 34.63% (178/514), respectively. Tissue typing condition: 99.05% (519/524) were hepatocellular carcinoma, and well-differentiated and moderately differentiated cases accounted for only 8.59%.Conclusions:In the real world, comprehensive, timely screening, standardized, and effective antiviral treatment have not yet been achieved for patients with chronic hepatitis B, resulting in the persistence of HBsAg and/or HBV DNA positivity (especially LVL and/or LLV). Although LVL does not account for a high proportion among all HBV-related PHC populations, the vast majority of LVL populations have not received any antiviral treatment. In addition, some PHC populations with HBV DNA>2 000 IU/ml have not received standard antiviral treatment before the onset of the disease, which should be paid attention to. At the same time, HBsAg-/anti-HBc+ populations may have latent HBV infection and may even progress to PHC. Notably, PHC may still occur after HBeAg seronegative conversion.

Objective:To explore the influencing factors and effectiveness of community follow-up in patients with cardiac implantable electronic device (CIED) implantation.Method:A total of 132 patients who received CIED implantation in the Department of Cardiology of Tongren Hospital, Shanghai Jiao Tong University School of Medicine from February 2021 to February 2022 were enrolled in this prospective cohort study. Among them 33 patients were followed up in community health service centers associated with Tongren Hospital (community follow-up group) and 99 matched patients were followed up in the CIED outpatient clinic of the hospital (outpatient follow-up group) with a ratio of 1∶3. The clinical data of the selected patients were collected through a questionnaire survey; the follow-up data were extracted through the CarelinkExpress electronic follow-up platform and the CIED outpatient information system of Tongren Hospital. Adjustment of the treatment protocol or CIED parameters at follow-up, and the referral from the community health service centers were defined as visit with-an-action (VWA). The endpoint of follow-up was the occurrence of major adverse events. The multivariate logistic regression model was used to analyze the factors influencing patient selection for community follow-up.Results:The univariate analysis showed that the frequency of visits to community health service centers and the service contracting rate in community follow-up group were higher than those of outpatient follow-up group ( P<0.05). The multivariate logistic regression analysis showed that the contracted community physician service was an independent influencing factor of patient choosing community follow-up ( OR=2.143, 95% CI: 1.103-4.166, P=0.025). A total of 469 visits of followed up occurred in 132 patients, including 45 community visits and 424 outpatient visits. VWA accounted for 22.2% (10/45) in the community follow-up group, and 17.2% (73/424) in the outpatient follow-up group ( P>0.05). There was no significant difference in the safety and effectiveness indicators (VWA, major adverse events, and unplanned follow-up) between the two groups ( P>0.05). More patients in the community follow-up group walked to the hospital than the outpatient follow-up group ( P<0.05);and the main transportation for the later was by bus or taxi(42(42.4%)or 41(41.4%)). The average waiting time in the community follow-up group was significantly shorter than that in outpatient follow-up group ( P<0.05). The total time required for a single follow-up in the community follow-up group was 50.0 (45.0, 59.5) minutes, which was significantly shorter than that in the routine outpatient follow-up group (107.0 (90.0, 135.0) minutes, P<0.05). Conclusions:The contracting with community physicians is an independent influencing factor for CIED implanted patients to choose community follow-up. The safety and effectiveness of community follow-up are comparable to routine outpatient follow-up, and community follow-up is more convenient.

Objective:To study the anatomy of the perforator propeller flap of superior lateral genicular artery, and to explore a surgical method and clinical application in repair of the soft tissue defect of anterolateral knee with the flap.Methods:From September 2019 to September 2021, 8 knees of 4 chilled fresh specimen of adults were studied. The perforators of the superior lateral genicular artery were observed. The length, outer diameter of the perforators, and the locations of the skin perforation were recorded. The superior lateral genicular artery perforator propeller flaps were then applied clinically to 5 patients(3 males and 2 females) with soft tissue defects of anterolateral knee. Two of the patients had combined ligament injury and(or) bone joint exposure. The age of patients ranged from 25 to 48 years old, at 33.4 years old in average. The sizes of soft tissue defects ranged from 4.0 cm×4.0 cm to 8.0 cm×5.0 cm. The sizes of perforator propeller flaps of superior lateral genicular artery were 10.0 cm×5.0 cm to 13.0 cm×6.0 cm. The superior perforating vessels of the superior lateral genicular artery were found and marked at the points of skin perforation. Preoperative contrast-enhanced ultrasound were performed to confirm the dominant perforating vessels and had the skin perforating points marked. Intraoperative CDU were further performed to confirm the points of dominant perforating vessels. Perforator propeller flaps were designed depending on the size of the anterolateral soft tissue defect, and flaps were prepared and transferred to the defect sites. Postoperative follow-ups were conducted at outpatient clinic. The survival of the flap and knee function were observed according to the Bai-ly knee scoring.Results:The anatomy showed that an average pedicle length of the superior lateral genicular artery perforator was(8.2±0.9) cm, with an average starting outer diameter at(1.1±0.2) mm. All 5 flaps survived during the follow-up that lasted for 10 to 24 months, with an average of 15.3 months. All flaps healed in 2 weeks after surgery without complications such as soft tissue infection, bone and joint infection were observed. At the last follow-up, no obvious bloated appearance of the flaps were observed. The colour and elasticity of the flaps were similar to the surrounding skin. The knee function was assessed: 4 patients were in excellent and 1 in good. The range of knee flexion and extension was from 100° to 150°. The patients were satisfied with the appearance and function of the knees.Conclusion:The size of the perforator of superior lateral genicular artery and the pedicle length are ideal. The propeller flap can be used to repair the soft tissue defect around the anterolateral knee, with satisfactory functional recovery of a knee. It is a good method to repair the soft tissue defect around anterolateral knee.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

Objective:To investigate the feasibility of surface-guided hypo-fractionated radiotherapy for intracranial metastasis with open face mask immobilization.Methods:Nineteen patients treated with hypo- fractionated radiotherapy for intracranial metastasis in our hospital were included. Before the start of treatment, each patient underwent simulation with open face mask immobilization. During the treatment, cone-beam CT(CBCT)images were collected for verification each time. Laser-guided positioning was used for the first time in the treatment, and surface images were captured after six-dimensional position correction as the reference images for subsequent treatment. Subsequent treatment was randomly divided into laser-guided positioning group(LG, 85/F)and optical surface-guided positioning group(SG, 101/F). The six-dimensional error data of patients with two positioning methods were compared and expressed as mean ± standard deviation. Meanwhile, the correlation and consistency between the optical surface error data and the gold standard CBCT error data were compared in the laser-guided fraction. GraphPad Prism 6.0 software was used for data processing and mapping, and SPSS 21.software was used for mean analysis and normality test. Pearson correlation analysis was used to analyze the correlation, and Bland-Altman plot analysis was used to test the coincidence between two methods.Results:Compared with the laser-guided positioning, the 3D error of optical surface-guided positioning was reduced from(0.35±0.16)cm to(0.14±0.07)cm. The Pearson coefficient of correlation along all three directions was less than 0.01,R 2 was 0.91,0.70 and 0.78 on Lat, Lng and Vrt, and R 2 was 0.75,0.85 and 0.77 on Pitch, Roll and Rtn(all P<0.01), respectively. The measurement results of two methods were positively correlated. The Bland-Altman plot analysis showed that the 95% limits of agreement were within preset 3 mm tolerance([-0.29 cm, 0.19 cm], [-0.25 cm, 0.25 cm], [-0.27 cm, 0.19 cm]), and the 95% limits of agreement were within preset 3° tolerance(Pitch[-1.76°,1.76°], Roll[-1.54°,1.60°], ROT[-2.18°,1.69°]), indicating agreement between two methods. Conclusions:The optical surface-guided positioning can reduce the setup errors in the hypo-fractionated radiotherapy for intracranial metastasis with open face mask immobilization. The optical surface error and CBCT error have good correlation and agreement.

Dyslipidemia is an important risk factor of atherosclerotic cardiovascular disease (ASCVD). Statins delay the occurrence and development of ASCVD, and reduce the risk of cardiovascular events and death. Due to safety concerns, there exist insufficient use of lipid-lowering agents and a high withdrawal rate of the agents in the elderly. To promote the prevention and treatment of ASCVD, this expert consensus is issued and focuses on the management of dyslipidemia of Chinese elderly basing on the clinical evidence of the use of lipid-lowering drugs by the elderly, and the lipid management guidelines and expert consensus recommendations at home and abroad.