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 explore the effect of PCSK9 inhibitor combined with atorvastatin on carotid atherosclerosis and its anti-inflammatory effect in patients with hypertension complicated with type 2 diabetes mellitus.Methods A total of 100 patients with hypertension complicated with type 2 diabetes mellitus who were treated in Nanchang Third Hospital from October 2022 to August 2023 were selected as the research subjects.They were divided into the control group and the study group by the random number table method,with 50 cases in each group.Both groups of patients received conventional antihypertensive,hypoglycemic,and antiplatelet therapy.The control group took 20 mg of atorvastatin calcium tablets orally,once a night.On the basis of the control group,the study group was additionally given 150 mg of evolocumab injection(a PCSK9 inhibitor)by subcutaneous injection,once every two weeks.Both groups of patients were followed up for 24 weeks.The levels of blood lipids,blood glucose,inflammatory cytokines,carotid intima-media thickness(IMT),atherosclerotic plaque score and adverse reactions of the patients in the two groups before and after treatment were detected and compared.Results The levels of TC,TG and LDL-C in the study group after treatment were lower than those before treatment and those in the control group at the same period,and the differences were statistically significant(P＜0.05).The levels of IL-1,IL-6,TNF-α,hs-CRP,as well as the ca-rotid IMT and atherosclerotic plaque score in the study group after treatment were lower than those before treatment and those in the control group at the same period,and the differences were statistically significant(P＜O.05).During the treatment period,there was no significant difference in the occurrence of adverse reac-tions between the two groups(P＞0.05).Conclusion The combination of PCSK9 inhibitor and atorvastatin can effectively regulate the blood lipid levels of patients with hypertension complicated and type 2 diabetes mellitus,alleviate the inflammatory response,and improve the degree of carotid atherosclerosis in these pa-tients.

OBJECTIVE To compare the ability of ultra-high-resolution CT(U-HRCT)and multi-slice spiral CT(MSCT)to display key vocal transmission structures in the middle ear.METHODS Subjects with normal middle ear structures who underwent 0.1 mm layer thickness U-HRCT and 0.625 mm layer thickness MSCT scans at the same time in Beijing Friendship Hospital affiliated to Capital Medical University from December 2019 to August 2024 were retrospectively enrolled.Two experienced head and neck radiologists reconstruct standard transsectional,coronal images based on the thinnest layer thickness.According to the 5-point method,16 key sound transmission structures of the middle ear,including malleus,incus and stapes,as well as joints,ligaments and tendons,were evaluated for image quality scoring.The standard deviation(SD)value,signal noise ratio(SNR),and contrast noise ratio(CNR)of bone in the malleus region and intratympanic gas were measured and calculated on the two examination images.RESULTS Thirty patients(47 sides)with normal middle ear structure were included,including 18 males and 12 females.The two physicians compared the results of U-HRCT in showing malleus head,malleus neck,malleus handle,incus body,long process,and short process,5 points accounted for 100%,and the 5-point scores of incudomalleolar joint space,incudostapedial joint space,stapes footplate and annular ligament were 100%,98.29%,75.83%and 77.83%,respectively,which were significantly higher than those of MSCT(P<0.001).In addition,U-HRCT showed higher scores for lenticular process,stapes head,anterior arch of stapes,posterior arch of stapes,annular ligament,stapes muscle,and tendo musculi tensoris tympani than MSCT(P<0.001),and the lenticular process showed a 100%display rate.There was no significant difference in the SNR between the two groups(P>0.05),but the SD value of the malleus in U-HRCT was 161.6±36.4,which was significantly lower than that in MSCT(297.8±128.1),and the difference was statistically significant(P<0.001).CONCLUSION U-HRCT can clearly visualize the key sound transmission structures of the middle ear,and its visualization ability is significantly better than that of MSCT.

Objective To compare image quality and radiation dose for abdominal CT angiography(CTA)in infants and young children after liver transplantation using energy spectrum CT and low tube voltage scanning.Methods Totally 41 infants or young children after liver transplantation were included,including 22 cases who underwent energy spectrum CT(energy spectrum group)and 19 cases who underwent low tube voltage(80 kV)CT scanning(low tube voltage group).50 keV single energy images of energy spectrum group were extracted to observe abdominal blood vessels.Subjective and objective evaluation on image quality were performed,the latter aimed at CT value and noise value of hepatic artery and portal vein,the contrast and contrast-to-noise ratio(CNR)of hepatic artery and portal vein.The examined volume CT dose index(CTDIvol),dose-length product(DLP)and effective dose(ED)of both groups were recorded.Results No significant difference of subjective image quality score was found between groups(P＞0.05).In low tube voltage group,during arterial phase,CT values of hepatic artery,contrastarteries and CNRarteries were higher,and during the portal vein phase,CT values of hepatic artery,liver tissue noise,contrastportalvein and CNRportalvein were all higher than those in energy spectrum group(all P＜0.05).CTDIvol,DLP and ED in energy spectrum group were higher than those in low tube voltage group(all P＜0.05).Conclusion Compared with energy spectrum CT,low tube voltage CT scanning combined with iterative reconstruction technology could result better image quality and lower radiation dose for abdominal CTA in infants and young children after liver transplantation.

Objectives:To construct a nomogram prediction model using common preoperative indicators for early weight loss (EWL) 1 year after laparoscopic sleeve gastrectomy (LSG).Methods:Relevant data of obese patients who had undergone LSG from January 2015 to May 2022 in Fujian Medical University Union Hospital and Quanzhou First Hospital Affiliated Fujian Medical University were analyzed. Patients with a history of major abdominal surgery, severe gastroesophageal reflux disease, pregnancy within 1 year after surgery, or who were lost to follow-up were excluded, resulting in a total of 200 patients in the study (190 from Fujian Medical University Union Hospital and 10 from Quanzhou First Hospital Affiliated Fujian Medical University). The participants were 51 men and 149 women of a mean age 29.9±8.2 years and a body mass index (BMI) 38.7±6.5 kg/m 2. All patients in this group underwent standardized LSG procedure. Achieving ideal weight (BMI≤25 kg/m 2) 1 year after LSG was defined as goal of EWL. Logistic regression analyses were performed to identify factors that independently influenced EWL. These factors were incorporated into the nomogram model. Receiver operating characteristic (ROC) curves (the larger the area under the curve [AUC], the better the predictive ability and accuracy of the model), likelihood ratio test (higher likelihood ratio indicates greater model homogeneity), decision curve analysis (higher net benefit indicates a better model), Akaike information criterion (AIC; smaller AIC indicates a better model), and Bayesian information criterion (BIC; smaller BIC indicates a better model) were used to validate the predictive ability of the column line diagram model. Results:In this study of 200 obese patients who underwent LSG surgery, 136 achieved EWL goal, whereas the remaining 64 did not. The rate of EWL goal achievement of the entire group was 68.0%. Compared with patients who did not achieve EWL goal, those who did had lower BMI, alanine transaminase, aspartate transaminase, triglycerides, and higher cholesterol. Additionally, the proportion of female was higher and the proportions of patients with fatty liver and hypertension lower in those who achieved EWL goal (all P<0.05). Univariate and multivariate logistic regression analysis revealed that preoperative BMI (OR=0.852, 95%CI: 0.796-0.912, P<0.001), alanine transaminase (OR=0.992, 95%CI: 0.985-0.999, P=0.024), presence of fatty liver (OR=0.185, 95%CI: 0.038-0.887, P=0.035) and hypertension (OR=0.374, 95%CI: 0.144-0.969, P=0.043) were independently associated with failure to achieve EWL goal. Cholesterol (OR=1.428, 95%CI: 1.052-1.939, P=0.022) was independently associated with achieving EWL goal. We used the above variables to establish an EWL nomogram model. ROC analysis, the likelihood ratio test, decision curve analysis, and AIC all revealed that the predictive value of the model was better than that of BMI alone (nomogram model vs. BMI: area under the curve 0.840 vs. 0.798, P=0.047; likelihood ratio: 58.785 vs. 36.565, AIC: 193.066 vs. 207.063, BIC: 212.856 vs. 213.660). Conclusion:Our predictive model is more accurate in predicting EWL after LSG compared with using BMI.

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 clinical value of analgesia and sedation under bispectral index (BIS) monitoring combined with hydraulic coupled intracranial pressure (ICP) monitoring in severe craniocerebral injury (sTBI). METHODS: (1) A prospective self-controlled parallel control study was conducted. A total of 32 patients with sTBI after craniotomy admitted to the intensive care unit (ICU) of the First People's Hospital of Huzhou from December 2020 to July 2021 were selected as the research objects. ICP was monitored by Codman monitoring system and hydraulically coupled monitoring system, and the difference and correlation between them were compared. (2) A prospective randomized controlled study was conducted. A total of 108 sTBI patients admitted to the ICU of the First People's Hospital of Huzhou from August 2021 to August 2022 were selected patients were divided into 3 groups according to the random number table method. All patients were given routine treatment after brain surgery. On this basis, the ICP values of the patients in group A (35 cases) were monitored by Codman monitoring system, the ICP values of the patients in group B (40 cases) were monitored by hydraulic coupling monitoring system, and the ICP values of the patients in group C (33 cases) were monitored combined with hydraulic coupling monitoring system, and the analgesia and sedation were guided by BIS. The ICP after treatment, cerebrospinal fluid drainage time, ICP monitoring time, ICU stay time, complications and Glasgow outcome score (GOS) at 6 months after surgery were compared among the 3 groups. In addition, patients in group B and group C were further grouped according to the waveforms. If P₁ = P₂ wave or P₂ and P₃ wave were low, they were classified as compensatory group. If the round wave or P₂ > P₁ wave was defined as decompensated group, the GOS scores of the two groups at 6 months after operation were compared. RESULTS: (1) There was no significant difference in ICP values measured by Codman monitoring system and hydraulic coupling monitoring system in the same patient (mmHg: 11.94±1.76 vs. 11.88±1.90, t = 0.150, P = 0.882; 1 mmHg≈0.133 kPa). Blan-altman analysis showed that the 95% consistency limit (95%LoA) of ICP values measured by the two methods was -4.55 to 4.68 mmHg, and all points fell within 95%LoA, indicating that the two methods had a good correlation. (2) There were no significant differences in cerebrospinal fluid drainage time, ICP monitoring time, ICU stay time, and incidence of complications such as intracranial infection, intracranial rebleeding, traumatic hydrocephalus, cerebrospinal fluid leakage, and accidental extubation among the 3 groups of sTBI patients (P > 0.05 or P > 0.017). The ICP value of group C after treatment was significantly lower than that of group A and group B (mmHg: 20.94±2.37 vs. 25.86±3.15, 26.40±3.09, all P < 0.05), the incidence of pulmonary infection (9.1% vs. 45.7%, 42.5%), seizure (3.0% vs. 31.4%, 30.0%), reoperation (3.0% vs. 31.4%, 40.0%), and poor prognosis 6 months after operation (33.3% vs. 65.7%, 65.0%) were significantly lower than those in group A and group B (all P < 0.017). According to the hydraulic coupling waveform, GOS scores of 35 patients in the compensated group were significantly higher than those of 38 patients in the decompensated group 6 months after operation (4.03±1.18 vs. 2.39±1.50, t = 5.153, P < 0.001). CONCLUSIONS The hydraulic coupled intracranial pressure monitoring system has good accuracy and consistency in measuring ICP value, and it can better display ICP waveform changes than the traditional ICP monitoring method, and has better prediction value for prognosis evaluation, which can replace Codman monitoring to accurately guide clinical work. In addition, analgesia and sedation under BIS monitoring combined with hydraulic coupled ICP monitoring can effectively reduce ICP, reduce the incidence of complications, and improve the prognosis, which has high clinical application value.
Humans ; Intracranial Pressure ; Prospective Studies ; Monitoring, Physiologic/methods* ; Craniocerebral Trauma ; Analgesia ; Cerebrospinal Fluid Leak

ObjectiveTo explore the clinical efficacy and safety of Qifu Yixin prescription in treating chronic heart failure in the patients with the syndrome of heart Qi deficiency， so as to provide clinical evidence for the treatment of chronic heart failure with this prescription and promote the clinical application and transformation of this prescription. MethodA total of 106 chronic heart failure patients with the syndrome of heart Qi deficiency who met the criteria in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine （TCM） from September 2022 to May 2023 were selected and randomized into an observation group （53 cases） and a control group （53 cases）. Both groups received routine Western medicine treatment. In addition， the observation group received Qifu Yixin prescription， while the control group received placebo. The treatment course for both groups was 12 weeks. The New York heart association （NYHA） cardiac function grading， N-terminal pro-B-type natriuretic peptide （NT-proBNP）， soluble growth-stimulating expression gene 2 （sST2）， left ventricular ejection fraction （LVEF）， the ratio of early diastolic maximum mitral flow velocity （E） to early diastolic mitral annular motion velocity （e'） （E/e'）， left ventricular end diastolic diameter （LVEDD）， TCM syndrome scores， 6-minute walking test （6MWT）， Minnesota Living with Heart Failure Questionnaire （MLHFQ）， and Kansas City Cardiomyopathy Questionnaire （KCCQ） were determined before and after treatment. ResultFinally， 102 patients were included for analysis， including 51 patients in the observation group and 51 patients in the control group. After treatment， 42 patients in the observation group showed improved cardiac function grading， with a total response rate of 82.35%， and 32 patients in the control group showed improved cardiac function grading， with a total response rate of 62.75%. The total response rate regarding the cardiac function in the observation group was higher than that in the control group （χ²=4.923， P<0.05）. The observation group outperformed the control group in lowering the NT-proBNP level， elevating LVEF， decreasing the E/e' ratio （P<0.05）， reducing LVEDD and sST2 levels， and recovering TCM syndrome score， 6MWT score， MLHFQ score， and KCCQ score （P<0.05）. None of the safety indexes in the two groups showed abnormal values before and after treatment， and no serious adverse reaction was observed. ConclusionQifu Yixin prescription can improve the heart function， exercise tolerance， and quality of life and alleviate the TCM syndrome of the chronic heart failure patients with the syndrome of heart Qi deficiency by inhibiting myocardial fibrosis.

Objectives:To construct a nomogram prediction model using common preoperative indicators for early weight loss (EWL) 1 year after laparoscopic sleeve gastrectomy (LSG).Methods:Relevant data of obese patients who had undergone LSG from January 2015 to May 2022 in Fujian Medical University Union Hospital and Quanzhou First Hospital Affiliated Fujian Medical University were analyzed. Patients with a history of major abdominal surgery, severe gastroesophageal reflux disease, pregnancy within 1 year after surgery, or who were lost to follow-up were excluded, resulting in a total of 200 patients in the study (190 from Fujian Medical University Union Hospital and 10 from Quanzhou First Hospital Affiliated Fujian Medical University). The participants were 51 men and 149 women of a mean age 29.9±8.2 years and a body mass index (BMI) 38.7±6.5 kg/m 2. All patients in this group underwent standardized LSG procedure. Achieving ideal weight (BMI≤25 kg/m 2) 1 year after LSG was defined as goal of EWL. Logistic regression analyses were performed to identify factors that independently influenced EWL. These factors were incorporated into the nomogram model. Receiver operating characteristic (ROC) curves (the larger the area under the curve [AUC], the better the predictive ability and accuracy of the model), likelihood ratio test (higher likelihood ratio indicates greater model homogeneity), decision curve analysis (higher net benefit indicates a better model), Akaike information criterion (AIC; smaller AIC indicates a better model), and Bayesian information criterion (BIC; smaller BIC indicates a better model) were used to validate the predictive ability of the column line diagram model. Results:In this study of 200 obese patients who underwent LSG surgery, 136 achieved EWL goal, whereas the remaining 64 did not. The rate of EWL goal achievement of the entire group was 68.0%. Compared with patients who did not achieve EWL goal, those who did had lower BMI, alanine transaminase, aspartate transaminase, triglycerides, and higher cholesterol. Additionally, the proportion of female was higher and the proportions of patients with fatty liver and hypertension lower in those who achieved EWL goal (all P<0.05). Univariate and multivariate logistic regression analysis revealed that preoperative BMI (OR=0.852, 95%CI: 0.796-0.912, P<0.001), alanine transaminase (OR=0.992, 95%CI: 0.985-0.999, P=0.024), presence of fatty liver (OR=0.185, 95%CI: 0.038-0.887, P=0.035) and hypertension (OR=0.374, 95%CI: 0.144-0.969, P=0.043) were independently associated with failure to achieve EWL goal. Cholesterol (OR=1.428, 95%CI: 1.052-1.939, P=0.022) was independently associated with achieving EWL goal. We used the above variables to establish an EWL nomogram model. ROC analysis, the likelihood ratio test, decision curve analysis, and AIC all revealed that the predictive value of the model was better than that of BMI alone (nomogram model vs. BMI: area under the curve 0.840 vs. 0.798, P=0.047; likelihood ratio: 58.785 vs. 36.565, AIC: 193.066 vs. 207.063, BIC: 212.856 vs. 213.660). Conclusion:Our predictive model is more accurate in predicting EWL after LSG compared with using BMI.

OBJECTIVE: To assess the practical and health economical values of non-invasive prenatal test (NIPT) in Changsha Municipal Public Welfare Program. METHODS: A retrospective analysis was carried out on 149 165 women undergoing NIPT test from April 9, 2018 to December 31, 2019. For pregnant women with high risks, invasive prenatal diagnosis and follow-up of pregnancy outcome were conducted. The cost-benefit of NIPT for Down syndrome was analyzed. RESULTS: NIPT was carried out for 149 165 pregnant women and succeeded in 148 749 cases (99.72%), for which outcome were available in 148 538 (99.86%). 90% of pregnant women from the region accepted the screening with NIPT. 415 (0.27%) were diagnosed as high risk. Among these, 381 (91.81%) accepted amniocentesis, which led to the diagnosis of 212 cases of trisomy 21 (PPV=85.14%), 41 cases with trisomy 18 (PPV=48.81%) and 10 cases with trisomy 13 (PPV=20.83%). The sensitivity and specificity of NIPT for trisomy 21, trisomy 18 and trisomy 13 were (97.70%, 99.98%), (97.62%, 9.97%) and (100%, 99.97%), respectively. In addition, 213 and 30 cases were diagnosed with sex chromosomal aneuploidies (PPV=46.2%) and other autosomal anomalies (PPV=16.57%), respectively. For Down syndrome screening, the cost and benefit of the project was 120.79 million yuan and 1,056.95 million yuan, respectively. The cost-benefit ratio was 1: 8.75, and safety index was 0.0035. CONCLUSION NIPT is a highly accurate screening test for trisomy 21, which was followed by trisomy 18 and sex chromosomal aneuploidies, while it was less accurate for other autosomal aneuploidies. The application of NIPT screening has a high health economical value.
Aneuploidy ; Cost-Benefit Analysis ; Female ; Humans ; Noninvasive Prenatal Testing ; Pregnancy ; Retrospective Studies ; Trisomy 18 Syndrome/genetics*