Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Attempts have been made to modulate motor sequence learning (MSL) through repetitive transcranial magnetic stimulation, targeting different sites within the sensorimotor network. However, the target with the optimum modulatory effect on neural plasticity associated with MSL remains unclarified. This study was therefore designed to compare the role of the left primary motor cortex and the left supplementary motor area proper (SMAp) in modulating MSL across different complexity levels and for both hands, as well as the associated neuroplasticity by applying intermittent theta burst stimulation together with the electroencephalogram and concurrent transcranial magnetic stimulation. Our data demonstrated the role of SMAp stimulation in modulating neural communication to support MSL, which is achieved by facilitating regional activation and orchestrating neural coupling across distributed brain regions, particularly in interhemispheric connections. These findings may have important clinical implications, particularly for motor rehabilitation in populations such as post-stroke patients.
Humans ; Transcranial Magnetic Stimulation ; Motor Cortex/physiology* ; Male ; Electroencephalography ; Neuronal Plasticity/physiology* ; Female ; Adult ; Evoked Potentials, Motor/physiology* ; Young Adult ; Learning/physiology*

OBJECTIVE: To explore whether hydrocortisone can improve the prognosis of patients with severe community-acquired pneumonia (sCAP) by Meta-analysis. METHODS: Randomized controlled trial (RCT) on hydrocortisone in the treatment of sCAP were extracted from the database including PubMed, Cochrane library, Web of Science, and Embase, and the search time was up to April 29, 2023. The patients in the standard treatment group received standard treatment such as antibiotics and supportive care, while those in the hydrocortisone group received hydrocortisone treatment on the basis of standard treatment. Meta-analysis was used to compare the mortality, duration of mechanical ventilation, mechanical ventilation rate and incidence of adverse reactions (hyperglycemia, gastrointestinal bleeding, secondary infection) between the two groups. The risk of literature bias was assessed. The studies that might have publication bias were corrected by the subtraction and complementation method. At the same time, trial sequential analysis (TSA) was conducted. RESULTS: A total of 5 RCTs involving 1 031 patients were finally enrolled, including 494 patients in the standard treatment group and 537 patients in the hydrocortisone group. Among the 5 studies, the research site of 2 studies was in the mixed ward. Considering the inclusion characteristics of the study population, there was doubt whether its research object was sCAP patients, which might have a certain impact on the results and introduce potential bias. Meta-analysis showed that the mortality in the hydrocortisone group was significantly lower than that in the standard treatment group [6.0% vs. 14.0%; odds ratio (OR) = 0.38, 95% confidence interval (95%CI) was 0.25-0.59, P < 0.01; I² = 9%]. The studies that were asymmetric were corrected by the reduction and supplementation method. Even after filling the missing studies, hydrocortisone could still reduce the death risk of the patient (OR = 0.49, 95%CI was 0.32-0.73, P < 0.01; I² = 31%). TSA showed that the average mortality of the standard treatment group was about 14.0%, and that of the hydrocortisone group was about 6.0%, with a relative risk reduction (RRR) = 57%. The calculated sample size was 699 cases, and the actual sample size was 1 031 cases. The actual sample size exceeded the required sample size, and the Z-curve crossed the O'Brien-Fleming boundary and the curve corresponding to P = 0.05, it meant that hydrocortisone could effectively reduce the mortality of sCAP. Compared with the standard treatment group, no statistical difference in the duration of mechanical ventilation was found in the hydrocortisone group [mean difference (MD) = -3.26, 95%CI was -6.72-0.21, P = 0.07; I² = 0%], but the 8-day mechanical ventilation rate was significantly lowered (19.5% vs. 55.4%; OR = 0.24, 95%CI was 0.12-0.45, P < 0.01; I² = 0%), and also no significantly difference was found in the incidence of hyperglycemia (54.3% vs. 44.6%, OR = 1.26, 95%CI was 0.56-2.84, P = 0.58; I² = 61%), gastrointestinal bleeding (2.5% vs. 3.6%; OR = 0.70, 95%CI was 0.34-1.46, P = 0.34; I² = 0%) and secondary infection (9.2% vs. 11.5%; OR = 0.46, 95%CI was 0.06-3.35, P = 0.45; I² = 53%). CONCLUSION Hydrocortisone can reduce the mortality rate of sCAP patients, decrease their need for mechanical ventilation, and does not increase the risk of hyperglycemia, gastrointestinal bleeding, or secondary infections.
Humans ; Hydrocortisone/therapeutic use* ; Community-Acquired Infections/drug therapy* ; Pneumonia/drug therapy* ; Randomized Controlled Trials as Topic ; Respiration, Artificial ; Community-Acquired Pneumonia

Objective To evaluate the safety and efficacy of profunda femoral vein thrombosis clearance in endovascular treatment of acute lower extremity deep venous thrombosis (DVT). Methods From January 2022 to September 2023, clinical data of acute lower extremity DVT patients who underwent percutaneous mechanical thrombectomy (PMT) for profunda femoral vein thrombosis were retrospectively analyzed. The 12-month primary patency rate of iliofemoral vein and incidence of post-thrombotic syndrome(PTS) were analyzed. Results Twenty-two patients were included in the study, and all patients underwent PMT for profunda femoral vein thrombosis. Five patients were treated through the contralateral common femoral vein via crossover approach, and 17 patients were treated through the contralateral common femoral vein combined with the ipsilateral deep vein approach. The 12-month primary patency rate of iliofemoral vein was 90.9% (20/22), and the incidence of PTS was 9.1% (2/22). Conclusions For patients with acute lower extremity DVT undergoing endovascular treatment, PMT for profunda femoral vein thrombosis is safe and effective, achieving good primary patency of iliofemoral vein and low incidence of PTS.

Objective To investigate the feasibility,safety and efficacy of transcatheter drug-loaded microsphere embolization(DLME)in treating patients with advanced bladder cancer with bleeding(ABCB).Methods A total of 26 ABCB patients who underwent DLME for tumor supply arteries were retrospectively selected.The postoperative efficacy and related complications were observed.The recurrence of hematuria and survival situation were followed up.Results All 26 surgeries achieved success with a technical success rate of 100.0％.There were 21 cases(80.8％)of bilateral bladder artery embolism and 5 cases(19.2％)of unilateral bladder artery embolism.Three days after the operation,24 patients(92.3％)had hematuria remission.And the other two patients(7.7％)had no hematuria remission,they were relieved after interventional embolization again.Compared with that before operation,the blood transfusion rate,blood transfusion volume,hematocrit and hemoglobin at one week after operation were significantly improved(P＜0.05).One month after the last intervention,there were 2 cases of complete response,19 cases of partial response,3 cases of stable disease,and 2 cases of progressive disease.The objective remission rate was 80.8％,and the disease control rate was 92.3％.Compared with that before operation,the T stage was significantly improved at one month after operation(P＜0.05).No patients had severe complications such as ectopic embolism.After follow-up for 3-36 months,5 cases(19.2％)had a recurrence of hematuria.Conclusion Transcatheter DLME is feasible,safe,and effective in the treatment of patients with ABCB.It is an optional,minimally invasive palliative measure.

Objective To explore the clinical effect of endovascular stent-graft exclusion in the treatment of acute Stanford B-type aortic dissection(AD)with distal left subclavian artery(LSA)rupture accompanied by arch intramural hematoma.Methods A total of 12 patients with acute AD treated by the endovascular stent-graft exclusion alone were retrospectively selected.All patients had primary rupture at the distal end of LSA with arch intramural hematoma and received endovascular treatment after 2 to 3 weeks of conservative treatment.The technique success rate and related complications were observed.Postoperative computed tomography angiography(CTA)of the aorta was reviewed to evaluate the remodeling of the true and false lumen,the absorption of the arch intramural hematoma,to observe whether there was a new rupture and endoleak,and to understand the position and shape of the stent and the blood supply of the branch arteries.Results All patients completed the operation with a technical success rate of 100％.Two patients partially blocked the opening of LSA,and one patient had type Ⅰ internal leakage after the operation,but the amount of internal leakage was small and was not treated.Other patients did not had serious complications such as aortic rupture,new rupture,paraplegia,stent displacement,stroke,upper limb ischemia or vertebral artery ischemia,internal leakage,and abdominal organ ischemia during and after the operation.The patients were followed up for 19 to 66 months,with an average follow-up of(36.7±13.9)months.During the follow-up period,no patient died.The aortic remodeling was satisfactory in all patients,the arch intramural hematoma was absorbed,and there were no new rupture,internal leakage,upper limb ischemia or vertebral artery ischemia,or other serious complications.One patient with type Ⅰ internal leakage showed no significant change in internal leakage after regular postoperative reexamination.Conclusion Endovascular stent-graft exclusion is safe and feasible in the treatment of acute AD patients with distal LSA rupture accompanied by arch intramural hematoma,and it is worth promoting and applying clinically.

Objectives:Fluid resuscitation is an important treatment for sepsis. However, the optimal choice of fluid is still controversial. This study aimed to investigate the effect of Sodium Bicarbonate Ringer’s Solution on the outcome of patients with sepsis.Methods:This was a single-center, prospective, randomized controlled clinical study, From July 2021 to June 2023, adult patients with Sepsis who met the diagnostic criteria of Sepsis 3.0 admitted to the Department of Critical Care Medicine of Jiangdu People's Hospital of Yangzhou were randomly assigned to the sodium bicarbonate ringer’s solution group or the normal saline group according to the random number table. Patients received either sodium bicarbonate ringer’s solution or normal saline as fluid for resuscitation and maintenance therapy. Clinicians determined the amount and rate of infusion based on volume assessment. The 30-day mortality, the degradation of endothelial glycocalyx degradation products at multiple time points, the mortality in intensive care unit (ICU), the incidence of major adverse renal events (MAKE30) within 30 days, and other clinical outcomes were compared between the two groups. Enzyme-Linked immunosorbent assay was used to determine the concentration of endothelial glycocalyx coating degradation products in peripheral blood. The count data were analyzed by χ 2 test, and the measurement data were analyzed by independent sample t test. Results:A total of 67 patients who met the inclusion criteria were enrolled during the study (32 patients in the sodium bicarbonate ringer’s solution group and 35 patients in the normal saline group). There were no significant differences in baseline data such as age, gender, underlying diseases, and SOFA score at enrollment between the two groups ( P>0.05).The 30-day mortality (28.1% vs. 40.0%), ICU mortality (15.6% vs. 20.0%) and MAKE30 (31.2% vs. 42.9%) in the sodium bicarbonate ringer’s solution group were lower than those in the normal saline group, but the differences were not statistically significant ( P>0.05). The levels of SCD-1(1317.3±206.9) pg/mL, HA (75.1±24.9) ng/mL and HS (75.6±13.8) ng/mL in the sodium bicarbonate ringer’s solution group were significantly lower than those in the normal saline group [(1514.6±264.9) pg/mL, (96.5±25.4) ng/mL, (85.8±15.8) ng/mL] on the third day (all P<0.05). Conclusion:Although the use of sodium bicarbonate ringer’s solution for resuscitation in sepsis patients cannot significantly reduce the 30-day mortality rate, but significantly reduce the degradation of polysaccharide coating, decrease the occurrence of hyperchloremia and acidosis.

Objective To explore the risk factors affecting the prognosis of sepsis patients progressing to chronic critical illness (CCI), and to construct and validate a Nomogram model for predicting in-hospital mortality risk. Methods Patients who met the criteria for sepsis progressing to CCI were selected from the Medical Information Mart for Intensive Care Ⅳ (MIMIC-Ⅳ) database in the United States as the research objects. Clinical materials of patients were collected retrospectively, and a total of 928 patients were included. The patients were randomly divided into modeling group (n=649) and validation group (n=279) at a ratio of 7 to 3; the patients were also divided into survival group and mortality group based on in-hospital mortality. Univariate and multivariate Logistic regression analyses were performed on the modeling group based on the outcomes; a Nomogram model for predicting in-hospital mortality in sepsis patients progressing to CCI was constructed based on independent risk factors; the discrimination and calibration of the Nomogram model were evaluated by the concordance index and calibration curve, and then validated by the validation group. Results Among the 928 sepsis patients progressing to CCI, 723 cases were in survival group and 205 cases in mortality group, with an in-hospital mortality rate of 22.1%. Age (OR=1.021, 95%CI, 1.007 to 1.036, P=0.004), body mass (OR=0.988, 95%CI, 0.979 to 0.997, P=0.016), the Acute Physiological Score Ⅲ (APS Ⅲ) score (OR=1.013, 95%CI, 1.004 to 1.023, P=0.004), blood alkaline phosphatase (OR=1.002, 95%CI, 1.000 to 1.003, P=0.023), continuous renal replacement therapy (CRRT) duration (OR=1.065, 95%CI, 1.023 to 1.108, P=0.002), and mechanical ventilation duration (OR=1.117, 95%CI, 1.056 to 1.184, P < 0.001) were identified as independent influencing factors for in-hospital mortality in sepsis patients progressing to CCI. A prediction model was constructed based on these risk factors, and the concordance index analysis showed that the concordance index was 0.75 (95%CI, 0.70 to 0.80) in the modeling group and 0.74 (95%CI, 0.68 to 0.81) in the validation group. The calibration curves of both themodeling group and the validation group were close to the standard curve. Conclusion Nomogram model constructed based on the 6 indicators including age, body mass, blood alkaline phosphatase, APS Ⅲ score, CRRT, and mechanical ventilation duration has good discrimination and calibration for predicting the mortality risk of sepsis patients progressing to CCI, which is helpful for clinicians to assess patient's prognosis.

OBJECTIVE: To investigate the correlation of hemoglobin (Hb) level with prognosis of elderly patients diagnosed as sepsis. METHODS: A retrospective cohort study was conducted. Information on the cases of elderly patients with sepsis in the Medical Information Mart for Intensive Care-IV (MIMIC-IV), including basic information, blood pressure, routine blood test results [the Hb level of a patient was defined as his/her maximum Hb level from 6 hours before admission to intensive care unit (ICU) and 24 hours after admission to ICU], blood biochemical indexes, coagulation function, vital signs, severity score and outcome indicators were extracted. The curves of Hb level vs. 28-day mortality risk were developed by using the restricted cubic spline model based on the Cox regression analysis. The patients were divided into four groups (Hb < 100 g/L, 100 g/L ≤ Hb < 130 g/L, 130 g/L ≤ Hb < 150 g/L, Hb ≥ 150 g/L groups) based on these curves. The outcome indicators of patients in each group were analyzed, and the 28-day Kaplan-Meier survival curve was drawn. Logistic regression model and Cox regression model were used to analyze the relationship between Hb level and 28-day mortality risk in different groups. RESULTS: A total of 7 473 elderly patients with sepsis were included. There was a "U" curve relationship between Hb levels within 24 hours after ICU admission and the risk of 28-day mortality in patients with sepsis. The patients with 100 g/L ≤ Hb < 130 g/L had a lower risk of 28-day mortality. When Hb level was less than 100 g/L, the risk of death decreased gradually with the increase of Hb level. When Hb level was ≥ 130 g/L, the risk of death gradually increased with the increase of Hb level. Multivariate Logistic regression analysis revealed that the mortality risks of patients with Hb < 100 g/L [odds ratio (OR) = 1.44, 95% confidence interval (95%CI) was 1.23-1.70, P < 0.001] and Hb ≥ 150 g/L (OR = 1.77, 95%CI was 1.26-2.49, P = 0.001) increased significantly in the model involving all confounding factors; the mortality risks of patients with 130 g/L ≤ Hb < 150 g/L increased, while the difference was not statistically significant (OR = 1.21, 95%CI was 0.99-1.48, P = 0.057). The multivariate Cox regression analysis suggested that the mortality risks of patients with Hb < 100 g/L [hazard ratio (HR) = 1.27, 95%CI was 1.12-1.44, P < 0.001] and Hb ≥ 150 g/L (HR = 1.49, 95%CI was 1.16-1.93, P = 0.002) increased significantly in the model involving all confounding factors; the mortality risks of patients with 130 g/L ≤ Hb < 150 g/L increased, while the difference was not statistically significant (HR = 1.17, 95%CI was 0.99-1.37, P = 0.053). Kaplan-Meier survival curve showed that the 28-day survival rate of elderly septic patients in 100 g/L ≤ Hb < 130 g/L group was significantly higher than that in Hb < 100 g/L, 130 g/L ≤ Hb < 150 g/L and Hb ≥ 150 g/L groups (85.26% vs. 77.33%, 79.81%, 74.33%; Log-Rank test: χ² = 71.850, P < 0.001). CONCLUSIONS Elderly patients with sepsis exhibited low mortality risk if their 100 g/L ≤ Hb < 130 g/L within 24 hours after admission to ICU, and both higher and lower Hb levels led to increased mortality risks.
Humans ; Male ; Female ; Aged ; Retrospective Studies ; Sepsis/diagnosis* ; Critical Care ; Intensive Care Units ; Prognosis ; Hemoglobins ; ROC Curve