Objective To investigate the mid- to long-term follow-up results of ascending aorta (AAO)-descending thoracic aorta (DTA) bypass grafting via median sternotomy incision for the treatment of complex aortic arch coarctation. Methods A retrospective analysis was conducted on the clinical data of patients with complex aortic arch coarctation who underwent AAO-DTA bypass grafting via median sternotomy incision at the First Hospital of Tsinghua University from August 2004 to May 2017. Results A total of 7 patients were enrolled, including 4 males and 3 females, aged (13.3±4.6) years, and weighted (40.2±12.2) kg. Six (85.7%) patients had concomitant upper limb hypertension. Four patients were aortic arch coarctation combined with intracardiac malformations, two were post-operative restenosis, and 1 was post-operative restenosis combined with intracardiac malformation. All patients underwent surgery under cardiopulmonary bypass. There were no perioperative deaths or major complications. The pre-operative upper-lower limb pressure difference was (39.3±19.2) mm Hg, which decreased to (2.9±2.7) mm Hg post-operatively (P<0.01). The follow-up period was (14.9±5.9) years. There were no long-term deaths or artificial graft-related complications. Except for one patient who still had mild hypertension, the blood pressure of the remaining patients returned to normal. Conclusion AAO-DTA bypass grafting via median sternotomy incision for the treatment of complex aortic arch coarctation can effectively reduce upper limb blood pressure and the upper-lower limb arterial pressure difference, has fewer complications, and demonstrates satisfactory mid- to long-term efficacy.

OBJECTIVE: To investigate the effectiveness of tibial transverse transport (TTT) in treating Wagner grade 3-4 type 2 diabetic foot ulcers and analyze dynamic changes in immunoglobulin levels. METHODS: The clinical data of 68 patients with Wagner grade 3-4 type 2 diabetic foot ulcers treated with TTT between May 2022 and September 2023 was retrospectively analyzed. The cohort included 49 males and 19 females, aged 44-91 years (mean, 67.3 years), with 40 Wagner grade 3 and 28 grade 4 ulcers. The duration of type 2 diabetes ranged from 5 to 23 years, with an average of 10 years. The number of wound healing cases, healing time, amputation cases, death cases, and complications were observed and recorded. Serum samples were collected at 6 key time points [1 day before TTT and 3 days, 7 days (the first day of upward transverse transfer), 14 days (the first day of downward transverse transfer), 21 days (the first day after the end of transfer), 36 days (the first day after the removal of the transfer device)], and the serum immunoglobulin levels were detected by flow cytometry including immunoglobulin G (IgG), IgA, IgM, IgE, complement C3 (C3), C4, immunoglobulin light chain κ (KAP), immunoglobulin light chain λ (LAM). RESULTS: All the 68 patients were followed up 6 months. Postoperative pin tract infection occurred in 3 cases and incision infection in 2 cases. Amputation occurred in 5 patients (7.4%) at 59-103 days after operation, and 8 patients (11.8%) died at 49-77 days after operation; the wounds of the remaining 55 patients (80.9%) healed in 48-135 days, with an average of 80 days. There was no recurrence of ulcer, peri-osteotomy fracture, or local skin necrosis during follow-up. The serum immunoglobulin levels of 55 patients with wound healing showed that the levels of IgG and IgM decreased significantly on the 3rd and 7th day after operation compared with those before operation ( P<0.05), and gradually returned to the levels before operation after 14 days, and reached the peak on the 36th day. IgA levels continued to decrease with time, and there were significant differences at all time points when compared with those before operation ( P<0.05). The level of IgE significantly decreased at 21 days after operation compared with that before operation ( P<0.05), while it was higher at other time points than that before operation, but the difference was not significant ( P>0.05). The level of C3 showed a clear treatment-related increase, which was significantly higher on the 7th, 14th, and 21st days after operation than that before operation ( P<0.05), and the peak appeared on the 14th day. The change trend of C4 level was basically synchronous with that of C3, but the amplitude was smaller, and the difference was significant at 7 and 14 days after operation compared with that before operation ( P<0.05). There was no significant difference in KAP/LAM between different time points before and after operation ( P>0.05). CONCLUSION TTT can accelerate wound healing, effectively treat diabetic foot ulcer, and reduce amputation rate, and has definite effectiveness. The potential mechanisms of TTT in the treatment of diabetic foot ulcers include the dynamic regulation of IgG, IgA, IgM, and IgE levels to balance the process of inflammation and repair, and the periodic increase of C3 and C4 levels may promote tissue cleaning, angiogenesis, and anti-infection defense.
Humans ; Male ; Female ; Middle Aged ; Aged ; Diabetic Foot/immunology* ; Wound Healing ; Adult ; Retrospective Studies ; Aged, 80 and over ; Treatment Outcome ; Tibia/transplantation* ; Diabetes Mellitus, Type 2/complications* ; Amputation, Surgical ; Immunoglobulins/blood* ; Immunoglobulin G/blood*

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

To investigate the protective effects and underlying mechanisms of Qin-Zhu-Liang-Xue decoction (QZLX) in atopic dermatitis (AD) and glucocorticoid resistance, we conducted a single-blinded, randomized controlled clinical trial to evaluate the efficacy and safety of this concoction. Network pharmacology analysis was performed and validated through clinical studies. The efficacy, safety, and mechanism of action of QZLX and glucocorticoid receptor (GR) α recombinant protein were assessed in AD mice induced by 2,4-dinitrofluorobenzene (DNFB). Correlation analysis was performed to determine the clinical relevance of GRα. The trial demonstrated that patients who received QZLX showed considerable improvements in their Scoring Atopic Dermatitis (SCORAD) and Dermatology Life Quality Index (DLQI) scores compared with those who received mizolastine at week 4. Network pharmacological analysis identified GRα as a key target for QZLX in AD treatment. QZLX administration increased the serum GRα expression in AD patients, alleviated AD symptoms in mice, decreased inflammatory cytokine expression, and increased GRα expression without affecting liver or kidney function. In addition, GRα recombinant protein improved AD-like skin lesions in DNFB-induced mice. A negative correlation was observed between GRα expression and clinical parameters, including SCORAD, DLQI, and serum IgE levels. QZLX alleviates AD symptoms through the upregulation of GRα and thus presents a novel therapeutic strategy for the prevention of glucocorticoid resistance in AD management.
Dermatitis, Atopic/drug therapy* ; Animals ; Drugs, Chinese Herbal/administration & dosage* ; Humans ; Mice ; Network Pharmacology ; Male ; Female ; Adult ; Receptors, Glucocorticoid/metabolism* ; Disease Models, Animal ; Single-Blind Method ; Middle Aged ; Young Adult

Kirsten rat sarcoma viral oncogene homolog (KRAS) protein inhibitors are a promising class of therapeutics, but research on molecules that effectively penetrate the blood-brain barrier (BBB) remains limited, which is crucial for treating central nervous system (CNS) malignancies. Although molecular generation models have recently advanced drug discovery, they often overlook the complexity of biological and chemical factors, leaving room for improvement. In this study, we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties. Our approach utilizes a variational autoencoder (VAE) generative model integrated with reinforcement learning for multi-objective optimization. This method specifically aims to enhance BBB permeability (BBBp) while maintaining high-affinity substructures of KRAS inhibitors. To support this, we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models. Additionally, we introduce two novel metrics, the knowledge-integrated reproduction score (KIRS) and the composite diversity score (CDS), to assess structural performance and biological relevance. Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets.

OBJECTIVE: To evaluate the prognosis of septic right ventricular dysfunction (SRVD) based on bedside ultrasound and explore its risk factors. METHODS: A prospective observational study was conducted involving septic and septic shock patients admitted to the intensive care unit (ICU) of the General Hospital of Ningxia Medical University from February 2021 to January 2022. Tricuspid annular plane systolic excursion (TAPSE) was measured by M-mode ultrasound within 24 hours after ICU admission. According to the results of TAPSE, the subjects were divided into SRVD group (TAPSE < 16 mm) and non-SRVD group (TAPSE ≥ 16 mm). The gender, age, occurrence of septic shock, underlying diseases, source of patients, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, maximal body temperature within 24 hours after ICU admission, location and number of infections, duration of mechanical ventilation, and 28-day mortality were collected. Hemodynamic parameters, organ function indexes, oxygen therapy parameters and arterial blood gas analysis indexes were recorded within 24 hours after ICU admission. The differences of the above indexes between the two groups were compared. Binary multivariate Logistic regression analysis was used to screen out the independent risk factors for SRVD, and a nomogram of SRVD risk factors was drawn. RESULTS: 116 patients with sepsis and septic shock were enrolled, of which 24 (20.7%) had SRVD and 92 (79.3%) had no SRVD. Compared with the non-SRVD group, the patients in the SRVD group had higher emergency transfer and infection site ≥ 2 ratio, APACHE II score, SOFA score, higher cardiac troponin I (cTnI), myoglobin (Mb), MB isoenzyme of creatine kinase (CK-MB), N-terminal pro-brain natriuretic peptide (NT-proBNP), serum creatinine (SCr), arterial blood lactic acid (Lac) and lower left ventricular ejection fraction (LVEF), platelet count (PLT) within 24 hours after ICU admission, and higher proportion of norepinephrine application and continuous renal replacement therapy (CRRT). Binary multivariate Logistic regression analysis showed that LVEF [odds ratio (OR) = 0.918, 95% confidence interval (95%CI) was 0.851-0.991, P = 0.028], PLT (OR = 0.990, 95%CI was 0.981-0.999, P = 0.035), SCr (OR = 1.008, 95%CI was 1.001-1.016, P = 0.025), and the usage of norepinephrine (OR = 15.198, 95%CI was 1.541-149.907, P = 0.020) were independent risk factors for SRVD in patients with sepsis and septic shock. Based on the above four independent risk factors, a nomogram of SRVD risk factors was drawn. The results showed that the score was 64 when LVEF was 0.50, 18 when SCr was 100 μmol/L, 85 when PLT was 100×10⁹/L, and 39 when norepinephrine was used. When the total score reached 253, the risk of SRVD was 88%. Compared with non-SRVD group, the duration of mechanical ventilation in SRVD group was slightly longer [hours: 80.0 (28.5, 170.0) vs. 47.0 (10.0, 135.0), P > 0.05], and the 28-day mortality was significantly higher [41.7% (10/24) vs. 21.7% (20/92), P < 0.05]. CONCLUSIONS Patients with sepsis may have right ventricular dysfunction, impaired renal function and increased mortality in the early stage. The decrease in LVEF and PLT, the increase in SCr and the application of norepinephrine are independent risk factors for SRVD in patients with sepsis.
Humans ; Prognosis ; Ventricular Dysfunction, Right/diagnostic imaging* ; Risk Factors ; Prospective Studies ; Intensive Care Units ; Shock, Septic ; Male ; Ultrasonography ; Female ; Sepsis/complications* ; Middle Aged ; Point-of-Care Systems ; Aged ; Logistic Models ; APACHE

Kirsten rat sarcoma viral oncogene homolog(KRAS)gene is one of the most commonly mutated oncogenes.It has been found that KRAS inhibitors have the potential therapeutic effect on cancer patients with this gene mutation.In this study,machine learning was applied to develop a QSAR(quantitative structure-activity relationship)model for KRAS small molecule inhibitors.A total of 1857data points of IC50 and SMILES(simplified molecular input line entry system)for KRAS inhibitors were collected from three databases:ChEMBL,BindingDB,and PubChem.And nine different classifiers were constructed using three different feature screening methods combined with three machine learning models,namely,random forest,support vector machine,and extreme gradient boosting machine.The results showed that the SVM model combined with mutual information feature selection exhibited the best performance:AUCtest=0.912,ACCtest=0.859,F1test=0.890.Moreover,it also demonstrated good predictive performance on the external validation set(AUCExt=0.944,RecallExt=0.856,FPRExt=0.111).This study provides a new technical route for KRAS inhibitor screening in natural product databases using artificial intelligence methods.

Refractory angina is characterized by recurrent and persistent angina with a duration of not less than three months， which is related to reversible ischemia and hypoxia caused by coronary stenosis and obstruction. It mainly involves obstructive coronary artery disease and non-obstructive coronary artery disease with coronary artery spasm and coronary microvascular dysfunction. “Stasis and toxin” play an important role in the pathogenesis of cardiovascular diseases. The pathogenesis of stasis and toxin is stubborn filthy turbidity featured by slow accumulation and sudden onset，and rapid changes，which coincides with the characteristics of refractory angina which is complex and changeable，prolonged and difficult to cure. The pathogenesis of refractory angina involves a combination of underlying deficiency and excessive manifestation， with "stasis and toxin" playing a crucial role as an important pathological factor in the whole process of refractory angina. Traditional Chinese medicine （TCM） employs a holistic approach known as "activating blood circulation and removing toxins"， which is supplemented by various methods to tonify Qi and warm Yang， nourish the kidneys and invigorate the spleen， clear heat and transform phlegm. This approach applies anti-inflammatory measures， regulates lipid metabolism， inhibits oxidative stress and thrombus formation， protects endothelial function in blood vessels， as well as establishes collateral circulation for the prevention and treatment of refractory angina. Therefore，based on the theory of "stasis and toxin"，combined with TCM theory and modern medical research，this paper discusses the pathogenesis of refractory angina and the prevention and treatment strategy of TCM，and elucidates the reasons for the difficulty in curing refractory angina and the relationship between refractory angina and common angina pectoris，coronary microvascular dysfunction，coronary artery spasm and obstructive coronary artery disease，hoping to provide certain theoretical basis and clinical ideas for the prevention and treatment of refractory angina with TCM.

Objective:To observe the change of retinal artery angle in eyes with idiopathic epiretinal membrane (ERM) and to analyze the relationship between retinal artery angle, ERM classification based on optical coherence tomography (OCT), and visual acuity.Methods:A retrospective cross-sectional clinical study. A total of 187 eyes in 187 patients diagnosed with monocular idiopathic ERM (IERM group) in Department of Ophthalmology of Zhejiang Provincial People's Hospital and the Affiliated Eye Hospital of Wenzhou Medical University at Hangzhou from November 2018 to January 2023 were included in the study. The contralateral healthy eyes were included as the control group. All patients underwent best corrected visual acuity (BCVA), fundus photography, spectral-domain OCT, OCT angiography (OCTA) and axial length (AL) measurement. BCVA examination was performed using the standard logarithmic visual acuity chart, which was converted to the logarithm of the minimum angle of resolution (logMAR) visual acuity. The foveal avascular zone (FAZ) area was measured by OCTA. The central macular thickness (CMT) was measured by spectral domain OCTaccording to the grading criteria of ectopic inner foveal layer (EIFL) was divided into stages 1 to 4 with 42, 45, 62, and 38 eyes, and the IERM group was subdivided into stage 1, stage 2, stage 3, and stage 4 groups accordingly. Image J was used to measure the retinal artery angle and the 1/2 retinal artery angle on fundus images. Multiple linear regression analysis was used to analyze the correlation between BCVA and artery angle, 1/2 artery Angle, CMT, FAZ area and AL.Results:Compared with the control group, eyes in IERM group had worse BCVA ( t=9.727), thicker CMT ( t=12.452), smaller FAZ area ( t=-14.329), smaller artery angle ( t=-9.165) and smaller 1/2 artery angle ( t=-9.549). The differences were statistically significant ( P<0.001). With the increase of IERM stage, the artery angle and 1/2 artery angle decreased significantly ( F=21.763, 12.515; P<0.001). There was no significant difference in artery angle and 1/2 artery angle between stage 1 group and stage 2 group, and 1/2 arterial angle between stage 2 group and stage 3 group ( P>0.05). There were significant differences in artery angle and 1/2 artery angle between the other groups ( P<0.05). There were significant differences in CMT and logMAR BCVA among different classification subgroups in IERM groups ( P<0.05). There was no significant difference in FAZ area between grade 3 group and grade 4 group ( P>0.05). There were significant differences in FAZ area between the other groups ( P<0.05). Correlation analysis showed that decreased artery angle ( P=0.013) and increased CMT ( P<0.001) were associated with decreased BCVA. Conclusions:Compared with healthy eyes, the artery angle decreases significantly with the increase of ERM stage. Decreased retinal artery angle is associated with decreased visual acuity in IERM eyes.

Objective To establish a risk prediction model for postoperative venous thromboembolism(VTE)in patients with gynecological tumors,and to validate the predictive efficacy of the established model.Methods A total of 420 patients with gynecological tumors who underwent surgical treatment at the Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine from September 2021 to November 2023 were selected as the research subjects.The 420 patients were divided into modeling group(n=280)and validation group(n=140)according to a ratio of 2∶1.The patients in the modeling group were divided into VTE group(n=42)and non-VTE group(n=238)based on whether they developed VTE after surgery.Univariate and multivariate logistic regression analyses were made to identify the factors related to the occurrence of VTE in patients,and a nomogram model for VTE risk prediction was constructed.Calibration curve,receiver operating characteristic(ROC)curve,and decision curve were used for internal and external validation to evaluate the predictive performance of the nomogram model.Results The univariate analysis results showed that age,body mass index,smoking,previous history of VTE,Caprini score,clinical stage,operation time,and postoperative bed rest time were associated with the occurrence of VTE in patients after surgery(P＜0.05).The multivariate logistic regression analysis results showed that high body mass index,previous history of VTE,Caprini score of 3-4 points and ≥5 points,clinical stage Ⅳ,operation time ≥ 2 hours,and postoperative bed rest time ≥3 days were independent risk factors for VTE in patients with gynecological tumors after surgery(P＜0.05).The calibration curve of the nomogram risk prediction model constructed based on independent risk factors of VTE showed good consistency between the predicted incidence and the actual incidenceof VTE.The ROC curve showed that the area under the curve(AUC)of ROC of the constructed nomogram prediction model was 0.839(95％confidence interval:0.770-0.909),indicating good discrimination.The validation of the model based on the validation set data showed that the AUC of the constructed model for predicting VTE in gynecological tumor patients after surgery was 0.857(95％confidence interval:0.777-0.938),indicating good discrimination.The decision curve showed that the constructed prediction model had good clinical net benefit when the threshold was between 0.18 and 0.80.Conclusion The factors that contribute to the occurrence of VTE in patients with gynecological tumors after surgery include high body mass index,previous history of VTE,Caprini score of 3-4 points and ≥5 points,clinical stage Ⅳ,operation time of ≥2 hours,and postoperative bed rest time of ≥3 days.The nomogram model constructed based on the above risk factors has good predictive performance and clinical applicability.