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

OBJECTIVES: Existing evidence suggests that miscarriage and stillbirth are associated with an increased risk of stroke in women. However, the impact of these events on stroke mortality remains unclear. This study aimed to elucidate the potential association between miscarriage and stillbirth and stroke mortality in women. METHODS: We employed a competing risk model using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to assess the relationship between miscarriage/stillbirth and stroke death. Death from other causes was considered as a competing risk, and we conducted a subgroup analysis to explore the potential impact. RESULTS: Our study included 68,629 women for miscarriage and 65,343 women for stillbirth. No significant association was observed between miscarriage and stroke mortality (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.84 to 1.10; p=0.58). While a single stillbirth did not show a significant association (HR, 0.81; 95% CI, 0.57 to 1.15; p=0.23), recurrent stillbirth (≥2) was associated with a significantly increased risk of stroke mortality compared to women with no stillbirths (HR, 2.24; 95% CI, 1.45 to 3.46; p<0.001). CONCLUSIONS Our findings suggest that recurrent stillbirth, but not single events, is associated with an elevated risk of stroke mortality in women. Further research is warranted to clarify the underlying mechanisms and potential long-term health implications of recurrent pregnancy loss.

Objective:To develop a candidate reference method for cortisol in human serum by isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC/MS/MS).Methods:An isotope-labeled internal standard was added to samples, followed by alkalizing with sodium carbonate solution and liquid-liquid extraction with n-hexane/ethyl acetate. Isoelution with a methanol aqueous solution was employed for liquid chromatographic separation, while ESI in the positive ion and multiple reaction monitoring mode were used for mass spectrometry. The volume of sample, standard, and internal standard solutions were all controlled by weighing, and the results were calculated by bracketing method. The accuracy, precision, specificity, linearity, LOD and LOQ of this method were evaluated referring to the CLSI C62-A and C50-A guidelines and the domestic expert consensus documents.Results:The method demonstrated excellent accuracy and precision with the bias of ERM-DA192, ERM-DA193 and RELA 2021-2023 all being less than 2%. The recovery of added cortisol ranged from 98.2% to 101.1%. Both intra- and inter-assay imprecisions was <2%. The method was free from interference by structural analogue and showed a good linearity in the range of 25-1 600 nmol/L. The LOD and LOQ were 0.5 nmol/L and 1.0 nmol/L, respectively. A cortisol assay kit (chemiluminescence immunoassay) traced to this candidate reference method was used to determine 46 clinical serum samples concurrently, and the two methods exhibited good correlation.Conclusions:A candidate reference method for the determination of cortisol in serum was established, demonstrating high sensitivity, good repeatability and accuracy. This method can serve as a reference for the measurement traceability and accuracy evaluation of routine methods.

OBJECTIVES: Existing evidence suggests that miscarriage and stillbirth are associated with an increased risk of stroke in women. However, the impact of these events on stroke mortality remains unclear. This study aimed to elucidate the potential association between miscarriage and stillbirth and stroke mortality in women. METHODS: We employed a competing risk model using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to assess the relationship between miscarriage/stillbirth and stroke death. Death from other causes was considered as a competing risk, and we conducted a subgroup analysis to explore the potential impact. RESULTS: Our study included 68,629 women for miscarriage and 65,343 women for stillbirth. No significant association was observed between miscarriage and stroke mortality (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.84 to 1.10; p=0.58). While a single stillbirth did not show a significant association (HR, 0.81; 95% CI, 0.57 to 1.15; p=0.23), recurrent stillbirth (≥2) was associated with a significantly increased risk of stroke mortality compared to women with no stillbirths (HR, 2.24; 95% CI, 1.45 to 3.46; p<0.001). CONCLUSIONS Our findings suggest that recurrent stillbirth, but not single events, is associated with an elevated risk of stroke mortality in women. Further research is warranted to clarify the underlying mechanisms and potential long-term health implications of recurrent pregnancy loss.

Objective:To analyze the proportion of patients with acute primary angle-closure glaucoma (PACG) after the outbreak of coronavirus disease 2019 (COVID-19) in patients undergoing glaucoma surgery and the factors influencing morbidity.Methods:A cross-sectional study was performed.The cluster sampling method was used to collect 141 glaucoma patients hospitalized for glaucoma surgery after the outbreak of COVID-19 in Xuzhou First People's Hospital from December 16, 2022, to January 16, 2023, and 231 glaucoma patients hospitalized for surgery in the same 1-month period from 2019 to 2020, 2020 to 2021, 2021 to 2022 through the hospital information system.Ninety-two eyes of 92 patients with acute PACG after the outbreak were selected as a study group, and 21 eyes of 21 patients with acute PACG hospitalized during the same 1-month period from 2021 to 2022 were selected as a control group.The proportion of patients with different types of glaucoma during the observation period was analyzed.The proportion of patients with acute PACG and the clinical characteristics of acute PACG were analyzed, including age, sex, visual acuity, intraocular pressure (IOP), and anterior chamber angle status.Epidemiological data such as the use of anti-cold medications, and changes in living habits and moods (including daily water intake and anxiety) of patients after COVID-19 infection were obtained by telephone follow-up.Anxiety levels of patients in the study group were assessed using the Hospital Depression and Anxiety Scale (HADS).The triggering factors of acute PACG attack after the COVID-19 outbreak were analyzed.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Xuzhou First People's Hospital (No.xyyll[2023]114).Written informed consent was obtained from each subject.Results:The proportion of acute PACG patients in Xuzhou First People's Hospital within one month after the outbreak in 2022 to 2023 increased significantly compared with the same period in 2021 to 2022, 2020 to 2021 and 2019 to 2020, and the differences were statistically significant ( χ2=31.066, 33.331, 20.804; all at P<0.001).There was no statistical significance in the distribution of the number of eyes with different grades of visual acuity, IOP, the number of eyes with IOP ≥30 mmHg (1 mmHg=0.133 kPa), and the distribution of the number of eyes with different anterior chamber angles between the two groups (all at P>0.05).Patients in the control group had no history of COVID-19 infection or use of cold medicines at disease onset.During disease onset, all 92 (100%) patients in the study group had positive COVID-19 nucleic acid test results, of which 57 (61.96%) patients had a history of oral anti-cold medication use.During the same period, 49 (100%) hospitalized patients with other types of glaucoma had positive COVID-19 nucleic acid test results, of which 20 (40.82%) patients had a history of oral cold medication.There was a statistically significant difference in the proportion of patients taking oral cold drugs between acute PACG and other types of glaucoma in the study group ( χ2=5.764, P=0.016).During the outbreak of COVID-19, the study group reported that the daily water intake had increased to varying degrees than before.In the study group, 76 patients had anxiety, accounting for 82.6%.Multiple linear regression analysis showed that IOP=19.052+ 0.009×daily water intake+ 0.858×HADS score ( R2=0.780), and the standardized coefficients of daily water intake and HADS score were 0.542 and 0.452, respectively.Daily water intake had a greater effect on IOP than HADS score. Conclusions:The proportion of acute PACG patients among hospitalized surgical glaucoma patients increased significantly after the COVID-19 outbreak, which is related to risk factors such as oral anti-cold medications containing vasoconstrictors or antihistamines, increased daily water intake, anxiety and other lifestyle, and mood changes.

OBJECTIVES: Existing evidence suggests that miscarriage and stillbirth are associated with an increased risk of stroke in women. However, the impact of these events on stroke mortality remains unclear. This study aimed to elucidate the potential association between miscarriage and stillbirth and stroke mortality in women. METHODS: We employed a competing risk model using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to assess the relationship between miscarriage/stillbirth and stroke death. Death from other causes was considered as a competing risk, and we conducted a subgroup analysis to explore the potential impact. RESULTS: Our study included 68,629 women for miscarriage and 65,343 women for stillbirth. No significant association was observed between miscarriage and stroke mortality (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.84 to 1.10; p=0.58). While a single stillbirth did not show a significant association (HR, 0.81; 95% CI, 0.57 to 1.15; p=0.23), recurrent stillbirth (≥2) was associated with a significantly increased risk of stroke mortality compared to women with no stillbirths (HR, 2.24; 95% CI, 1.45 to 3.46; p<0.001). CONCLUSIONS Our findings suggest that recurrent stillbirth, but not single events, is associated with an elevated risk of stroke mortality in women. Further research is warranted to clarify the underlying mechanisms and potential long-term health implications of recurrent pregnancy loss.