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

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

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*

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 explore the role of LncRNA NKILA/NF-κB signal pathway in the injury of keratinocytes in oral lichen planus(OLP).Methods:Immortalized human epidermal cells(HaCaTs)were induced by bacterial lipopolysaccharide(LPS)to establish an in vitro cell model of OLP.HaCaTs stably overexpressing NKILA were constructed by lentivirus method.HaCaTs were divided into 4 groups:Control group,Control+LPS group,empty vector infected with lentivirus(NC)+LPS group,overexpressed NKILA(OE)+LPS group.Cell proliferation,apoptosis,total superoxide dismutase(SOD)activity,lipid malondialdehyde oxide(MDA),reactive oxygen species(ROS),expression of related inflammatory factors,p65(nuclear,mass)and NF-κB signaling pathway related protein expression and p65 expression and localization were respectively detected.Results:Compared with Control group,the expression of NKILA,cell proliferation activity and SOD enzyme activity in Control+LPS group were significantly de-creased,while the apoptosis rate,MDA,ROS,IL-6,IL-1β,TNF-α and p65(nuclear and plasma)expression levels were signifi-cantly up-regulated(P＜0.05).Compared with Control+LPS group,the cell proliferation activity and SOD activity were increased in OE+LPS group,and the expression levels of cell apoptosis,MDA,ROS,IL-6,IL-1β,TNF-α and p65(nuclear and plasma)were significantly decreased(P＜0.05),and the localization of p65 protein in the nucleus was significantly decreased in OE+LPS group.Conclusion:LncRNA NKILA may reduce the damage of keratinocytes in oral lichen planus by inhibiting NF-κB signal pathway.

Objective:To conduct a scoping review of the role responsibilities and competencies of oncology nurse specialist in the management of cutaneous immune-related adverse events (cirAEs), with a view to providing scientific guidance and reference for nursing practice in the field of oncology immunotherapy.Methods:Using the scoping review methodology as the framework, the relevant literatures on oncology nurse specialist in the management of cirAEs in databases including PubMed, Web of Science, CINAHL, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, and China Biology Medicine from their inception to September 20, 2024 were systematically searched. Two researchers independently screened the included literature, extracted information, and conducted a summary analysis.Results:A total of 24 articles were included. Based on the summary and categorization of the literature, six categories were identified, including dynamic monitoring and assessment, classification and intervention of cirAEs, precise symptom management, multidisciplinary management, continuity of care, and specialized training, along with 18 related responsibility items.Conclusions:Oncology nurse specialist plays a significant role in the management of cirAEs. In the future, it should draw on the training models and curricula of advanced practice oncology nurses from abroad to optimize oncology nurse specialist training and nursing practices, thereby enhancing the professionalism of nursing services and the quality of patient care.

Home rehabilitation is the main rehabilitation model for elderly patients with hip fractures in China, and the application of digital health technology shows great potential in improving the quality of home rehabilitation for this population. This paper describes the concept of digital health technology, the current application status of different types of digital health technology in home rehabilitation for elderly patients with hip fractures, and discusses existing issues and future prospects, aiming to provide a reference for digital home rehabilitation nursing for elderly hip fracture patients.

Nanomaterials have been used in a variety of industries recently,involving foods,chemi-cals and biomedicine.There are multiple routes through which humans are exposed to nanomaterials,and their toxic effects deserve more attention.In vivo studies have confirmed that nanomaterials expo-sure can lead to toxicity in such target organs as the heart,liver,kidney,skin and nerve.The toxicity mechanism is related to changes in organelles such as the endoplasmic reticulum,lysosomes and mito-chondria.Increasing studies suggest that mitochondria are critical targets for the toxicity of nanomaterials.Mitochondrial biogenesis serves as an important mechanism for maintaining mitochondrial homeostasis,which plays a vital role in the process of nanomaterials-induced cellular toxicity.This article summarizes the current research on the effects of nanomaterials on mitochondrial biogenesis,and elaborates the mechanism through which nanomaterials disrupt mitochondrial biogenesis by triggering oxidative stress,upsetting the homeostasis of calcium ion and disturbing toxicity pathways.This article is expected to provide a reference for toxicity testing and risk assessment of nanomaterials.

Objective To investigate the mechanism by which fatty acid-binding protein 4(Fabp4)regulates neuroinflamma-tion after traumatic brain injury(TBI).Methods Adult wild-type C57 male mice were randomly divided into sham group and TBI group,with 6 mice in each group.Fabp4 knockout(Fabp4-/-)male mice were randomly divided into sham group and TBI group,with 6 mice in each group.Western blot was used to detect the expression levels of Fabp4,IL-1β,TNF-α,NLRP3,Caspase-1,and ASC proteins in brain tissue from each group.Brain water content was assessed using the wet-to-dry weight method,and neuronal damage was evaluated by Nissl staining.Immunofluorescence double staining was performed to detect the expression of microglial M1 polarization markers(CD86 and iNOS),M2 polarization marker(CD206),and astrocytic polarization marker(C3).Enzyme-linked immunosorbent assay(ELISA)was used to measure the levels of pro-inflammatory factors IL-1βand TNF-α in the culture supernatant of BV2 cells.MitoSOX red fluorescence staining was used to assess mitochondrial ROS levels in BV2 cells,and ELISA was employed to determine the levels of malondialdehyde(MDA)and 8-hydroxy-2'-deox-yguanosine(8-OHdG)in brain tissue after TBI.Immunofluorescence was performed to detect NLRP3 protein expression in BV2 cells.Results In wild-type mice,the expression of Fabp4 protein in the injured brain region was significantly increased at 12 hours post-TBI compared to the sham group(P＜0.01)and peaked at 3 days post-injury(P＜0.01).Compared to the wild-type TBI group,protein expression levels of IL-1β and TNF-α were reduced(P＜0.01),and brain water content was decreased(P＜0.05)in Fabp4-/-mice from TBI group.Nissl staining revealed that the volume of brain damage following TBI was reduced af-ter Fabp4 deletion(P＜0.05).Immunofluorescence experiments showed that M1 polarization of microglia was inhibited after Fabp4 deletion(P＜0.01),and M2 polarization was promoted(P＜0.01).Fabp4 deletion had no significant effect on astrocytic polarization.BV2 cell experiments demonstrated that the levels of IL-1β and TNF-α in the culture supernatant were increased(P＜0.01)after Fabp4 overexpression,and mitochondrial ROS production was elevated(P＜0.01).After LPS stimulation,Fabp4 protein expression in BV2 cells was increased(P＜0.01),the levels of IL-1β and TNF-α(P＜0.05)as well as mitochondrial ROS(P＜0.01)were reduced after BMS309403 intervention.In the mouse model,the levels of MDA and 8-OHdG in the brain tissue of Fabp4-/-TBI mice were significantly lower than those of wild-type TBI mice(P＜0.01).The levels of NLRP3,ASC,and Caspase-1 proteins in BV2 cells were increased after Fabp4 overexpression(P＜0.01),while ROS scavenger treatment reversed this effect(P＜0.01,P＜0.05,P＜0.01).In the mouse model,the levels of NLRP3,ASC,and Caspase-1 proteins in Fabp4-/-TBI mice were significantly lower than those in wild-type TBI mice(P＜0.01,P＜0.05,P＜0.01).Conclusion Fabp4 pro-motes microglia-induced neuroinflammation after TBI by regulating mitochondrial ROS production and NLRP3 inflammasome formation.These findings suggest that Fabp4 may serve as a potential therapeutic target for TBI.