Objective·To explore the value of combined diaphragm and intercostal muscle ultrasound assessment compared with conventional diaphragm ultrasound in predicting the weaning outcome in mechanically ventilated patients with sepsis.Methods·Mechanically ventilated patients with sepsis,consecutively admitted to the Department of Critical Care Medicine of Affiliated Hospital of Nantong University from October 2022 to December 2023,were selected.During the peri-weaning period,after the patient's sepsis condition improved and the patient passed the spontaneous breathing trial(SBT),ultrasound evaluation of respiratory muscles was performed by ultrasound qualified personnel with ultrasound qualification and experience in bedside ultrasound examination.Diaphragm excursion(DE),thickening fraction of diaphragm(TFD),and thickening fraction of intercostal muscle(TFic)were measured,respectively.The patients were divided into a successful weaning group(n=114)and a failed weaning group(n=24)according to the weaning results.Receiver operating characteristic(ROC)curves were used to analyze the value of diaphragm ultrasound and intercostal muscle ultrasound,alone and in combination,in predicting ventilator weaning outcome.Results·TFic and TFic/TFD were significantly higher in the failed weaning group during SBT than in the successful weaning group(all P<0.05).The areas under the ROC curve(AUROC)of DE,TFD,and TFic to predict weaning failure in mechanically ventilated patients with sepsis during the period of SBT were 0.689(0.591?0.776),0.657(0.557?0.747),and 0.769(0.676?0.846),respectively,whereas the combined indexes TFic/TFD and TFic&TFD_mix had AUROCs of 0.867(0.786?0.925)and 0.860(0.778?0.920),respectively.TFic/TFD with a cutoff value of>0.95 had a sensitivity of 86.7%and a specificity of 75.3%in predicting weaning failure,and TFic&TFD_mix with a cutoff value of>0.13 had a sensitivity of 86.6%and a specificity of 80.9%in predicting weaning failure.Moreover,the intercostal muscle ultrasonography method had an intra-observer intraclass correlation coefficient(ICC)of 0.890 and an extra-observer ICC of 0.876 for measurement reliability,which were both rated as good(P<0.001).Conclusion·Combined diaphragm and intercostal muscle ultrasonography provides a more comprehensive picture of the patient's overall respiratory muscles,and has a higher guiding value in predicting the weaning outcomes in mechanically ventilated patients with sepsis than diaphragm ultrasound alone.

Objective The objective of this study was to investigate the effects of maytansine on proliferation,migration,in-vasion,apoptosis and autophagy of human thyroid cancer C643 cells.Methods C643 cells were treated with different concentrations(0.049,0.195,0.781,3.125,12.5,50 and 200 μmol/L)of maytansine,the effect of maytansine on the proliferation of C643 cells was detected by the sulforhodamine B(SRB)method,and the concentration of subsequent experiments was determined.C643 cells in the logarithmic growth stage period were divided into the control group,low-dose group,mid-dose group and high-dose group.The effects of maytansine on migration and invasion abilities of C643 cells were detected by cell scratch and Transwell chamber assay;The levels of reactive oxygen species(ROS)were detected by 2′,7′-dichlorofluorescein diacetate(DCFH-DA)fluorescent probe experi-ment;The apoptosis rate of C643 cells was detected by flow cytometry;The expression of proteins related to apoptosis or autophagy was detected by Western blot.Results Maytansine at concentrations of 0.049,0.195,0.781,3.125,12.5,50 and 200 μmol/L could in-hibit the proliferation of C643 cells(P<0.05),and exhibited a significant concentration time dependence.The half maximal inhibitory concentrations(IC50)at 24,48 and 72 h were 54.255,5.193 and 0.647 μmol/L,respectively;The cell scratch and Transwell chamber results showed that maytansine at concentrations of 0.1,1 and 10 μmol/L could reduce the migration and invasion abilities of C643 cells(P<0.05 and P<0.01).The fluorescence probe results showed that maytansine at concentrations of 0.1,1 and 10μmol/L could increase the intracellular ROS levels of C643 cells(P<0.01).The flow cytometry results showed that maytansine at concentrations of 0.1,1 and 10 μmol/L could concentration dependently increase the apoptosis rate of C643 cells(P<0.01).The Western blot results showed that with the increase of maytansine concentrations,the expression of Bax protein related to apoptosis in C643 cells increased(P<0.05),the expression of Bcl-2 decreased(P<0.05),the expression of LC3Ⅱ/Ⅰ(P<0.05)and Beclin-1(P<0.01)increased,while the expression of p62 decreased(P<0.001).Conclusion Maytansine can inhibit the proliferation,migration and invasion of human thyroid cancer C643 cells,and induce the synergistic effect on apoptosis and autophagy by increasing intracellular ROS levels.

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

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 In this study,we investigated the correlation between the scores for different Liebowitz Social Anxiety Scale(LSAS)subscale models and the metabolic activity in specific regions of the brain using 18F-fluorodeoxyglucose(FDG)positron emission tomography/computed tomography(PET/CT)(18F-FDG PET),thereby improving the understanding of the neurobiological characteristics of social anxiety.Methods A total of 39 cognitively normal participants(29 men and 10 women,aged 30-63 years)were enrolled.All participants underwent LSAS assessment and brain 18F-FDG PET scanning.Correlations between metabolic activities in various brain regions and scores from the different LSAS subscales were analyzed accordingly.Results LSAS subscale scores were significantly correlated with metabolic activity in specific brain regions.In the Safren model,the score for the observation by others subscale was positively correlated with the left fusiform gyrus(P<0.001,false discovery rate[FDR]-corrected)and the left caudate tail(P<0.001,FDR-corrected),suggesting a close association between mood states related to observation by others and the metabolic activity in these regions.In the Baker model,the score for the eating and drinking subscale was negatively correlated with the right precuneus(P<0.001,FDR-corrected),while the score for the assertiveness subscale was positively correlated with the left caudate nucleus(P<0.001,FDR-corrected).These findings revealed the complex associative patterns between various mood and behavioral dimensions and metabolic activities in specific brain regions.Conclusion Social anxiety symptoms are closely associated with metabolic changes in specific brain regions,including the left insula,left caudate tail,and right precuneus.Moreover,different social situations activate distinct brain regions.Compared with individuals with social anxiety disorder,normal individuals exhibit involvement of fewer brain regions when experiencing social anxiety.These findings provide new experimental evidence for understanding the neural mechanisms underlying social anxiety.

Objective To evaluate the value of imaging quantification parameters in artificial intelligence (AI) assisted diagnosis systems in clinical decision-making for lung nodules≤2 cm and the diagnostic efficacy of AI. Methods Lung nodule patients admitted to Affiliated Zhongshan Hospital of Dalian University from 2020 to 2023 were included. Imaging parameters of lung nodules were extracted using AI assisted diagnosis systems. Multifactor analysis was used to screen predictors for distinguishing benign and malignant nodules and high-risk predictors for recurrent invasive adenocarcinoma, and a diagnostic model was established and its performance evaluated. The diagnostic efficacy of the AI system was judged according to pathological results. Results A total of 594 patients with lung nodules were included, including 202 males and 392 females, with an average age of (58.75±11.55) years. Volume, average CT value, and 3D maximum diameter of non-solid nodules were independent predictors of malignant nodules, with thresholds of 287.4 mm3, −491 HU, and 12.0 mm, respectively. The area under the curve (AUC) for diagnostic efficacy was ranked from high to low as combined model (0.802), volume (0.783), average CT value (0.749), and 3D maximum diameter (0.714). The average CT value and 3D long diameter of solid nodules were independent predictors of malignant nodules, with thresholds of −81 HU and 17.5 mm, respectively, and AUC values of 0.874 and 0.686, respectively, with the combined prediction AUC of 0.957. The mass of cystic nodules was an independent predictor of malignancy when the mass>180.7 mg. Independent predictors of high recurrence risk of invasive adenocarcinoma in non-solid nodules were consolidation-tumor ratio (CTR), average CT value, 3D long diameter, and volume, with thresholds of 0.14, −386 HU, 15.6 mm, and 1018.9 mm3, respectively, and diagnostic efficacy was ranked from high to low as combined model (0.788), 3D long diameter (0.735), volume (0.725), average CT value (0.720), and CTR (0.697). The accuracy of AI in predicting benign and malignant target nodules was 87.4%, with positive predictive value of 96.6% and negative predictive value of 58.9%. Conclusion In clinical decision-making for lung nodules ≤2 cm, AI assisted diagnosis systems have high application value.

γ-Aminobutyric acid(GABA),a pivotal inhibitory neurotransmitter in the central nervous system,plays an essential role in maintaining normal ocular physiological functions.GABA and its receptors are widely distributed through-out the retina,optic nerve,and visual pathways.Research indicates that GABA dysregulation is implicated in the pathogen-esis and progression of certain ophthalmic disorders.This article provides a comprehensive exploration of the relationship between GABA and ophthalmic diseases,including myopia,amblyopia,glaucoma,and dry eye syndrome.Moreover,the potential mechanisms and recent research advances are discussed.The findings may offer novel options and chances for the diagnosis and treatment of ophthalmic diseases.

γ-Aminobutyric acid(GABA),a pivotal inhibitory neurotransmitter in the central nervous system,plays an essential role in maintaining normal ocular physiological functions.GABA and its receptors are widely distributed through-out the retina,optic nerve,and visual pathways.Research indicates that GABA dysregulation is implicated in the pathogen-esis and progression of certain ophthalmic disorders.This article provides a comprehensive exploration of the relationship between GABA and ophthalmic diseases,including myopia,amblyopia,glaucoma,and dry eye syndrome.Moreover,the potential mechanisms and recent research advances are discussed.The findings may offer novel options and chances for the diagnosis and treatment of ophthalmic diseases.

Objective·To explore the value of combined diaphragm and intercostal muscle ultrasound assessment compared with conventional diaphragm ultrasound in predicting the weaning outcome in mechanically ventilated patients with sepsis.Methods·Mechanically ventilated patients with sepsis,consecutively admitted to the Department of Critical Care Medicine of Affiliated Hospital of Nantong University from October 2022 to December 2023,were selected.During the peri-weaning period,after the patient's sepsis condition improved and the patient passed the spontaneous breathing trial(SBT),ultrasound evaluation of respiratory muscles was performed by ultrasound qualified personnel with ultrasound qualification and experience in bedside ultrasound examination.Diaphragm excursion(DE),thickening fraction of diaphragm(TFD),and thickening fraction of intercostal muscle(TFic)were measured,respectively.The patients were divided into a successful weaning group(n=114)and a failed weaning group(n=24)according to the weaning results.Receiver operating characteristic(ROC)curves were used to analyze the value of diaphragm ultrasound and intercostal muscle ultrasound,alone and in combination,in predicting ventilator weaning outcome.Results·TFic and TFic/TFD were significantly higher in the failed weaning group during SBT than in the successful weaning group(all P<0.05).The areas under the ROC curve(AUROC)of DE,TFD,and TFic to predict weaning failure in mechanically ventilated patients with sepsis during the period of SBT were 0.689(0.591?0.776),0.657(0.557?0.747),and 0.769(0.676?0.846),respectively,whereas the combined indexes TFic/TFD and TFic&TFD_mix had AUROCs of 0.867(0.786?0.925)and 0.860(0.778?0.920),respectively.TFic/TFD with a cutoff value of>0.95 had a sensitivity of 86.7%and a specificity of 75.3%in predicting weaning failure,and TFic&TFD_mix with a cutoff value of>0.13 had a sensitivity of 86.6%and a specificity of 80.9%in predicting weaning failure.Moreover,the intercostal muscle ultrasonography method had an intra-observer intraclass correlation coefficient(ICC)of 0.890 and an extra-observer ICC of 0.876 for measurement reliability,which were both rated as good(P<0.001).Conclusion·Combined diaphragm and intercostal muscle ultrasonography provides a more comprehensive picture of the patient's overall respiratory muscles,and has a higher guiding value in predicting the weaning outcomes in mechanically ventilated patients with sepsis than diaphragm ultrasound alone.

Objective The objective of this study was to investigate the effects of maytansine on proliferation,migration,in-vasion,apoptosis and autophagy of human thyroid cancer C643 cells.Methods C643 cells were treated with different concentrations(0.049,0.195,0.781,3.125,12.5,50 and 200 μmol/L)of maytansine,the effect of maytansine on the proliferation of C643 cells was detected by the sulforhodamine B(SRB)method,and the concentration of subsequent experiments was determined.C643 cells in the logarithmic growth stage period were divided into the control group,low-dose group,mid-dose group and high-dose group.The effects of maytansine on migration and invasion abilities of C643 cells were detected by cell scratch and Transwell chamber assay;The levels of reactive oxygen species(ROS)were detected by 2′,7′-dichlorofluorescein diacetate(DCFH-DA)fluorescent probe experi-ment;The apoptosis rate of C643 cells was detected by flow cytometry;The expression of proteins related to apoptosis or autophagy was detected by Western blot.Results Maytansine at concentrations of 0.049,0.195,0.781,3.125,12.5,50 and 200 μmol/L could in-hibit the proliferation of C643 cells(P<0.05),and exhibited a significant concentration time dependence.The half maximal inhibitory concentrations(IC50)at 24,48 and 72 h were 54.255,5.193 and 0.647 μmol/L,respectively;The cell scratch and Transwell chamber results showed that maytansine at concentrations of 0.1,1 and 10 μmol/L could reduce the migration and invasion abilities of C643 cells(P<0.05 and P<0.01).The fluorescence probe results showed that maytansine at concentrations of 0.1,1 and 10μmol/L could increase the intracellular ROS levels of C643 cells(P<0.01).The flow cytometry results showed that maytansine at concentrations of 0.1,1 and 10 μmol/L could concentration dependently increase the apoptosis rate of C643 cells(P<0.01).The Western blot results showed that with the increase of maytansine concentrations,the expression of Bax protein related to apoptosis in C643 cells increased(P<0.05),the expression of Bcl-2 decreased(P<0.05),the expression of LC3Ⅱ/Ⅰ(P<0.05)and Beclin-1(P<0.01)increased,while the expression of p62 decreased(P<0.001).Conclusion Maytansine can inhibit the proliferation,migration and invasion of human thyroid cancer C643 cells,and induce the synergistic effect on apoptosis and autophagy by increasing intracellular ROS levels.