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Abstract Background Alagille syndrome (ALGS) is a multisystem genetic disorder frequently characterized by hepatic manifestations. This study analyzed the clinical, pathological, and molecular genetic features of ALGS to improve the efficiency of clinical diagnosis. Methods We retrospectively analyzed the clinical manifestations, pathological examination findings, and genetic testing results of 17 children diagnosed with ALGS based on the revised criteria and hospitalized at our center from January 2012 to January 2022. Results The clinical manifestations are as follows: Cholestasis (16/17, 94%), characteristic facies (15/17, 88%), heart disease (12/16, 75%), butterfly vertebrae (12/17, 71%) and posterior embryotoxon (7/12, 58%). Among the 15 patients who underwent liver pathology examination, 13 (87%) were found to have varying degrees of bile duct paucity. Genetic testing was performed on 15 children, and pathogenic variants of the jagged canonical Notch ligand 1 (JAG1) gene were identified in 13 individuals, including 4 novel variants. No pathogenic variant in the notch homolog 2 (NOTCH2) gene were identified, and 2 children exhibited none of the aforementioned gene pathogenic variants. The median follow-up duration was 7 years. Of the remaining 15 patients (excluding 2 lost to follow-up), 11 remained stable, 4 deteriorated, and no patient died during the follow-up period. Conclusions Among children diagnosed with ALGS, cholestasis stands as the most common feature. To minimize the risk of misdiagnosis, genetic testing should be performed on children exhibiting cholestasis, followed by the application of the revised diagnostic criteria for ALGS. While pharmacological therapy has shown effectiveness for ALGS patients, liver transplantation may be considered in instances of severe pruritus.

Abstract Background ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. Results The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. Conclusion ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation. Graphical Abstract

Abstract Extracellular matrix (ECM) assembly/disassembly is a critical regulator for airway epithelial development and remodeling. Airway organoid is widely used in respiratory research, yet there is limited study to indicate the roles and mechanisms of ECM organization in epithelial growth and differentiation by using in vitro organoid system. Moreover, most of current Matrigel-based airway organoids are in basal-out orientation where accessing the apical surface is challenging. We present a human apical-out airway organoid using a biochemically defined hybrid hydrogel system. During human nasal epithelial progenitor cells (hNEPCs) differentiation, the gel gradually degrade, leading to the organoid apical surfaces facing outward. The expression and activity of ECM-degrading enzymes, matrix metalloproteinases (MMP7, MMP9, MMP10 and MMP13) increases during organoid differentiation, where inhibition of MMPs significantly suppresses the normal ciliation, resulting in increased goblet cell proportion. Moreover, a decrease of MMPs is found in goblet cell hyperplastic epithelium in inflammatory mucosa. This system reveals essential roles of epithelial-derived MMPs on epithelial cell fate determination, and provides an applicable platform enabling further study for ECM in regulating airway development in health and diseases.

Background: Antiretroviral medications have increased the lifespan of persons living with HIV (PLWH) thereby unmasking memory decline that may be attributed to chronological age, HIV symptomatology, HIV disease chronicity, and/or substance use (especially cannabis use which is common among PLWH). To date, few studies have attempted to disentangle these effects. In a sample of daily cannabis-using PLWH, we investigated whether hippocampal memory function, assessed via an object-location associative learning task, was associated with age, HIV chronicity and symptom severity, or substance use. Methods: 48 PLWH (12.9 ± 9.6 years since HIV diagnosis), who were 44 years old on average (range: 24–64 years; 58 % male) and reported daily cannabis use (recent use confirmed by urinalysis) completed the study. We assessed each participant's demographics, substance use, medical history, current HIV symptoms, and hippocampal memory function via a well-validated object-location associative learning task. Results: Multiple regression analyses found that living more years since HIV+ diagnosis predicted significantly worse associative learning total score (r=-0.40) and learning rate (r=-0.34) whereas chronological age, cannabis-use characteristics, and recent HIV symptom severity were not significantly related to hippocampal memory function. Conclusions: In daily cannabis-using PLWH, HIV chronicity was related to worse hippocampal memory function independent from cannabis use, age, and HIV symptomatology. Object-location associative learning performance could serve as an ‘early-warning’ metric of cognitive decline among PLWH. Future research should examine longitudinal changes in associative learning proficiency and evaluate interventions to prevent hippocampal memory decline among PLWH. ClinicalTrials.gov: NCT01536899.

Background Tumour characteristics and orthotopic liver transplantation (OLT) criteria are risks for recurrence of hepatocellular carcinoma (HCC). In Asia, most HCC is caused by chronic hepatitis B infection. Whether hepatitis B virus DNA (HBV DNA) is a risk factor for HCC recurrence after OLT is not clear.Patients and methods In this retrospective study, we classified patients into groups of detectable and undetectable HBV DNA, non-HCC recurrence, and recurrence and performed analyses on differed characteristics between groups and risk factors for HCC recurrence after OLT.Results Among patients who underwent OLT for HCC, 117 were secondary to CHB infection. CHB was not a risk, but advanced tumour characteristics were risk factor for HCC recurrence. In patients with CHB-HCC, 24 (20.5%) of 117 patients had HCC recurrence. Compared to patients with HBV DNA undetectable (n = 75), patients with detectable HBV DNA (n = 42) had higher AFP concentration (p 2000 IU/mL was an independent risk factor for HCC recurrence (OR = 8.35, 95% CI 1.40, 50.00, p = .020). HBV DNA detectable was not a risk for HCC-related death.Conclusion Individuals with preoperative undetectable HBV DNA had advanced tumour characteristics and a higher proportion of HCC recurrence. Antiviral treatment for HCC should be performed, and HBV DNA undetectable should be obtained before OLT. But for an urgent OLT, preoperative detectable HBV DNA may not affect long-term survival.KEY MESSAGESPatients with HBV DNA detectable had advanced tumour characteristics, a higher proportion of extended OLT criteria, and HCC-recurrence.HBV DNA >2000 IU/mL was a risk factor for HCC recurrence.HBV DNA detectable was not a risk for HCC related death; extended OLT criteria affected long-term survival.

Abstract Background Postoperative discomfort is one of the important manifestations of disease changes, but few studies have reported detailed description of postoperative discomfort in patients with aortic dissection after discharge. The aim of this study is to investigate the discomfort symptoms and to explore the possible influencing factors of discomfort symptoms. Method This cross-sectional study based on convenience sampling collected medical records from 999 patients hospitalized in Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of science and technology, Wuhan, Hubei, China from January 1, 2019 to December 31, 2019. Postoperative patients with first onset and confirmed aortic dissection were eligible for follow-up. Telephone follow-up was conducted from July 20, 2020 to August 20, 2020. Symptoms of discomfort were reported by patients or their immediate family members. Univariate and multivariable logistic regression analysis were performed to identify factors associated with symptoms of discomfort. Results A total of 675 patients were followed up, 185 patients (27.4%) were lost to follow-up, and the remaining 490 patients were divided into survival group (N = 428) and death group (N = 62) and were included in the study. There was no difference in gender and age among the three groups. 152 of 428 patients reported discomfort. The uncomfortable symptoms of postoperative patients were diverse, and mainly manifested as back and chest pain (32.24%, 49/152), chest tightness (15.79%, 24/152), dizzy (10.53%, 16/152) and weakness (10.53%, 16/152). Multivariable logistic regression analysis of postoperative discomfort showed length of discharge (OR 0.995; P 0.018; 95% CI 0.990–0.999) and positive history of drinking (OR 3.519; P 0.018; 95% CI 1.236–10.022) were significant among patients with Stanford A AD, and diagnosis was made in the first visiting hospital (OR 0.395; P 0.001; 95% CI 0.230–0.677) was a protective factor for patients. Conclusions The incidence of postoperative discomfort in patients with aortic dissection was high and the symptoms were diverse and not single. In order to reduce the possibility of postoperative discomfort, it is important to formulate effective public policies to limit the public to drink alcohol and timely diagnose aortic dissection. Long term follow-up is necessary for patients with aortic dissection to observe the recovery process of aortic dissection.

Our objective was to provide evidence for exercise-based cardiac rehabilitation (ECR) for patients with aortic dissection (AD), so as to better improve the prognosis of patients and improve the quality of life (QoL) after discharge. The database PubMed, Embase, MEDLINE, Web of Science, Cochrane Library, WanFang Chinese database, ZhiWang Chinese database, Chinese Clinical Trials Registry from establishment of each database until February 2021 were included. A total of 1684 records were found by searching the database and clinical trial registry, 178 duplicate records were deleted, and 11 records met the inclusion criteria according to the screening process. We can conclude that ECR for patients with AD can effectively reduce complications and shorten the course of the disease. In addition, it is very safe because there are no serious adverse events occurring. Further research should be developed from three aspects, including the development of systematic evaluation indicators and standardized clinical exercise rehabilitation pathway, more randomized controlled trials, and the development of individualized exercise program so as to help patients with AD better improve the prognosis and QoL.

ObjectiveTo explore the relations among perceived stress, fatigue, sleepiness, and the pathway of their effects on the ambulatory arterial stiffness index (AASI) among medical staff.MethodsThis cross-sectional study was conducted at a tertiary hospital in Wuhan, China. Perceived stress, fatigue, and sleepiness were measured using the perceived stress scale (PSS), Fatigue assessment scale (FAS), and Epworth Sleepiness Scale (ESS), respectively. AASI was obtained from 24-h ambulatory blood pressure monitoring. Path analysis was used to clarify the relations among the PSS, FAS, and ESS scores, and their relations to AASI values.ResultsA total of 153 participants were included herein. The PSS and FAS correlated with the ESS (r = 0.424, p

Holarrhena pubescens Wall. ex G. Don (H. pubescens), belonging to the Apocynaceae family, is distributed in deciduous forests of the tropical Himalayas. H. pubescens is an important traditional medicinal plant, especially its seeds and barks. Therefore, we assessed the antioxidant capacity of H. pubescens extracts in Lipopolysaccharide (LPS)-induced dendritic cells (DCs) for sepsis treatment. Our results indicated that H. pubescens extracts with different doses (25 μg/mL, 50 μg/mL, 100 μg/mL) reduced the reactive oxygen species (ROS) level, and weakened the nitric oxide synthases (NOS) activity and nitric oxide (NO) level in LPS (100 ng/mL)-irritated DCs. In addition, H. pubescens extracts decreased the oxidized glutathione (GSSG) production but increased the reduced glutathione (GSH) production, thereby preserving the cellular reductive status owing to the raised GSH/GSSG ratio. Furthermore, H. pubescens extracts strengthened the antioxidant enzymes activity in LPS-induced DCs, such as glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Finally, we found that H. pubescens extracts significantly improved the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) and the heme oxygenase 1 (HO–1) in LPS-irritated DCs. These results indicated that H. pubescens extracts suppressed the LPS-irritated oxidative stress in DCs via Nrf2/HO–1 signaling pathway, providing a potential strategy for sepsis therapy.

Melatonin, an indoleamine synthesized in the pineal gland of mammals, is a natural bioactive compound with powerful antioxidant and anti-inflammatory properties. Here, we evaluated whether melatonin has the capacity to moderate the oxidative stress of dendritic cells (DCs) for inflammatory control in an acute lung injury (ALI) model. Our findings showed that melatonin remarkably inhibited total nitric oxide synthase (T-NOS) activity, nitric oxide (NO) production, intracellular reactive oxygen species (ROS) levels, and lipid peroxidation (MDA detection) levels in both an LPS-induced murine ALI model and LPS-induced DCs. Meanwhile, the reduced glutathione (GSH) level and the GSH/GSSG ratio were recovered. In addition, antioxidant enzymes, such as glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD), were increased in these processes. Moreover, melatonin also inhibited the LPS-induced secretions of IL-1β, IL-6, and TGF-β in vivo and in vitro. Finally, we found that the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) axis was required in the inhibition of LPS-induced oxidative stress in DCs by melatonin. Altogether, these data indicate that melatonin strongly suppresses the LPS-induced oxidative stress in DCs, which is a promising DC-targeted strategy via inflammatory control for ALI treatment.

Purpose: Our study aimed to develop a questionnaire to assess the reliability and validity of exercise attitudes and behavior intentions among survivors of an aortic dissection (AD). Methods: There were two phases to the study between April 2021 and April 2022. Phase I involved the development of an initial version of the Exercise Attitudes and Behavior Intentions Questionnaire (EABIQ) through literature reviews, qualitative interviews, Delphi expert consultations and a pre-experimental study. During Phase II, the reliability and validity of the questionnaire was assessed in 160 survivors with AD. Results: A 62-item EABIQ for AD survivors was developed. Eleven common components with eigenvalues larger than 1 were identified by exploratory factor analysis. The scale’s variance explained cumulatively rate was 75.216%. The content validity index at the item level for the EABIQ varied from 0.813 to 1.000 and the S-CVI/Ave was 0.934. The correlation coefficients between each scale dimension and the overall scale ranged from 0.405 to 0.785, with all p-values less than 0.05. Cronbach’s alpha for the whole scale was 0.929, with Cronbach’s alpha for each domain ranging from 0.835 to 0.965. The overall scale split-half reliability coefficient was 0.960, with each domain’s split-half reliability coefficient ranging from 0.844 to 0.962. Conclusions: The AD exercise attitudes and behavior intentions questionnaire has high reliability and validity and is generally consistent with the hypothetical theoretical framework. It can be used as a judgment tool to measure the exercise behavior for AD patients.

Currently, brucellosis seriously threatens the health of humans and animals and hinders the development of animal husbandry. However, the diagnostic methods for brucellosis have some disadvantages, such as low sensitivity, long detection time, professional operation, and high cost. This study aims to establish a convenient, fast, effective, and inexpensive detection method for brucellosis. Gold nanoparticles with β-cyclodextrin as a reducing agent were prepared and optimized, applied to rapid vertical flow technology (RVFT), and used to establish a kit for the detection of brucellosis. In this study, gold nanoparticles prepared from β-cyclodextrin were applied to RVFT for the first time, and on this basis, silver staining amplification technology was introduced, which further improved the sensitivity and reduced the detection limit of this method. Standard Brucella-Positive Serum (containing Brucella antibody at 4000 IU/mL) could be detected in this system even for a dilution factor of 1 × 10−3. The detection limit was 4 IU/mL. RVFT is simple to operate, has a short reaction time, and is 5–6 min visible to the naked eye, without any equipment.

In the present study, the biosynthesis of silver nanoparticles (AgNPs) and their antibacterial activity against gram-positive and gram-negative bacteria were investigated. Glycyrrhizin (GL) was used as a reducing agent and stabilizer to rapidly prepare the AgNPs. The distinctive absorption peak at 419 nm confirmed the formation of GL-reduced AgNPs. The TEM and particle size analysis shows that the prepared GL-reduced AgNPs were mostly circular with good dispersion and a relatively uniform particle size of 35 nm on average. Fourier transform infrared spectroscopy analysis was performed to identify the possible biomolecules in the capping and active stabilization of the GL-reduced AgNPs. The antibacterial activity of the GL-reduced AgNPs was analyzed with the Oxford cup diffusion method and filter paper diffusion method. The experimental results show that these properties endowed the GL-reduced AgNPs with high antibacterial activity against Escherichia coli and Staphylococcus aureus and lay a foundation for the use of colloidal silver in antibacterial applications. The GL-reduced AgNPs also had stronger antibacterial activity than sodium citrate-reduced AgNPs, which indicates the advantages of GL-reduced AgNPs compared with sodium citrate-reduced AgNPs in inducing bacteriostasis. The cytotoxicity of GL-reduced AgNPs on human kidney epithelial 293A (HEK293) cells was evaluated via the MTT assay. The results show that GL-reduced AgNPs had lower toxicity to HEK293 cells than sodium citrate-AgNPs, which indicates that the as-prepared GL-reduced AgNPs are environmentally friendly.

Background: Exercise can help patients with aortic dissection (AD) control blood pressure, prevent further progression of AD, promote mental health, improve the prognosis of cardiovascular disease, and improve their overall quality of life. However, it is not clear what the attitudes and behavioral intentions of AD survivors are towards exercise. Methods: This exploratory qualitative research was based on the Health Action Process Approach (HAPA) theory to explore the cognition, attitude, motivational factors, behavior intention, barriers and facilitators of exercise in patients with AD. Face-to-face and telephone semi-structured interviews were conducted in 24 AD patients from the Department of Cardio-Vascular Surgery of third-grade Class A hospitals in Wuhan, China from April 2021 to June 2021. The patient’s current stage of behavior was evaluated according to the Patient-Centered Assessment and Counseling for Exercise (PACE) questionnaire. Results: Among the 24 participants interviewed, 9 (37.5%) were in the pre-intention stage, 8 (33.3%) were in the intention stage, and 7 (29.2%) were in the action stage. The three groups were significantly different in terms of their history of previous cardiac surgery (Fisher’s exact test, p = 0.043) and in the type of interview conducted (Fisher’s exact test, p < 0.001). In-patients with a history of cardiac surgery were more likely to be in the pre-intention stage (post-hoc test, p < 0.05). Patients from different stages had different structures. AD patients in the pre-intention stage were more likely to express risk perception and negative results for exercise. The self-efficacy of this group was often low, and lacked exercise intention and clear action plans (post-hoc test, p < 0.05). Conclusions: More attention should be paid to in-patients with a history of cardiac surgery, including health advice on exercise after discharge and promotion of changes in their health behavior. Guidelines based on the available exercise data in AD patients should be established to provide recommendations for individualized exercise programs. This should provide a basis for promoting patient rehabilitation and improving postoperative quality of life.

Objective: To explore the relations among perceived stress, fatigue, sleepiness, and the pathway of their effects on the ambulatory arterial stiffness index (AASI) among medical staff. Methods: This cross-sectional study was conducted at a tertiary hospital in Wuhan, China. Perceived stress, fatigue, and sleepiness were measured using the perceived stress scale (PSS), Fatigue assessment scale (FAS), and Epworth Sleepiness Scale (ESS), respectively. AASI was obtained from 24-h ambulatory blood pressure monitoring. Path analysis was used to clarify the relations among the PSS, FAS, and ESS scores, and their relations to AASI values. Results: A total of 153 participants were included herein. The PSS and FAS correlated with the ESS (r = 0.424, p < 0.001), and the PSS correlated with the FAS (r = 0.614, p < 0.001). In addition, the ESS correlated with the AASI (r = 0.225, p = 0.005). According to the path analysis results, the PSS and FAS had no direct effect on the AASI, but did have an indirect effect on this index (β = 0.059, 95% confidence interval [CI] = 0.017–0.128, p = 0.005; β = 0.059, 95%CI = 0.016–0.135, p = 0.006, respectively) by influencing the ESS (β = 0.263, β = 0.262, p = 0.004). Conclusion: Sleepiness was a mediator of the effects of perceived stress and fatigue on AASI. [ABSTRACT FROM AUTHOR]

To prevent the transmission of brucellosis, rapid vertical flow technology (RVFT) was developed to detect brucellosis antibodies. To improve the sensitivity of the technique, lipopolysaccharides (LPS) were purified and used to detect brucellosis antibodies. To improve the sensitivity of serum antibody detection, a single multifunctional buffer was established in whole blood and other biological samples, and the advantages of the lateral flow immunoassay were retained. Flower-like gold nanoparticles were applied to RVFT for the first time. In this study, silver ions were catalyzed by flower-like gold nanoparticles into metal silver deposited on the surface of gold nanoparticles for the first time, which not only increased the particle size of gold nanoparticles, but also showed a more distinguishable black color on the test zone, further improving the sensitivity of RVFT. Standard Brucella-positive serum (containing Brucella antibody at 4000 IU mL-1) could be detected in this system even for a dilution factor of 2 x 10-3. The detection limit was 2 IU mL-1. RVFT can effectively avoid the false negative phenomenon in lateral flow immunoassay. RVFT is simple to operate, with a short reaction time, 2-3 minutes visible to the naked eye, without any equipment. Because it is very important to control the brucellosis epidemic, this approach has great application prospects in basic medical units and for veterinarians. [ABSTRACT FROM AUTHOR]

Patients with temporal lobe epilepsy have inexplicable fear attack as the aura. However, the underlying neural mechanisms of seizure-modulated fear are not clarified. Recent studies identified stathmin as one of the key controlling molecules in learning and innate fear. Stathmin binds to tubulin, inhibits microtubule assembly and promotes microtubule catastrophes. Therefore, stathmin is predicted to play a crucial role in the association of epilepsy seizures with fear conditioning. Firstly, a pilocarpine model of epilepsy in rats was established, and subsequently the fear condition training was performed. The epileptic rats with fear conditioning (epilepsy + fear) had a much longer freezing time compared to each single stimulus. The increased freezing levels revealed a significantly strengthened effect of the epileptic seizures on the learned fear of the tone-shock contextual. Subsequently, the stathmin expression was compared in the hippocampus, the amygdale, the insular cortex and the temporal lobe. The significant change of stathmin expression occurred in the insular and the hippocampus, but not in the amygdale. Stathmin expression and dendritic microtubule stability were compared between fear and epilepsy in rats. Epilepsy was found to strengthen the fear conditioning with increased expression of stathmin and a decrease in microtubule stability. Fear conditioning slightly increased the expression of stathmin, whereas epilepsy with fear conditioning increased it significantly in the hippocampus, insular cortex and hypothalamus. The phosphorylated stathmin slightly increased in the epilepsy with fear conditioning. The increased expression of stathmin was contrary to the decrease of the stathmin microtubule-associated protein (MAP2) and α-tubulin in the epileptic rats with fear conditioning in all three areas of the brain. The most significant change of the ratio of MAP2 and α-tubulin/stathmin occurred in the insular cortex and hippocampus. In conclusion, epilepsy can strengthen the fear conditioning with increased stathmin and decreased microtubule stability, particularly in the insular cortex and hippacampus. Therefore, the insular cortex may play a more important role between fear and epilepsy. [ABSTRACT FROM AUTHOR]