Emerging evidences have indicated the role of ferroptosis in the progression of metabolic-associated fatty liver disease (MAFLD); thus, inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeutics. Recent studies have demonstrated the antioxidative effect of the gut commensal bacterium Akkermansia muciniphila (A. muc); however, whether it can alleviate ferroptosis remains unclear. The current study indicates A. muc intervention efficiently reversed high-fat high-fructose diet (HFHFD)-induced lipid peroxidation and ferroptosis in the liver. These beneficial effects were mediated by activation of the hepatic AMPK/SIRT1/PGC-1α axis, as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation in vitro and in vivo. Furthermore, the short-chain fatty acids (SCFAs) were enriched upon A. muc treatment, and acetate was identified as a key activator of hepatic AMPK signalling. Mechanistically, microbiota-derived acetate was transported to the liver and metabolized to adenosine monophosphate (AMP), which triggered AMPK activation. Furthermore, a colonization assay in germ-free mice confirmed that A. muc mediated antiferroptotic effects in the absence of other microbes. These data indicated that A. muc exerts antiferroptotic effects against MAFLD, at least partially by producing acetate, which activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis via the inhibition of polyunsaturated fatty acid (PUFA) synthesis.

OBJECTIVE: To compare the efficacy and safety of intravenous colistin sulfate combined with nebulized inhalation versus intravenous monotherapy for pulmonary infections caused by carbapenem-resistant organism (CRO). METHODS: A multicenter retrospective cohort study was conducted. Clinical data were collected from patients admitted to the intensive care unit (ICU) of 10 tertiary class-A hospitals in Henan Province between July 2021 and May 2023, who received colistin sulfate for CRO pulmonary infections. Data included baseline characteristics, inflammatory markers [white blood cell count (WBC), neutrophil count (NEU), procalcitonin (PCT), C-reactive protein (CRP)], renal function indicators [serum creatinine (SCr), blood urea nitrogen (BUN)], life support measures, anti-infection regimens, clinical efficacy, microbiological clearance rate, and prognostic outcomes. Patients were divided into two groups: intravenous group (colistin sulfate monotherapy via intravenous infusion) and combination group ((intravenous infusion combined with nebulized inhalation of colistin sulfate). Changes in parameters before and after treatment were analyzed. RESULTS: A total of 137 patients with CRO pulmonary infections were enrolled, including 89 in the intravenous group and 48 in the combination group. Baseline characteristics, life support measures, daily colistin dose, and combination regimens (most commonly colistin sulfate plus carbapenems in both groups) showed no significant differences between two groups. The combination group exhibited higher clinical efficacy [77.1% (37/48) vs. 59.6% (52/89)] and microbiological clearance rate [60.4% (29/48) vs. 39.3% (35/89)], both P < 0.05. Pre-treatment inflammatory and renal parameters showed no significant differences between two groups. Post-treatment, the combination group showed significantly lower WBC and CRP [WBC (×10⁹/L): 8.2±0.5 vs. 10.9±0.6, CRP (mg/L): 14.0 (5.7, 26.6) vs. 52.1 (24.4, 109.6), both P < 0.05], whereas NEU, PCT, SCr, and BUN levels showed no significant between two groups. ICU length of stay was shorter in the combination group [days: 16 (10, 25) vs. 21 (14, 29), P < 0.05], although mechanical ventilation duration and total hospitalization showed no significant differences between two groups. CONCLUSIONS Intravenous colistin sulfate combined with nebulized inhalation improved clinical efficacy and microbiological clearance in CRO pulmonary infections with an acceptable safety profile.
Humans ; Colistin/therapeutic use* ; Retrospective Studies ; Administration, Inhalation ; Anti-Bacterial Agents/therapeutic use* ; Carbapenems/pharmacology* ; Male ; Female ; Middle Aged ; Gram-Negative Bacteria/drug effects* ; Aged ; Treatment Outcome ; Respiratory Tract Infections/drug therapy*

The 2019 Chinese practice guideline for the prevention and treatment of mother-to-child transmission of hepatitis B virus developed by Chinese Society of Infectious Diseases,Chinese Medical Association,has shown a good guiding effect in standardizing the process for blocking the mother-to-child transmission of hepatitis B virus in China.Clinical practice guidelines and consensus statements require timely updates based on new research evidence,in order to better guide clinical practice and research.Chinese Physician Association for Infectious Diseases,Chinese Medical Doctor Association,and Chinese Society of Infectious Diseases,Chinese Medical Association,cooperated with multidisciplinary experts and performed updates and supplementations to the above guideline,in order to provide guidance and a reference for clinical physicians and medical staff engaged in maternal and child health care.

Background::Hypertension and non-alcoholic fatty liver disease (NAFLD) share several pathophysiologic risk factors, and the exact relationship between the two remains unclear. Our study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 and Mendelian randomization (MR) analyses.Methods::Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES 2017-2018. Subsequently, a two-sample MR study was performed using the genome-wide association study (GWAS) summary statistics to identify the causal association between hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and NAFLD. The primary inverse variance weighted (IVW) and other supplementary MR approaches were conducted to verify the causal association between hypertension and NAFLD. Sensitivity analyses were adopted to confirm the robustness of the results.Results::A total of 3144 participants were enrolled for our observational study in NHANES. Weighted multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk (odds ratio [OR] = 1.677; 95% confidence interval [CI], 1.159-2.423). SBP ≥130 mmHg and DBP ≥80 mmHg were also significantly positively correlated with NAFLD. Moreover, hypertension was independently connected with liver steatosis ( β = 7.836 [95% CI, 2.334-13.338]). The results of MR analysis also supported a causal association between hypertension (OR = 7.203 [95% CI, 2.297-22.587]) and NAFLD. Similar results were observed for the causal exploration between SBP (OR = 1.024 [95% CI, 1.003-1.046]), DBP (OR = 1.047 [95% CI, 1.005-1.090]), and NAFLD. The sensitive analysis further confirmed the robustness and reliability of these findings (all P >0.05). Conclusion::Hypertension was associated with an increased risk of NAFLD.

Objective:To compare the application effects of electric impedance tomography (EIT)-guided positive end-expiratory pressure conventional PEEP and PEEP-fraction of inspired oxygen (FiO 2) table-guided PEEP in the mechanical ventilation of patients with traumatic brain injury (TBI) complicated with acute respiratory distress syndrome (ARDS). Methods:A retrospective cohort study was conducted on the clinical data of 80 TBI patients complicated with ARDS admitted to Zhengzhou Central Hospital Affiliated to Zhengzhou University from July 2020 to December 2022, including 42 males and 38 females, aged 29-59 years [(42.4±7.8)years]. The Glasgow coma scale (GCS) scores were 3-12 points [(7.7±2.2)points]. According to ARDS classification, 33 were mild, 26 moderate and 21 severe. All the patients were treated with mechanical ventilation according to lung protective ventilation strategy, including 42 patients treated with EIT-guided PEEP (EIT group) and 38 treated with conventional PEEP-FiO 2 table-guided PEEP (conventional group). At 12 hours, 1, 3 and 5 days after ventilation, the optimal PEEP, respiratory mechanics [driving pressure (ΔP), static compliance (C St), mechanical power (MP)], pulmonary gas exchange [arterial blood pH value, arterial partial pressure of carbon dioxide (PaCO 2), oxygenation index (P/F)], ventilation distribution [heterogeneity index (GI), regions of interest (ROI)1-4], hemodynamics [heart rate (HR), central venous pressure (CVP), mean arterial pressure (MAP)], cerebral perfusion status [intracranial pressure (ICP), regional cerebral oxygen saturation (rScO 2) grading], and treatment outcomes (mechanical ventilation duration, incidence of ventilator-induced lung injury (VILI), length of ICU stay, 6-month survival rate) separately at their optimal PEEP were compared between the two groups. Results:All the patients were followed up for 6 months. The optimal PEEP of the EIT group was (7.4±1.0)cm, (8.2±1.2)cm, (9.8±0.8)cm and (8.4±0.7)cm respectively at 12 hours, 1, 3 and 5 days after mechanical ventilation, which were higher than (7.0±1.0)cm, (7.6±1.0)cm, (9.0±0.6)cm and (7.2±0.5)cm of the conventional group ( P<0.05 or 0.01). At their optimal PEEP separately, at 12 hours, 1, 3 and 5 days after treatment, the ΔP of the EIT group was (7.1±1.3)cmH 2O, (7.7±1.3)cmH 2O, (9.5±1.1)cmH 2O and (6.1±1.3)cmH 2O respectively, which were all lower than (8.9±1.3)cmH 2O, (10.5±1.3)cmH 2O, (11.2±1.2)cmH 2O and (8.7±1.2)cmH 2O of the conventional group respectively ( P<0.05 or 0.01); the C St of the EIT group was (51.5±4.2)ml/cmH 2O, (52.9±4.6)ml/cmH 2O, (55.1±4.3)ml/cmH 2O and (57.5±3.6)ml/cmH 2O, which were all higher than (46.8±3.9)ml/cmH 2O, (47.6±4.4)ml/cmH 2O, (49.9±4.3)ml/cmH 2O and (53.3±3.6)ml/cmH 2O of the conventional group respectively ( P<0.05); the MP of the EIT group was (7.9±1.8)J/min, (8.8±1.3)J/min, (10.6±1.3)J/min and (7.8±0.9)J/min, which were lower than (8.6±1.5)J/min, (9.5±1.0)J/min, (12.2±1.8)J/min and (8.6±0.9)J/min of the conventional group respectively ( P<0.05 or 0.01); the P/F of the EIT group was (207.1±7.1)mmHg, (213.1±6.9)mmHg, (239.3±13.1)mmHg and (255.5±11.8)mmHg, which were all higher than (179.6±7.2)mmHg, (187.8±9.6)mmHg, (212.8±9.6)mmHg and (228.1±12.3)mmHg of the conventional group respectively ( P<0.05 or 0.01); the GI of the EIT group were 0.381±0.013, 0.387±0.012, 0.392±0.010 and 0.395±0.010, lower than 0.403±0.005, 0.406±0.005, 0.409±0.005 and 0.411±0.004 of traditional group respectively ( P<0.01); there were no significant differences in the arterial blood pH value, PaCO 2, ROI1-4, HR, CVP, MAP, ICP, or rScO 2 grading between the two groups (P>0.05). The ventilation duration of the EIT group was (78.5±9.0)hours, which was shorter than (83.1±7.4)hours of the conventional group ( P<0.05). The incidence of VILI was 0.0% (0/42) in the EIT group, which was lower than 7.8% (3/38) in the conventional group ( P<0.05). There were no significant differences in the ICU stay or 6-month survival rate between the two groups ( P>0.05). Conclusions:In mechanical ventilation treatment of TBI complicated with ARDS, the optimal PEEP guided by EIT was higher than that guided by PEEP-FiO 2 table. At this optimal PEEP, the respiratory mechanics and oxygen supply of the patients can be improved more effectively, making regional lung ventilation more uniform, reducing the mechanical ventilation time and decreasing the incidence of VILI without affecting their hemodynamics and brain perfusion.

Objective:To explore the influencing factors of efficacy of combination therapy of nucleos（t）ide analogues（NAs）with pegylated interferon α-2a（Peg IFNα-2a）for patients with chronic hepatitis B（CHB）.Methods:The clinical data of 141 CHB patients receiving combination therapy of NAs and Peg IFNα-2a for ≥48 weeks in the First Affiliated Hospital of Zhejiang University School of Medicine from January 1，2013 to December 1，2023 was retrospectively analyzed. Patients were divided into clinical cure group（ n=45）and non-clinical cure group（ n=96）. Multivariate Logistic regression analysis was used to analyze the influencing factors of clinical cure. Results:Multivariate Logistic regression analysis showed that baseline HBsAg <1 500 IU/mL（ OR=0.160，95% CI 0.049-0.522， P=0.002），a decrease by >1 lg IU/mL in HBsAg at week 48 compared to the baseline level（ OR=0.114，95% CI 0.027-0.484， P=0.003），and sequential combination therapy（ OR=0.351，95% CI 0.128-0.960， P=0.041）were independent predicting factors for the efficacy of combination therapy of NAs and Peg IFNα-2a in CHB patients. Conclusions:The study indicates that the efficacy of the sequential combination therapy is superior to that of the treatment-na?ve therapy，and patients with baseline HBsAg<1 500 IU/mL is more likely to achieve clinical cure than those with higher baseline levels. A primary course of 48 weeks was recommended，with the possibility of an extension of the course by evaluating the degree of HBsAg decline at 48 weeks.

Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the discovery of revolutionary anti-TB drugs such as streptomycin, isoniazid, pyrazinamide, ethambutol and rifampicin, along with drug combination treatment, has greatly improved TB control globally. As anti-TB drugs were widely used, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis emerged due to acquired genetic mutations, and this now presents a major problem for effective treatment. Genes associated with drug resistance have been identified, including katG mutations in isoniazid resistance, rpoB mutations in rifampin resistance, pncA mutations in pyrazinamide resistance, and gyrA mutations in quinolone resistance. The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation, drug target alteration, overexpression of drug target, and overexpression of the efflux pump. During the disease process, Mycobacterium tuberculosis may reside in different microenvironments where it is expose to acidic pH, low oxygen, reactive oxygen species and anti-TB drugs, which can facilitate the development of non-replicating persisters and promote bacterial survival. The mechanisms of persister formation may include toxin-antitoxin (TA) modules, DNA protection and repair, protein degradation such as trans-translation, efflux, and altered metabolism. In recent years, the use of new anti-TB drugs, repurposed drugs, and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB. The importance of developing more effective drugs targeting persisters of Mycobacterium tuberculosis is emphasized. In addition, host-directed therapeutics using both conventional drugs and herbal medicines for more effective TB treatment should also be explored. In this article, we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant and persistent tuberculosis to inform future therapeutic development.
Humans ; Pyrazinamide/therapeutic use* ; Isoniazid/therapeutic use* ; Antitubercular Agents/therapeutic use* ; Tuberculosis, Multidrug-Resistant/microbiology* ; Mycobacterium tuberculosis/genetics* ; Tuberculosis/drug therapy* ; Rifampin/therapeutic use* ; Mutation ; Drug Resistance, Multiple, Bacterial/genetics*

Despite the achievements obtained worldwide in the control of tuberculosis in recent years, many countries and regions including China still face challenges such as low diagnosis rate, high missed diagnosis rate, and delayed diagnosis of the disease. The discovery strategy of tuberculosis in China has changed from "active discovery by X-ray examination" to "passive discovery by self-referral due to symptoms", and currently the approach is integrated involving self-referral due to symptoms, active screening, and physical examination. Active screening could help to identify early asymptomatic and untreated cases. With the development of molecular biology and artificial intelligence-assisted diagnosis technology, there are more options for active screening among the large-scale populations. Although the implementation cost of a population-based active screening strategy is high, it has great value in social benefits, and active screening in special populations can obtain better benefits. Active screening of tuberculosis is an important component of the disease control. It is suggested that active screening strategies should be optimized according to the specific conditions of the regions to ultimately ensure the benefit of the tuberculosis control.
Humans ; Artificial Intelligence ; Tuberculosis/prevention & control* ; Mass Screening ; China

Objective:To investigate the neuroprotective effect of histone deacetylase 3 (HDAC3) specific inhibitor RGFP966 on traumatic brain injury (TBI) and its mechanism in rats.Methods:Forty-eight SD rats were randomly divided into sham-operated group, TBI group, TBI+vehicle group and TBI+RGFP966 group ( n=12). Rats in the later 3 groups accepted hydraulic impact brain injury to establish TBI models; and then, RGFP966 (dissolved in 1% DMSO at a dose of 10 mg/kg) was injected intraperitoneally 30 min after modeling, twice a day for 3 d, in TBI+RGFP966 group; same amount of DMSO was injected into TBI+vehicle group at the same time. Three d after modeling, neurological function was tested by modified neurological severity score (mNSS), water content of brain tissues was detected by dry-wet weight method, proportion of injured neurons at the frontal cortical tissues on the affected side was detected by Nissl staining, expressions of HDAC3 and pyroptosis related proteins were detected by immunohistochemical staining and Western blotting, and serum content of inflammatory factors was detected by ELISA. Results:Three d after modeling, compared with the TBI+vehicle group, the TBI+RGFP966 group had significantly decreased mNSS scores (9.83±0.75 vs. 6.67±0.82), water content of the injured cerebral cortex (82.73%±0.36% vs. 80.92%±0.66%), proportion of damaged neurons (75.60%±7.44% vs. 55.87%±4.10%), and HDAC3 protein expression (0.67±0.09 vs. 0.51±0.07), and significantly increased acetylated H3 (Ace-H3) and acetylated H4 (Ace-H4) protein expressions (0.81±0.02 vs. 1.22±0.02; 0.74±0.01 vs. 1.07±0.02), and statistically decreased protein expressions of nuclear factor-κB (NF-κB, 1.20±0.05 vs. 0.94±0.04), NOD-like receptor thermal protein domain associated protein 3 (NLRP3, 0.72±0.02 vs. 0.40±0.03), Caspase-1 containing cysteine (Caspase-1), dermatin D N-terminal fragment (GSDMD-N, 0.71±0.03 vs. 0.52±0.01), significantly decreased NF-κB and NLRP3 immunohistochemical staining scores, and significantly decreased serum contents of tumor necrosis factor-α, interleukin(IL)-1β and IL-18 ( P<0.05). Conclusion:Early intervention with RGFP966 after TBI can reduce the pyroptosis and inflammatory reaction of nerve cells and play neuroprotective role, whose mechanism may be related to inhibited activation of NF-κB/NLRP3/GSDMD pathway.

Autoimmune hepatitis (AIH) is a severe globally distributed liver disease that could occur at any age. Human menstrual blood-derived stem cells (MenSCs) have shown therapeutic effect in acute lung injury and liver failure. However, their role in the curative effect of AIH remains unclear. Here, a classic AIH mouse model was constructed through intravenous injection with concanavalin A (Con A). MenSCs were intravenously injected while Con A injection in the treatment groups. The results showed that the mortality by Con A injection was significantly decreased by MenSCs treatment and liver function tests and histological analysis were also ameliorated. The results of phosphoproteomic analysis and RNA-seq revealed that MenSCs improved AIH, mainly by apoptosis and c-Jun N-terminal kinase/mitogen-activated protein signaling pathways. Apoptosis analysis demonstrated that the protein expression of cleaved caspase 3 was increased by Con A injection and reduced by MenSCs transplantation, consistent with the TUNEL staining results. An AML12 co-culture system and JNK inhibitor (SP600125) were used to verify the JNK/MAPK and apoptosis signaling pathways. These findings suggested that MenSCs could be a promising strategy for AIH.
Mice ; Animals ; Humans ; Hepatitis, Autoimmune/pathology* ; Signal Transduction ; Disease Models, Animal ; Stem Cells