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AIMS: This study aimed to evaluate the diagnostic performance of metagenomic next-generation sequencing (mNGS) with pancreatic fluid aspiration for the detection of infected pancreatic necrosis (IPN). METHODS: This retrospective observational study included 66 patients with suspected IPN. The participants simultaneously underwent pancreatic fluid aspiration mNGS, and microbial and blood culture. We compared the diagnostic performance of mNGS with that of culture in the detection of pathogens associated with IPN. RESULTS: Of the 66 patients, 45 (68.2 %) were confirmed to have IPN. Pancreatic fluid aspiration mNGS yielded positive results in 32 of these patients (71.1 %), significantly outperforming microbial culture results (25 patients, 55.6 %; P = 0.039); however, both methods exhibited similar specificity (95.2% vs. 100 %). The results of pancreatic fluid aspiration mNGS and microbial culture matched in 73.3 % (33/45) of patients with IPN. The turnaround time for the mNGS results was significantly shorter than that for the microbial culture method (P < 0.001). In addition, survival analysis demonstrated that a positive mNGS result was not associated with increased mortality (hazard ratio, 0.652; 95 % confidence interval 0.157-2.699, P = 0.555). CONCLUSIONS: Our study highlights the potential of mNGS for diagnosing IPN, with implications for improving patient care by facilitating early and accurate diagnosis, guiding appropriate interventions, and possibly improving patient outcomes.
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This study aimed to investigate the association between glucocorticoid administration and outcomes in critically ill patients with ARDS using the Medical Information Mart for Intensive Care (MIMIC)-III database. Data were collected from the MIMIC-III database, which consists of critically ill participants between 2001 and 2012 in the USA. A total of 1831 adult critically ill patients with ARDS were enrolled from the MIMIC-III database. The 60-day and in-hospital mortality, were the primary endpoints. Secondary outcomes included length of stay (LOS) in the hospital and intensive care unit (ICU), 28-day ventilator-free days, ICU mortality, and 28-day mortality. A total of 1831 patients were included in the data analysis. After propensity score (PS) matching, 464 patients diagnosed with ARDS were matched between the glucocorticoid treatment and control groups. Glucocorticoids were associated with increased in-hospital mortality [hazard ratio (HR) 1.32; 95% CI 1.01-1.71; Pâ =â .039], longer ICU stay [HR 2.25; 95% CI 0.84-3.65; Pâ =â .002], and shorter ventilation-free days at 28 days in all ARDS patients [HR -2.70; 95% CI -4.28--1.13; Pâ =â .001]. The 60-day mortality was higher in the glucocorticoid group (44.83% vs 35.34%; Pâ =â .154; HR 1.24; 95% CI 0.93-1.66). Excluding the impact of the glucocorticoid initiation time, from day 15 to day 60, mortality was significantly higher in the glucocorticoid group compared to the non-glucocorticoid group (27.16% vs 12.70%; Pâ <â .001; HR 1.75; 95% CI 1.32-2.32). Glucocorticoid administration was associated with worse 60-day and in-hospital survival, longer ICU stay, and shorter ventilator-free days on day 28 in patients with ARDS. Our findings suggest careful consideration of glucocorticoids for ARDS.
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Glucocorticoides , Mortalidade Hospitalar , Unidades de Terapia Intensiva , Tempo de Internação , Pontuação de Propensão , Síndrome do Desconforto Respiratório , Humanos , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Masculino , Feminino , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/tratamento farmacológico , Pessoa de Meia-Idade , Tempo de Internação/estatística & dados numéricos , Unidades de Terapia Intensiva/estatística & dados numéricos , Idoso , Bases de Dados Factuais , Estado Terminal/mortalidade , Adulto , Respiração Artificial/estatística & dados numéricos , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: More robust non-human primate models of Alzheimer's disease (AD) will provide new opportunities to better understand the pathogenesis and progression of AD. METHODS: We designed a CRISPR/Cas9 system to achieve precise genomic deletion of exon 9 in cynomolgus monkeys using two guide RNAs targeting the 3' and 5' intron sequences of PSEN1 exon 9. We performed biochemical, transcriptome, proteome, and biomarker analyses to characterize the cellular and molecular dysregulations of this non-human primate model. RESULTS: We observed early changes of AD-related pathological proteins (cerebrospinal fluid Aß42 and phosphorylated tau) in PSEN1 mutant (ie, PSEN1-ΔE9) monkeys. Blood transcriptome and proteome profiling revealed early changes in inflammatory and immune molecules in juvenile PSEN1-ΔE9 cynomolgus monkeys. DISCUSSION: PSEN1 mutant cynomolgus monkeys recapitulate AD-related pathological protein changes, and reveal early alterations in blood immune signaling. Thus, this model might mimic AD-associated pathogenesis and has potential utility for developing early diagnostic and therapeutic interventions. HIGHLIGHTS: A dual-guide CRISPR/Cas9 system successfully mimics AD PSEN1-ΔE9 mutation by genomic excision of exon 9. PSEN1 mutant cynomolgus monkey-derived fibroblasts exhibit disrupted PSEN1 endoproteolysis and increased Aß secretion. Blood transcriptome and proteome profiling implicate early inflammatory and immune molecular dysregulation in juvenile PSEN1 mutant cynomolgus monkeys. Cerebrospinal fluid from juvenile PSEN1 mutant monkeys recapitulates early changes of AD-related pathological proteins (increased Aß42 and phosphorylated tau).
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Doença de Alzheimer , Modelos Animais de Doenças , Macaca fascicularis , Mutação , Presenilina-1 , Animais , Doença de Alzheimer/genética , Doença de Alzheimer/sangue , Presenilina-1/genética , Mutação/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/genética , Sistemas CRISPR-Cas , Éxons/genética , Masculino , Transcriptoma , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidianoRESUMO
The potential long-term effects of anesthesia on cognitive development, especially in neonates and infants, have raised concerns. However, our understanding of its underlying mechanisms and effective treatments is still limited. In this study, we found that early exposure to isoflurane (ISO) impaired fear memory retrieval, which was reversed by dexmedetomidine (DEX) pre-treatment. Measurement of c-fos expression revealed that ISO exposure significantly increased neuronal activation in the zona incerta (ZI). Fiber photometry recording showed that ZI neurons from ISO mice displayed enhanced calcium activity during retrieval of fear memory compared to the control group, while DEX treatment reduced this enhanced calcium activity. Chemogenetic inhibition of ZI neurons effectively rescued the impairments caused by ISO exposure. These findings suggest that the ZI may play a pivotal role in mediating the cognitive effects of anesthetics, offering a potential therapeutic target for preventing anesthesia-related cognitive impairments.
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Medo , Isoflurano , Transtornos da Memória , Zona Incerta , Isoflurano/farmacologia , Isoflurano/efeitos adversos , Animais , Medo/efeitos dos fármacos , Camundongos , Transtornos da Memória/induzido quimicamente , Zona Incerta/efeitos dos fármacos , Masculino , Anestésicos Inalatórios/efeitos adversos , Anestésicos Inalatórios/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Camundongos Endogâmicos C57BL , Dexmedetomidina/farmacologia , Feminino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Memória/efeitos dos fármacosRESUMO
The current investigation deployed Mendelian randomization (MR) to elucidate the causal relationship between circulating proteins and sepsis. A rigorous two-sample MR analysis evaluated the effect of plasma proteins on the sepsis susceptibility. To affirm the integrity of MR findings, a suite of supplementary analyses, including Bayesian colocalization, Steiger filtering, the assessment of protein-altering polymorphisms, and the correlation between expression quantitative trait loci and protein quantitative trait loci (pQTLs), was employed. The study further integrated the examination of protein-protein interactions and pathway enrichment, along with the identification of pharmacologically actionable targets, to advance our comprehension and outline potential sepsis therapies. Subsequent analyses leveraging cis-pQTLs within MR studies unveiled noteworthy relationships: 94 specific proteins exhibited significant links with sepsis-related 28 day mortality, while 96 distinct proteins correlated with survival outcomes in sepsis. Furthermore, incorporating both cis- and trans-pQTLs in MR investigations revealed more comprehensive findings, associating 201 unique proteins with sepsis-related 28 day mortality and 199 distinct proteins with survival outcomes in sepsis. Markedly, colocalization analyses confirmed that eight of these proteins exhibited prominent evidence for colocalization, emphasizing their potential criticality in sepsis pathophysiology. Further in silico analyses were conducted to delineate putative regulatory networks and to highlight prospective drug targets among these proteins. Employing the MR methodology has shed light on plasma proteins implicated in the etiopathogenesis of sepsis. This novel approach unveiled numerous biomarkers and targets, providing a scientific rationale for the development of new therapeutic strategies and prophylactic measures against sepsis.
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Exposure to fine particulate matter (PM2.5) during pregnancy has been inversely associated with neonatal neurological development. However, the associations of exposure to specific PM2.5 constituents with neonatal neurological development remain unclear. We investigated these associations and examined the mediating role of meconium metabolites in a Chinese birth cohort consisting of 294 mother-infant pairs. Our results revealed that exposure to PM2.5 and its specific constituents (i.e., organic matter, black carbon, sulfate, nitrate, and ammonium) in the second trimester, but not in the first or third trimester, was inversely associated with the total neonatal behavioral neurological assessment (NBNA) scores. The PM2.5 constituent mixture in the second trimester was also inversely associated with NBNA scores, and sulfate was identified as the largest contributor. Furthermore, meconium metabolome analysis identified four metabolites, namely, threonine, lysine, leucine, and saccharopine, that were associated with both PM2.5 constituents and NBNA scores. Threonine was identified as an important mediator, accounting for a considerable proportion (14.53-15.33%) of the observed inverse associations. Our findings suggest that maternal exposure to PM2.5 and specific constituents may adversely affect neonatal behavioral development, in which meconium metabolites may play a mediating role.
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Exposição Materna , Mecônio , Material Particulado , Humanos , Feminino , Mecônio/química , Gravidez , Estudos de Coortes , Recém-Nascido , Adulto , Poluentes AtmosféricosRESUMO
Many environmental toxicants can cause systemic effects, such as fine particulate matter (PM2.5), which can penetrate the respiratory barrier and induce effects in multiple tissues. Although metabolomics has been used to identify biomarkers for PM2.5, its multi-tissue toxicology has not yet been explored holistically. Our objective is to explore PM2.5 induced metabolic alterations and unveil the intra-tissue responses along with inter-tissue communicational effects. In this study, following a single intratracheal instillation of multiple doses (0, 25, and 150 µg as the control, low, and high dose), non-targeted metabolomics was employed to evaluate the metabolic impact of PM2.5 across multiple tissues. PM2.5 induced tissue-specific and dose-dependent disturbances of metabolites and their pathways. The remarkable increase of both intra- and inter-tissue correlations was observed, with emphasis on the metabolism connectivity among lung, spleen, and heart; the tissues' functional specificity has marked their toxic modes. Beyond the inter-status comparison of the metabolite fold-changes, the current correlation network built on intra-status can offer additional insights into how the multiple tissues and their metabolites coordinately change in response to external stimuli such as PM2.5 exposure.
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Poluentes Atmosféricos , Metabolômica , Material Particulado , Material Particulado/toxicidade , Animais , Camundongos , Poluentes Atmosféricos/toxicidade , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Biomarcadores/metabolismo , MasculinoRESUMO
Acute pancreatitis (AP) is a common systemic inflammatory disease resulting from the activation of trypsinogen by various incentives in ICU. The annual incidence rate is approximately 30 out of 100,000. Some patients may progress to severe acute pancreatitis, with a mortality rate of up to 40%. Therefore, the goal of this article is to explore the key genes for effective diagnosis and treatment of AP. The analysis data for this study were merged from two GEO datasets. 1357 DEGs were used for functional enrichment and cMAP analysis, aiming to reveal the pathogenic genes and potential mechanisms of AP, as well as potential drugs for treating AP. Importantly, the study used LASSO and SVM-RFE machine learning to screen the most likely AP occurrence biomarker for Prdx4 among numerous candidate genes. A receiver operating characteristic of Prdx4 was used to estimate the incidence of AP. The ssGSEA algorithm was employed to investigate immune cell infiltration in AP. The biomarker Prdx4 gene exhibited significant associations with a majority of immune cells and was identified as being expressed in NKT cells, macrophages, granulocytes, and B cells based on single-cell transcriptome data. Finally, we found an increase in Prdx4 expression in the pancreatic tissue of AP mice through immunohistochemistry. After treatment with recombinant Prdx4, the pathological damage to the pancreatic tissue of AP mice was relieved. In conclusion, our study identified Prdx4 as a potential AP hub gene, providing a new target for treatment.
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Pancreatite , Animais , Humanos , Camundongos , Doença Aguda , Algoritmos , Biomarcadores , Aprendizado de Máquina , Pancreatite/diagnóstico , Pancreatite/genéticaRESUMO
To investigate the clinical value of contrast-enhanced ultrasound in the prediction of hepatic encephalopathy (HE) in patients with hepatitis B cirrhosis after intrahepatic portal-systemic shunt via jugular vein. In this retrospective study, we collected data from 75 patients with hepatitis B, cirrhosis, and portal hypertension who underwent jugular intrahepatic portosystemic shunt from February 2019 to February 2022. The diagnostic instrument used was the TOSHIBA Aplio500 color Doppler ultrasound with contrast-enhanced ultrasound capabilities. The trial group comprised 20 patients with HE within 3 months postsurgery, while the control group (CG) included 55 patients without HE within the same postoperative period. All patients underwent various examinations before and within 48 hours after surgery, including observation of liver and spleen size and stent position, as well as assessment of blood flow direction in portal and hepatic veins. Subsequently, contrast-enhanced ultrasound was employed to examine and observe perfusion changes of contrast agents in hepatic veins, hepatic arteries, and portal veins (PV). Changes in PV pressure gradient, intrahepatic, and stent blood flow perfusion (BFP) were explored in both postoperative trials and CGs. The trial group exhibited higher BFP volume, PV pressure gradient difference, and percentage decrease compared to the CG. A weak positive correlation was observed between blood flow within the liver stent and PV pressure gradient difference, as well as the percentage decrease in PV pressure gradient. The correlation coefficient between blood flowing perfusion volume within the stent and the difference in PV pressure gradient was Râ =â 0.415 (Pâ =â .000). The correlating coefficient between BFP amount within the stent and the percentage decrease in PV pressure gradient was Râ =â 0.261 (Pâ =â .027). The area under the receiver operating characteristic curve for stent perfusion volume, difference in PV pressure gradient, and percentage decrease in PV pressure gradient was 0.691, 0.759, and 0.742, respectively. An increase in PV pressure gradient accelerates blood flow within the stent, predisposing to HE. Changes in hepatic BFP following transjugular intrahepatic portosystemic shunt can effectively predict the occurrence of HE, demonstrating significant clinical relevance.
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Meios de Contraste , Derivação Portossistêmica Transjugular Intra-Hepática , Humanos , Masculino , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Hipertensão Portal/cirurgia , Hipertensão Portal/fisiopatologia , Hipertensão Portal/diagnóstico por imagem , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/cirurgia , Ultrassonografia Doppler em Cores/métodos , Adulto , Cirrose Hepática/cirurgia , Cirrose Hepática/fisiopatologia , Cirrose Hepática/diagnóstico por imagem , Circulação Hepática/fisiologia , Idoso , Veia Porta/diagnóstico por imagem , Veia Porta/fisiopatologia , Relevância ClínicaRESUMO
Objective: To study the changes in the serum markers in chronic hepatitis B patients who have had previous treatment with long-acting interferon therapy of nucleoside and those who have not and to assess the value of the serum markers for clinical prognosis evaluation. Methods: The clinical data of 411 cases of chronic hepatitis B were collected. All cases were given the additional treatment of long-acting interferon between October 2019 to April 2022. The cases were divided into two groups, a previously treated group consisting of patients who had been treated with nucleoside and nucleotide analogues (NAs) for more than 6 months after they became infected with hepatitis B virus (HBV) for over 6 months and an initial treatment group, or treatment naïve group, consisting of patients who had HBV infection for over 6 months and received no treatment or patients who have stopped NAs therapy for more than 6 months. The serum marker levels of the previously treated group and the initial treatment group, i.e., the previously treatment-naïve patients, were compared, and the receiver operating characteristics (ROC) curve was used to evaluate the value of the baseline levels of hepatitis B surface antigen (HBsAg) and HBV pregenomic RNA (pgRNA) for predicting the rate of cured cases in the two groups. Results: There was no significant difference in the rate of cured cases between the previously treated group and the initial treatment group. The baseline HBV DNA, HBsAg, and hepatitis B e antigen (HBeAg) levels of the cured cases in both groups were significantly lower than those in the uncured cases (P<0.0001). After 48 weeks of treatment, the serum HBsAb levels (mIU/mL) of the cured cases in both the previously treated and initial treatment groups were significantly higher than those of the uncured cases in the two groups (previously treated group: 78.97±22.57 vs. 0.99±0.38, P<0.0001; initial treatment group: 235.50±175.00 vs. 1.32±0.88, P<0.0001). The serum HBsAb levels (mIU/mL) of the cured cases in the initial treatment groups were significantly higher than that of cured cases in the previously treated group (235.50±175.00 vs. 78.97±22.57, P<0.0001). Within 0 to 60 weeks of treatment, HBV pgRNA levels of cured cases in both groups were significantly lower than those of the the uncured cases in both groups (P<0.0001). Multivariate logistic regression and ROC curve analysis showed that baseline serum HBsAg was the influencing factor and predictor of interferon efficacy in both the previously treated cases and the initial treatment cases, with the area under the curve (AUC) being 0.80 (95% confidence interval [CI]: 0.7423-0.8615, P<0.0001) and 0.74 (95% CI: 0.6283-0.8604, P=0.0079), respectively, and the optimal cut-off values being 244.60 IU/mL and 934.40 IU/mL, respectively. However, the baseline serum HBV pgRNA level of under 1340.00 copies/mL in the initial treatment cases led to better sensitivity and better specificity in efficacy prediction, with the AUC of the baseline HBV pgRNA being 0.9649 (95% CI: 0.9042-1.0000, P<0.0001). Conclusion: Among the previously treated cases and the initial treatment cases, patients who achieve clinical cure have lower levels of HBV DNA, HBsAg, and HBeAg at baseline, lower level of HBV pgRNA over the course of their treatment, and higher level of HBsAb at week 48. Baseline HBsAg levels can be used to effectively predict the clinical cure outcomes in previously treated cases and initial treatment cases. Baseline HBV pgRNA levels also exhibit a high predictive value for treatment outcomes in initial treatment cases.
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Antivirais , Biomarcadores , Antígenos de Superfície da Hepatite B , Hepatite B Crônica , Humanos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/sangue , Antivirais/uso terapêutico , Feminino , Masculino , Antígenos de Superfície da Hepatite B/sangue , Biomarcadores/sangue , Adulto , Vírus da Hepatite B/genética , Prognóstico , Interferons/uso terapêutico , Pessoa de Meia-Idade , Antígenos E da Hepatite B/sangue , DNA Viral/sangue , Curva ROC , RNA Viral/sangueRESUMO
There is no detailed study on how tidal volume (VT) affects patients during one-lung ventilation (OLV). The present study conducted a meta-analysis to assess the effect of VT on physiology and clinical outcomes in OLV patients. Databases until February 2023 were retrieved from PubMed, Cochrane Library and Web of Science. Randomized controlled trials comparing the application of low and high VT ventilation in adults with OLV were performed. Demographic variables, VT, physiology, and clinical outcomes were retrieved. The random-effects model calculated the summary of odds ratios with 95% confidence intervals (CI) and mean difference with standard deviation. A total of 12 studies involving a total of 876 participants met the inclusion criteria. Low VT ventilation was associated with decreased risk of acute lung injury [relative risk 0.50, 95% CI (0.28, 0.88), P=0.02]. Low VT ventilation decreased the driving pressure (ΔP) and peak pressure (Ppeak) and improved arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2). Furthermore, the present study suggested that a significant difference in blood IL-6 was observed between low and high VT ventilation [mean difference, -35.51 pg/ml, 95% CI (-66.47, -4.54 pg/ml), P=0.02]. A decrease in the length of stay at the hospital occurred in the low VT group when set to 4-5 ml/kg. In the OLV patients, low VT ventilation decreased the risk of acute lung injury, blood IL-6, ΔP and Ppeak, and improved PaO2/FiO2. Furthermore, when low VT was set to 4-5 ml/kg, the length of stay at the hospital decreased.
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Exposure to ozone has been associated with metabolic disorders in humans, but the underlying mechanism remains unclear. In this study, the role of the gut-liver axis and the potential mechanism behind the metabolic disorder were investigated by histological examination, microbiome and metabolome approaches in mice during the subacute (4-week) and subchronic (12-week) exposure to 0.5 ppm and 2.5 ppm ozone. Ozone exposure resulted in slowed weight gain and reduced hepatic lipid contents in a dose-dependent manner. After exposure to ozone, the number of intestinal goblet cells decreased, while the number of tuft cells increased. Tight junction protein zonula occludens-1 (ZO-1) was significantly downregulated, and the apoptosis of epithelial cells increased with compensatory proliferation, indicating a compromised chemical and physical layer of the intestinal barrier. The hepatic and cecal metabolic profiles were altered, primarily related to lipid metabolism and oxidative stress. The abundance of Muribaculaceae increased dose-dependently in both colon and cecum, and was associated with the decrease of metabolites such as bile acids, betaine, and L-carnitine, which subsequently disrupted the intestinal barrier and lipid metabolism. Overall, this study found that subacute and subchronic exposure to ozone induced metabolic disorder via disturbing the gut-liver axis, especially the intestinal barrier. These findings provide new mechanistic understanding of the health risks associated with environmental ozone exposure and other oxidative stressors.
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Microbiota , Ozônio , Humanos , Camundongos , Animais , Fígado/metabolismo , Metaboloma , Lipídeos , Ozônio/toxicidadeRESUMO
BACKGROUND: In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy. METHODS: We conducted a multicenter study involving PBC patients with moderate-to-severe interface hepatitis who underwent paired liver biopsies. Firstly, we compared the efficacy of the combination therapy with UDCA monotherapy on improving biochemistry, histology, survival rates, and prognosis. Subsequently we investigated the predictors of a beneficial response. RESULTS: This retrospective cohort study with prospectively collected data was conducted in China from January 2009 to April 2023. Of the 198 enrolled patients, 32 underwent UDCA monotherapy, while 166 received combination therapy, consisting of UDCA combined with prednisolone, prednisolone plus mycophenolate mofetil (MMF), or prednisolone plus azathioprine (AZA). The monotherapy group was treated for a median duration of 37.6 months (IQR 27.5-58.1), and the combination therapy group had a median treatment duration of 39.3 months (IQR 34.5-48.8). The combination therapy showed a significantly greater efficacy in reducing fibrosis compared to UDCA monotherapy, with an 8.3-fold increase in the regression rate (from 6.3% to 52.4%, P < 0.001). Other parameters, including biochemistry, survival rates, and prognosis, supported its effectiveness. Baseline IgG >1.3 × ULN and ALP <2.4 × ULN were identified as predictors of regression following the combination therapy. A predictive score named FRS, combining these variables, accurately identified individuals achieving fibrosis regression with a cut-off point of ≥ -0.163. The predictive value was validated internally and externally. CONCLUSION: Combination therapy with IS improves outcomes in PBC patients with moderate-to-severe interface hepatitis compared to UDCA monotherapy. Baseline IgG and ALP are the most significant predictors of fibrosis regression. The new predictive score, FRS, incorporating baseline IgG and ALP, can effectively identify individuals who would benefit from the combination therapy.
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Hepatite , Cirrose Hepática Biliar , Humanos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêutico , Imunossupressores/uso terapêutico , Prednisolona/uso terapêutico , Terapia de Imunossupressão , Hepatite/complicações , Imunoglobulina GRESUMO
BACKGROUND AND AIMS: We aimed to define gender-specific, optimal alanine aminotransferase (ALT) cut-off values for the prediction of significant liver histological changes (SLHC) in Chinese patients with grey zone (GZ) chronic hepatitis B (CHB) and normal ALT. METHODS: In a retrospective study, we included 1101 consecutive patients with GZ CHB and normal ALT assigned to training or internal validation cohorts. We included an independent cohort of 842 patients for external validation. We performed receiver operating characteristic (ROC) curve, smoothed curve fitting, and threshold effect analyses to determine optimal ALT cut-off values. Area under the curve (AUC) values were calculated to assess their predictive performance. RESULTS: A proportion of 79.3% of patients with GZ CHB and normal ALT (≤40 U/L) had SLHC. ROC curve analysis initially identified optimal ALT cut-off values of 29 U/L (male) and 22 U/L (female). After smoothed curve fitting and threshold effect analyses, new optimal cut-off values were 27 U/L for males and 24 U/L for females. AUCs for these values were 0.836 (male) and 0.833 (female) in the internal validation cohort, and 0.849 (male) and 0.844 (female) in the external validation cohort. The accuracy and discriminative ability of the newly defined ALT cut-off values were greater than those of the current recommendations. CONCLUSION: This study established novel optimal ALT cut-off values for more precise prediction of SLHC among Chinese patients with GZ CHB and normal ALT levels. This may help identify individuals who will benefit from timely antiviral therapy.
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Hepatite B Crônica , Humanos , Masculino , Feminino , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/patologia , Estudos Retrospectivos , Cirrose Hepática , Curva ROC , Alanina Transaminase , Vírus da Hepatite B , Antígenos E da Hepatite BRESUMO
BACKGROUND: The evaluation of patients with fatty liver as defined by metabolic dysfunction-associated fatty liver disease (MAFLD) in the real world remains poorly researched. This study aimed to analyse the clinical and histological features of patients with MAFLD and nonalcoholic fatty liver disease (NAFLD) and to characterize each metabolic subgroup of MAFLD. METHODS: A total of 2563 patients with fatty liver confirmed by ultrasonography and/or magnetic resonance tomography and/or liver biopsy-proven from three hospitals in China were included in the study. Patients were divided into different groups according to diagnostic criteria for MAFLD and NAFLD, and MAFLD into different subgroups. RESULTS: There were 2337 (91.2%) patients fitting the MAFLD criteria, and 2095 (81.7%) fitting the NAFLD criteria. Compared to patients with NAFLD, those with MAFLD were more likely to be male, had more metabolic traits, higher liver enzyme levels, and noninvasive fibrosis scores. Among the patients with liver biopsy, the extent of advanced fibrosis in cases with MAFLD was significantly higher than those with NAFLD, 31.8% versus 5.2% (P < .001); there was no significant difference in advanced fibrosis between obese cases and lean individuals in MAFLD (P > .05); MAFLD complicated with diabetes had significantly higher advanced fibrosis than those without diabetes (43.3% and 17.2%, respectively; P < .001). CONCLUSIONS: Patients with MAFLD have a higher degree of liver fibrosis than NAFLD patients. In addition, diabetic patients should be screened for fatty liver and liver fibrosis degree.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Masculino , Feminino , Estudos Transversais , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Pessoa de Meia-Idade , China/epidemiologia , Biópsia , Adulto , Fígado Gorduroso/patologia , Cirrose Hepática/patologia , Ultrassonografia , Fígado/patologia , Fígado/diagnóstico por imagem , Imageamento por Ressonância MagnéticaRESUMO
Certain sub-groups, including men and obese individuals, are more susceptible to ozone (O3) exposure, but the underlying molecular mechanisms remain unclear. In this study, the male mice were divided into two dietary groups: one fed a high-fat diet (HFD), mimicking obesity conditions, and the other fed a normal diet (ND), then exposed to 0.5 ppm and 2 ppm O3 for 4 h per day over two days. The HFD mice exhibited significantly higher body weight and serum lipid biochemical indicators compared to the ND mice. Obese mice also exhibited more severe pulmonary inflammation and oxidative stress. Using a multi-omics approach including proteomics, metabolomics, and lipidomics, we observed that O3 exposure induced significant pulmonary molecular changes in both obese and normal mice, primarily arachidonic acid metabolism and lipid metabolism. Different molecular biomarker responses to acute O3 exposure were also observed between two dietary groups, with immune-related proteins impacted in obese mice and PPAR pathway-related proteins affected in normal mice. Furthermore, although not statistically significant, O3 exposure tended to aggravate HFD-induced disturbances in lung glycerophospholipid metabolism. Overall, this study provides valuable molecular insights into the responses of lung to O3 exposure and highlights the potential impact of O3 on obesity-induced metabolic changes.
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Multiômica , Ozônio , Humanos , Camundongos , Masculino , Animais , Camundongos Obesos , Pulmão , Obesidade/metabolismo , Ozônio/farmacologiaRESUMO
Acute respiratory distress syndrome (ARDS) is independently associated with a poor prognosis in patients with sepsis. Macrophage M1 polarization plays an instrumental role in this process. Therefore, the exploration of key molecules affecting acute lung injury and macrophage M1 polarization may provide therapeutic targets for the treatment of septic ARDS. Here, we identified that elevated levels of Ankyrin repeat domain-containing protein 22 (ANKRD22) were associated with poor prognosis and more pronounced M1 macrophage polarization in septic patients by analyzing high-throughput data. ANKRD22 expression was also significantly upregulated in the alveolar lavage fluid, peripheral blood, and lung tissue of septic ARDS model mice. Knockdown of ANKRD22 significantly attenuated acute lung injury in mice with sepsis-induced ARDS and reduced the M1 polarization of lung macrophages. Furthermore, deletion of ANKRD22 in macrophages inhibited M1 macrophage polarization and reduced levels of phosphorylated IRF3 and intracellular interferon regulatory factor 3 (IRF3) expression, while re-expression of ANKRD22 reversed these changes. Further experiments revealed that ANKRD22 promotes IRF3 activation by binding to mitochondrial antiviral-signaling protein (MAVS). In conclusion, these findings suggest that ANKRD22 promotes the M1 polarization of lung macrophages and exacerbates sepsis-induced ARDS.
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Retrograde adeno-associated viruses (AAVs) are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks. However, few retrograde AAV capsids have been shown to offer access to cortical projection neurons across different species and enable the manipulation of neural function in non-human primates (NHPs). Here, we report the development of a novel retrograde AAV capsid, AAV-DJ8R, which efficiently labeled cortical projection neurons after local administration into the striatum of mice and macaques. In addition, intrastriatally injected AAV-DJ8R mediated opsin expression in the mouse motor cortex and induced robust behavioral alterations. Moreover, AAV-DJ8R markedly increased motor cortical neuron firing upon optogenetic light stimulation after viral delivery into the macaque putamen. These data demonstrate the usefulness of AAV-DJ8R as an efficient retrograde tracer for cortical projection neurons in rodents and NHPs and indicate its suitability for use in conducting functional interrogations.
Assuntos
Axônios , Neurônios Motores , Animais , Haplorrinos , Interneurônios , Macaca , Dependovirus/genética , Vetores GenéticosRESUMO
Promoters are essential tools for basic and translational neuroscience research. An ideal promoter should possess the shortest possible DNA sequence with cell-type selectivity. However, whether ultra-compact promoters can offer neuron-specific expression is unclear. Here, we report the development of an extremely short promoter that enables selective gene expression in neurons, but not glial cells, in the brain. The promoter sequence originates from the human CALM1 gene and is only 120 bp in size. The CALM1 promoter (pCALM1) embedded in an adeno-associated virus (AAV) genome directed broad reporter expression in excitatory and inhibitory neurons in mouse and monkey brains. Moreover, pCALM1, when inserted into an all-in-one AAV vector expressing SpCas9 and sgRNA, drives constitutive and conditional in vivo gene editing in neurons and elicits functional alterations. These data demonstrate the ability of pCALM1 to conduct restricted neuronal gene expression, illustrating the feasibility of ultra-miniature promoters for targeting brain-cell subtypes.