Sepsis-associated liver dysfunction is a life-threatening condition with a high mortality rate and no mechanism-based therapy. In this study, we identify the cross-linking enzyme transglutaminase 2 (TG2) as a driver of liver inflammation by activating macrophages in a mouse model of sepsis. Pharmacological inhibition of TG2 improves survival and reduces multiorgan inflammation, with the liver as a primary therapeutic target. Mechanistically, TG2 activity was up-regulated in macrophages, where it cross-linked vimentin to promote oligomerization and intermediate filament remodeling. Genetic ablation of TG2 or vimentin suppressed macrophage cytokine production and attenuated lipopolysaccharide-induced inflammation. Notably, vimentin-deficient macrophages exhibited enhanced proteasome recruitment to detergent-insoluble protein aggregates, accelerating the degradation of proinflammatory mediators such as Traf6, thereby dampening nuclear factor κB signaling. Proteomic profiling revealed a previously unrecognized Rab27a-positive vesicle trafficking pathway for inflammatory aggregate clearance. Together, these findings define a TG2-vimentin axis that controls macrophage activation through proteostasis regulation, linking cytoskeletal remodeling to inflammatory signaling.

OBJECTIVES:Psittacosis pneumonia caused by Chlamydia psittaci is often difficult to diagnose. Objective severity risk stratification at hospital admission is crucial for clinical management but remains challenging. This retrospective study aimed to evaluate admission baseline clinical characteristics for severity risk stratification in patients with psittacosis pneumonia. METHODS:We analyzed 60 patients diagnosed with psittacosis pneumonia, comprising 31 severe and 29 non-severe cases. All clinical and laboratory data were obtained from the initial evaluation within 24 h of admission. Firth penalized logistic regression was employed to identify potential indicators associated with disease severity. RESULTS:Of 60 patients with confirmed psittacosis pneumonia, 31 (52%) were classified as severe and had a higher frequency of respiratory failure, longer hospitalization, and more complications. Severe cases exhibited higher levels of CRP, PCT, d-dimer, LDH, AST, and BUN, lower albumin and lymphocyte counts, and more frequent bilateral lung lesions. Higher Strictly Mapped Read Number (SMRN) of C. psittaci was observed in severe cases, whereas monoinfection predominated in non-severe cases. Firth penalized logistic regression identified d-dimer, monocyte count, and LDH as key variables for admission risk stratification. The model showed good discriminative performance for admission risk stratification (AUC=0.888). CONCLUSIONS:Baseline d-dimer, monocyte count, and lactate dehydrogenase (LDH) appear to reflect distinct pathophysiological processes, including coagulation activation, inflammatory response, and systemic tissue injury. Their integration offers a potential framework for objective severity risk stratification at hospital admission. Such assessments may assist in clinical triage and the optimization of resource allocation for patients with psittacosis pneumonia.

Objectives:To identify independent risk factors for postcontrast acute kidney injury (PC-AKI) in patients with postoperative AKI (PO-AKI) following acute Stanford type A aortic dissection (ATAAD), and to develop a clinically applicable prediction model. Methods:This retrospective cohort study enrolled 604 PO-AKI patients (2014-2024, Nanjing Drum Tower Hospital) who underwent ≥1 postoperative contrast-enhanced CTA. PC-AKI was diagnosed per 2018 ESUR guidelines (sCr elevation ≥26.5 μmol/L or ≥1.5 times baseline within 48-72 h, with baseline defined as the most recent pre-CTA sCr). Three variable-selection strategies (backward stepwise AIC, LASSO and XGBoost-SHAP) were used. A multivariable logistic regression model was constructed, internally validated by bootstrap resampling (1,000 repetitions), and evaluated via AUC, calibration curves, Brier score, decision curve analysis, and clinical impact curve. Results:PC-AKI incidence was 9.8% (59/604), with striking recovery-dependent stratification: 3.5% in fully recovered PO-AKI vs. 52.5% in unrecovered PO-AKI. Independent predictors included PO-AKI stage 3 (OR = 3.144, 95% CI: 1.41-7.06) and unrecovered PO-AKI before first CTA (OR = 25.212, 95% CI: 12.57-53.49). The model exhibited good discrimination (AUC=0.848, 95% CI: 0.78-0.91) and calibration (Brier=0.057). PC-AKI was independently associated with prolonged ICU stay (RR = 1.521, 95% CI: 1.19-1.97) and incomplete renal recovery at discharge (OR = 2.554, 95% CI: 1.30-4.86), but not with 30-day mortality (P = 0.606). Conclusion:Dynamic PO-AKI recovery and advanced AKI stage are strongly associated with PC-AKI risk in post-ATAAD patients. The internally validated model may aid individualized risk stratification before contrast procedures in this high-risk subgroup. External validation is needed before clinical deployment.

This study aims to evaluate the diagnostic potential of L-carnitine (LC) for the early detection of cardiac surgery-associated acute kidney injury (CSA-AKI). We collected clinical data and serum samples from 27 patients admitted to the Intensive Care Unit (ICU) of Nanjing Medical University Affiliated Nanjing Hospital between February 2024 and March 2024. Among these, 13 patients were diagnosed with CSA-AKI, while 14 served as non-AKI controls. Untargeted metabolomic analysis revealed LC as a differentially expressed metabolite between the two groups. In addition, clinical data and serum samples were prospectively collected from patients undergoing cardiac surgery at Nanjing Medical University Affiliated Nanjing Hospital between May 2024 and July 2024. Serum samples were taken preoperatively (immediately upon entering the operating room) and postoperatively (immediately upon ICU admission). The levels of blood urea nitrogen (BUN), serum creatinine (Scr), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and LC were measured. Multivariate logistic regression analysis was used to find independent risk variables for CSA-AKI. The predictive performance of the biomarkers, the clinical model, and their combination were evaluated using the area under the receiver operating characteristic curve (AUC). This study included 170 patients who met the inclusion criteria for cardiac surgery. The incidence of CSA-AKI was 27.06

Sepsis-induced liver injury (SILI) is a severe complication of sepsis and is strongly associated with adverse clinical outcomes. However, the molecular mechanisms driving SILI pathogenesis remain poorly understood. In this study, we applied data-independent acquisition (DIA)-based quantitative proteomics to characterize protein expression profiles in liver tissues from 7 patients with SILI and 14 control patients. A total of 335 proteins were significantly dysregulated in SILI liver tissues, including 126 upregulated and 209 downregulated proteins. GO and KEGG pathway analyses revealed that the upregulated proteins were predominantly enriched in the cellular response to hypoxia and lysosome pathways, whereas the downregulated proteins were mainly associated with metabolic processes, particularly glutathione metabolism. Six key glutathione metabolism-related enzymes (GCLC, GSTO1, SOD1, GPX4, PRDX6, and IDH1) were selected for validation and were confirmed to be markedly reduced in SILI liver tissues by immunoblotting and qPCR. Correlation analyses further demonstrated that decreased expression of these enzymes was strongly associated with elevated markers of inflammation, coagulation disorders, and hepatic dysfunction, linking impaired antioxidant capacity to disease severity. Collectively, our findings reveal a distinct proteomic signature in SILI, characterized by profound suppression of glutathione metabolism, offering mechanistic insight into redox imbalance during SILI. These results highlight glutathione metabolic pathways as promising therapeutic targets for mitigating hepatocellular dysfunction in sepsis.

Abstract Background Cardiac surgery patients face significant postoperative risks. The albumin-corrected anion gap (ACAG) has emerged as a potential prognostic marker, but its role in predicting outcomes following cardiac surgery remains understudied. This study examined the association between preoperative ACAG levels and 28-day mortality following ICU admission in patients undergoing cardiac surgery. Methods This retrospective cohort study analyzed 5,006 cardiac surgery patients from the MIMIC-IV database. Patients were categorized based on ACAG levels: low (< 12 mmol/L), normal (12–20 mmol/L), and high (> 20 mmol/L). Hierarchical Cox proportional hazards models, restricted cubic spline (RCS) analysis, and exploratory mediation analysis were used to evaluate the association between preoperative ACAG and 28-day mortality following ICU admission. Incremental predictive analyses were additionally performed to assess whether ACAG improved the prognostic performance of models based on SOFA and SAPS II. Results Elevated ACAG levels (> 20 mmol/L) were significantly associated with a heightened risk of 28-day mortality following ICU admission across all models. In the most comprehensively adjusted model, the hazard ratio was 1.049 (95% CI 1.024–1.075, P < 0.001). ACAG demonstrated superior predictive value for 28-day mortality following ICU admission compared to the traditional anion gap (AUC 0.776 vs. 0.690). RCS revealed a nonlinear relationship, with mortality risk sharply increasing at ACAG levels above 20 mmol/L.In incremental predictive analyses, adding ACAG improved the prognostic performance of both SOFA- and SAPS II-based models. Exploratory mediation analyses suggested that SAPS II, GCS, and several electrolyte-related variables accounted for part of the observed association between preoperative ACAG and 28-day mortality. Conclusions Elevated preoperative ACAG levels were associated with increased 28-day mortality risk in cardiac surgery patients. Although part of this association may reflect overall illness severity and postoperative physiological stress, ACAG may serve as a useful early risk-stratification marker and could complement existing prognostic assessment frameworks. However, its causal role cannot be inferred from this observational study, and prospective studies are needed to validate these findings.

Background : Patients with severe acute pancreatitis (SAP) are at high risk for developing chronic critical illness (CCI) and persistent inflammation, immunosuppression, and catabolism syndrome (PICS). However, the specific risk factors and prognostic implications of these conditions remain unclear. Methods : This single-center retrospective cohort study enrolled adult patients with SAP requiring ICU stay > 14 days. Least absolute shrinkage and selection operator (LASSO) regression was used to select risk factors, followed by multivariable logistic regression to identify independent predictors for CCI and PICS. Discriminative ability of early severity scores was assessed using the area under the curve (AUC) and compared via the DeLong's test. Kaplan-Meier and Cox regression evaluated in-hospital and 90-day mortality differences. Results : Among 156 SAP patients, 60 (38.5%) developed CCI, 38 (24.4%) progressed to PICS, and 32 (20.5%) met both criteria. After multivariable adjustment and sensitivity analyses, the computed tomography severity index (CTSI) emerged as an independent risk factor for both CCI (odds ratio [OR]: 1.40, 95% confidence interval [CI] 1.18-1.66) and PICS (OR: 1.56, 95% CI 1.29-1.89), with AUC values of 0.747 and 0.804, respectively. Significant differences in both the in-hospital and 90-day mortality rates were observed among the three groups (p < 0.001). The patients meeting both CCI and PICS criteria exhibited markedly increased risks of in-hospital (hazard ratio [HR]: 7.80, 95% CI 1.53-39.77; p = 0.013) and 90-day mortality (HR: 3.11, 95% CI 1.08-8.95; p = 0.035) after the multivariable adjustment. Conclusions : CTSI is an independent risk factor for CCI and PICS in patients with SAP. Both CCI and PICS were associated with a heightened risk of adverse outcomes. Future studies are warranted to explore the clinical characteristics and targeted interventions for this high-risk subgroup.

BACKGROUND:Liver transplantation is a well-established treatment for end-stage liver disease, but the shortage of donor organs and the risk of ischemia-reperfusion injury remain significant challenges. Machine perfusion, an emerging technology, offers a promising solution by dynamically preserving and even repairing donor livers through extracorporeal perfusion. Recent advances in understanding the molecular mechanisms of ischemia-reperfusion injury have further highlighted the potential of machine perfusion to enhance liver preservation and expand the pool of viable donor organs. AIM OF REVIEW:This review aims to comprehensively summarize the research progress on machine perfusion strategies for liver preservation and explore their potential therapeutic applications beyond transplantation. We focus on the classification of machine perfusion methods based on temperature, their integration with novel therapeutic strategies, and their implications for improving liver viability and function. Key Scientific Concepts of Review: The review delves into three main types of machine perfusion: hypothermic machine perfusion (HMP), subnormothermic machine perfusion (SNMP), and normothermic machine perfusion (NMP). Each method offers distinct advantages in preserving liver function and reducing injury. We discuss how machine perfusion can be combined with mesenchymal stem cells, gene regulation, defatting cocktails, and modulators of autophagy and apoptosis to enhance liver repair and regeneration. Additionally, we highlight the potential of machine perfusion in supportive liver treatment, liver cancer therapy, and treatment efficacy evaluation. Despite these advancements, challenges such as optimizing perfusion parameters, understanding the immune status during perfusion, and ensuring long-term functionality of treated livers remain. This review emphasizes the need for further research to address these challenges and facilitate the clinical translation of machine perfusion technologies for advanced liver therapies.

MYCN is a key oncogenic driver in hepatocellular carcinoma (HCC) and a therapeutic challenge due to the historical undruggability of MYC transcription factors (TFs). Using a high-throughput MYCN promoter-luciferase reporter, we identified PhiKan 083 (PK83), a small molecule previously recognized as a mutant p53 activator, that dose-dependently suppresses MYCN expression in HCC cells. PK83 impaired the proliferation and survival of MYCN-high HCC cells, inducing DNA damage, apoptosis, and loss of clonogenic and spheroid growth potential, while sparing MYCN-low HCC cells and normal hepatocytes. Structure-activity analysis revealed that polar, hydrogen-bond-capable substituents on PK83's tricyclic scaffold are critical for its activity. Although PK83 broadly activates p53 signaling, its cytotoxicity in MYCN-high cells is not strictly dependent on intact p53, as confirmed in p53-knockout systems. Transcriptome profiling and pathway analysis demonstrated robust suppression of MYC/MYCN targets along with modulation of pathways linked to stress, differentiation, and metabolism. In primary HCC tumors, PK83-downregulated TFs, including oncogenic TFs ZMIZ1 and TARBP1, positively correlated with MYCN, whereas upregulated stress-responsive TFs ATF3 and FOSL2 showed a negative correlation. These findings suggest that PK83 suppresses MYCN expression and preferentially affects MYCN-high HCC cells in a p53-independent manner, warranting further preclinical investigation of PK83 and related compounds in MYCN-associated cancers.

Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is a severe complication in critically ill patients, accompanied by profound disturbances in lipid metabolism. However, the sequential changes in these lipoproteins and apolipoproteins and their association with ongoing clinical status remain unclear. This study aimed to elucidate the temporal patterns of lipid and apolipoprotein changes and their associations with subsequent day-14-window PIICS adjudication in intensive care unit (ICU) patients. This retrospective study included 262 ICU patients with a length of stay over 14 days, divided into PIICS and non-PIICS groups. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I), and apolipoprotein B (ApoB) were measured on ICU days 1 and 7, and in the day-14 assessment window. Logistic regression and receiver operating characteristic (ROC) analyses were used to assess discriminative ability for subsequent day-14-window PIICS adjudication, and survival was evaluated using Kaplan–Meier curves. PIICS patients had lower TC, LDL-C, and ApoA-I levels at all three timepoints, lower HDL-C on days 7 and 14, and lower ApoB levels on days 1 and 14 compared with non-PIICS patients. On day 7, HDL-C and ApoA-I demonstrated good discriminative ability for subsequent day-14-window PIICS adjudication. Exploratory analyses within the PIICS cohort suggested associations between higher day-14-window levels of these markers and more favorable 90-day survival patterns. Progressive hypolipidemia and hypoapolipoproteinemia, particularly involving HDL-C and ApoA-I, were associated with day-14-window PIICS adjudication, with exploratory associations observed for 90-day survival patterns. These changes may reflect shared inflammatory and metabolic processes rather than acting as independent prognostic markers.

BackgroundMaternal sepsis and other maternal infections (MSMI) remain major contributors to global maternal morbidity and mortality. However, the integration of epidemiological trends with causal inference evidence remains limited.MethodsUsing data from the Global Burden of Disease (GBD) 2021 study, we assessed temporal trends in MSMI burden from 1990 to 2021 and projected future patterns using ARIMA and Bayesian age-period-cohort (BAPC) models. In parallel, we conducted a two-sample multivariable Mendelian randomization (MVMR) analysis to evaluate the causal effects of inflammatory biomarkers and related factors on MSMI risk.ResultsAlthough age-standardized rates declined globally, absolute case numbers increased in low-SDI regions, largely driven by population growth. Forecasting results differed between ARIMA and BAPC models, reflecting distinct underlying assumptions regarding temporal dynamics. MVMR analysis identified inflammatory biomarkers, including CRP, IL-13, IL-10, RANTES, and NT-proBNP, as key causal factors associated with MSMI.ConclusionsThis study provides the first integrated framework combining global disease burden analysis with multivariable MR. By linking population-level trends with causal inference, our findings offer dual evidence to support targeted prevention strategies and advance precision public health interventions for MSMI.

BACKGROUND:Organ failure (OF) is a frequent and critical feature of severe acute pancreatitis (SAP). However, the association between OF patterns and mortality is still a subject of debate. AIM:To compare the clinical profiles of SAP cases with and without new-onset OF (NOOF) and identify adverse outcome predictors. METHODS:We conducted a retrospective cohort study of patients with SAP at a tertiary referral hospital to assess OF patterns. Based on the observed OF episodes, the cohort was categorized into OF (n = 113) and NOOF (n = 38) groups, with the latter further subdivided into new-onset single OF (n = 17) and new-onset multi-OF (n = 21). Independent predictors of mortality were identified through multivariable logistic regression and Cox proportional-hazards models. RESULTS:Significant differences were observed between the OF and NOOF groups in clinical severity and adverse outcomes, characterized by prolonged OF, extended organ support, and increased hospital length of stay. Binary logistic regression revealed significant associations with major complications [odds ratio (OR) = 13.2, 95% confidence interval (CI): 2.1-83.5, P = 0.006], NOOF (OR = 7.4, 95%CI: 1.3-42.5, P = 0.024), and Bedside Index for Severity in Acute Pancreatitis score (OR = 4.0, 95%CI: 1.3-12.0, P = 0.013). The 90-day mortality Cox proportional-hazards regression showed similar results [new-onset single OF hazard ratio (HR) = 6.8, 95%CI: 1.4-33.5, P = 0.019; new-onset multi-OF HR = 33.2, 95%CI: 9.4-117.3, P < 0.001; Bedside Index for Severity in Acute Pancreatitis score HR = 2.5, 95%CI: 1.3-4.6, P = 0.005]. CONCLUSION:New-onset persistent OF, particularly multi-OF, substantially increases mortality after multivariable adjustment in patients with SAP, highlighting the need for further investigation.

Background/Objectives: The gut-liver axis is central to sepsis, but assessing mesenteric perfusion remains challenging. Indocyanine green (ICG) clearance reflects hepatic blood flow. Since portal flow is derived from mesenteric circulation and supplies most of the liver, reduced ICG clearance may indicate mesenteric hypoperfusion, which can lead to enteral feeding intolerance (EFI). This study examines whether reduced ICG clearance in septic patients without overt liver injury is associated with EFI. Methods: This study is a secondary analysis of a prospective cohort study (March-May 2024, 20-bed ICU). Septic patients without sepsis-related liver injury or recent abdominal surgery were included. ICG plasma disappearance rate (ICG-PDR) was measured at admission; patients were grouped by ICG-PDR (≤18%/min vs. >18%/min). The primary outcome was EFI within 7 days. Multivariate logistic regression and correlation analyses were performed. Results: Among 77 patients (44 with ICG-PDR > 18%/min, 33 with ≤18%/min), the decreased ICG-PDR group had higher SOFA scores (8.4 ± 4.2 vs. 5.4 ± 3.5, p = 0.001) and higher EFI rates (66.7% vs. 43.1%, p = 0.041). Univariate analysis showed ICG-PDR ≤ 18%/min associated with EFI (OR = 2.632, p = 0.043), but this was attenuated after SOFA adjustment (OR = 2.247, p = 0.171). Reduced ICG-PDR correlated with central venous pressure (CVP) (r = 0.626, p < 0.001) but not with mean arterial pressure (r = -0.175, p = 0.129). Conclusions: In septic patients with preserved hepatocyte function, reduced ICG clearance is associated with EFI, but this relationship is largely explained by disease severity (SOFA). Reduced ICG clearance correlates with CVP; however, ICG-PDR cannot distinguish between portal venous and arterial inflow components. The exact mechanism remains speculative.

ABSTRACT Background Sepsis‐induced liver injury (SILI) is a fatal complication of organ failure that currently lacks reliable biomarkers for early diagnosis and risk prediction. This study aimed to explore the link between the systemic immune‐inflammatory index (SII) and SILI in adult patients with sepsis in the intensive care unit (ICU) at Nanjing Drum Tower Hospital. Methods This single‐center retrospective study analyzed the baseline characteristics of patients with sepsis admitted to the ICU between 2020 and 2024. Multifactorial logistic regression was used to identify independent risk factors for SILI. Curve fitting and Subgroup analyzes were performed to provide evidence for the stratified management of patients with different clinical characteristics. Receiver operating characteristic (ROC) curve analysis was performed to determine the predictive capacity of the SII. Results A total of 231 patients were included, of whom 53 (22.9%) developed SILI during ICU hospitalization. Patients with SILI exhibited a significantly higher in‐hospital mortality rate than non‐SILI cases (52.8% vs. 25.3%, p < 0.001). Elevated SII at ICU admission was strongly associated with SILI development (p < 0.001). Multivariable logistic regression identified the SII as an independent risk factor for SILI. ROC curve analysis demonstrated that SII had superior predictive performance for SILI occurrence, with an area under the curve of 0.85 (95% CI: 0.784–0.907). Conclusion This retrospective study revealed a substantial association between high SII and SILI in adult ICU patients with sepsis, suggesting that SII is a promising indicator for post‐sepsis SILI risk prediction.

BACKGROUND:The role of early enteral nutrition (EEN) in septic shock remains unclear. This study aimed to evaluate the association between EEN and clinical outcomes in septic patients requiring vasopressor therapy and invasive mechanical ventilation. METHODS:This retrospective cohort study used the MIMIC-IV database and included adult septic patients receiving vasopressors and mechanical ventilation at ICU admission. EEN was defined as enteral nutrition initiated within 48 hours. The primary outcome was 28-day mortality. Secondary outcomes included ICU and hospital length of stay, and duration of mechanical ventilation. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline confounders. Vasopressor dose was stratified based on the maximum norepinephrine-equivalent dose in the first 48 hours: low (<0.1 micrograms/kg/min), medium (0.1-0.5), and high (>0.5). Multivariable regression models were used to assess associations. RESULTS:A total of 4,673 patients were included, of whom 997 (21.3%) received EEN. Before weighting, EEN was associated with higher 28-day mortality (21.9% vs. 15.3%). After IPTW adjustment, early feeding remained significantly associated with increased mortality (adjusted odds ratio 1.80; 95% confidence interval, 1.42 to 2.27). In stratified analyses, EEN was associated with increased mortality in the medium-dose (odds ratio 1.66; 95% confidence interval, 1.26 to 2.19, p < 0.001) and high-dose groups (1.90; 1.21 to 2.98, p < 0.001), but not in the low-dose group(1.92, 1.12 to 3.27, p = 0.016). CONCLUSIONS:In critically ill septic patients receiving vasopressors and mechanical ventilation, EEN was associated with increased 28-day mortality, particularly among those receiving medium- or high-dose vasopressor therapy.

Recent studies highlight the role of skeletal muscle wasting in the sepsis-associated long-term mortality. Despite clinical recommendations for increased protein intake to counteract muscle wasting, the outcomes have been suboptimal, suggesting that anabolic resistance should be considered in addition to nutritional support. Emerging evidence suggests that impaired mitophagy hampers anabolic processes in skeletal muscle, exacerbating muscle wasting in sepsis. Furthermore, thyroid hormone (TH), which is essential for both anabolism and mitophagy, is locally inactivated by type 3 Deiodinase (Dio3) at the onset of sepsis, potentially disrupting mitophagy and contributing to anabolic resistance. Here we demonstrate that local hypothyroidism is a key factor impairing mitophagy in skeletal muscle during early sepsis, leading to metabolic disturbances and muscle wasting. Dio3 knockdown preserves muscle mass, and ameliorates metabolic dysfunction via mitophagy promotion in sepsis models. Mechanistically, the knockdown of Dio3 triggers an upregulation of NRK2, facilitating the restoration of NAD salvage synthesis. This enhancement of NAD levels subsequently activates Sirtuins deacetylase, which in turn decreases PINK1 acetylation, preventing its proteolytic processing by OMA1. Therefore, targeting Dio3 offers a promising therapeutic approach to counteract sepsis-induced muscle wasting.

Glycerol-3-phosphate dehydrogenase 1 (GPD1) gene defect can cause hypertriglyceridemia (HTG), which usually occurs in infants. The gene defect has rarely been reported in adult HTG patients. In the present study, we described the clinical and functional analyses of a novel GPD1 missense variant in a Chinese adult patient with recurrent hypertriglyceridemia‑related acute pancreatitis (HTG-AP), consuming a high-fat diet and smoking heavily. Exome sequencing was used to analyze the DNA of the adult patient’s blood sample. It was found that there was a new variant of GPD1 gene-p.K327N, which was verified by gold standard-sanger sequencing method. In vitro, the corresponding plasmid was constructed and transfected into human renal HEK-293T cells, and GPD1 protein levels were detected. A biogenic analysis was performed to study the population frequency, conservation, and electric potential diagram of the new variant p.K327N. Finally, the previously reported GPD1 variants were sorted and their phenotypic relationships were compared. A novel heterozygous variant of GPD1, p.K327N (c.981G > C), was found in the proband. Furthermore, the patient’s daughter carried this variant, whereas his wife did not carry the variant. The proband with obesity suffered eight episodes of HTG-AP from the age of 36 years, and each onset of AP was correlated to high-fat diet consumption and heavy smoking. In vitro, this variant exerted a relatively mild effect on GPD1 functions, which were associated with its effect upon secretion ( 25

OBJECTIVE:To develop and validate a nomogram model for predicting 30-day mortality among elderly patients with sepsis-associated liver dysfunction (SALD), to identify high-risk patients and improve prognosis. METHODS:A retrospective cohort study was conducted using data extracted from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database for elderly patients with SALD who were first admitted to the intensive care unit (ICU) of Beth Israel Deaconess Medical Center between 2008 and 2019, including basic characteristics, severity scores, underlying diseases, infection foci, 24-hour vital signs, initial laboratory indicators, 24-hour complications, and prognosis related indicators. Patients were randomly assigned to training group and validation group in a ratio of 7 : 3. The training group used the LASSO regression analysis, as well as multivariate Logistic regression analysis to screen for independent risk factors for 30-day mortality. A nomogram prediction model was constructed, and receiver operator characteristic curve (ROC curve), calibration curves, and decision curve analysis (DCA) were used to evaluate the model, and validate the model using the validation cohort. RESULTS:A total of 630 elderly patients with SLAD were included in the study, including 441 in the training group and 189 in the validation group. Oxford acute severity of illness score (OASIS) for training group [odds ratio (OR) = 1.060, 95% confidence interval (95%CI) was 1.034-1.086], 24-hour pulse oxygen saturation (SpO2; OR = 0.876, 95%CI was 0.797-0.962), initial mean corpuscular volume (MCV; OR = 1.043, 95%CI was 1.009-1.077), initial red blood cell distribution width (RDW; OR = 1.237, 95%CI was 1.123-1.362), initial blood glucose (OR = 1.008, 95%CI was 1.004-1.013), and initial aspartate aminotransferase (AST; OR = 1.000, 95%CI was 1.000-1.001) were independent risk factors for 30-day mortality in patients (all P < 0.05). Based on the above variables, a nomogram model was constructed, and the ROC curve showed that the area under the curve (AUC) of the model in the training group was 0.757 (95%CI was 0.712-0.803), with a sensitivity of 65.05% and a specificity of 74.90%; the AUC of the model in the validation group was 0.712 (95%CI was 0.631-0.792), with a sensitivity of 58.67% and a specificity of 81.58%. The calibration curves of the training and validation groups show that both the fitted curves were close to the standard curves. The Hosmer-Lemeshow test: the training group (χ 2 = 6.729, P = 0.566), the validation group (χ 2 = 13.889, P = 0.085), indicating that the model can fit the observed data well. The DCA curve shows that when the threshold probability of the training group was 16% to 94% and the threshold probability of the validation group was 27% to 99%, the net benefit of the model was good. CONCLUSIONS:OASIS, 24-hour SpO2, initial MCV, initial RDW, initial blood glucose and initial AST are independent risk factors for 30-day mortality in elderly patients with SALD. The nomogram based on these six variables demonstrates good predictive performance.

OBJECTIVE:To investigate the predictive value of combined detection of pro-opiomelanocortin (POMC) and α-melanocyte stimulating hormone (α-MSH) for progression to persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) in critical patients. METHODS:A retrospective cohort study was conducted, including critical patients admitted to the intensive care unit (ICU) of Nanjing Drum Tower Hospital between March 2020 and July 2021. Baseline data were collected, encompassing gender, age, infection source, smoking history, alcohol consumption history, and underlying diseases. On the first day of ICU admission, sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation II(APACHE II), serum POMC and α-MSH levels were recorded, along with the incidence of PIICS during ICU stay. Spearman correlation analysis was used to evaluate the correlation between POMC and α-MSH levels and disease severity. Receiver operator characteristic curve (ROC curve) was constructed to evaluate the predictive accuracy of POMC and α-MSH for PIICS progression. RESULTS:A total of 63 critical patients were included, among whom 47 (75%) developed PIICS and 16 (25%) did not. Compared with the non-PIICS group, the PIICS group showed significantly higher APACHE II and SOFA scores, while no statistical differences were observed in other baseline characteristics. The POMC level on the first day of ICU admission was significantly higher in the PIICS group than in the non-PIICS group, while the α-MSH level showed the opposite trend [POMC (ng/L): 2 149.02 (1 939.54, 2 761.06) vs. 1 884.73 (1 651.83, 2 234.99), α-MSH (ng/L): 1 526.95 (982.84, 2 092.94) vs. 2 182.76 (1 500.57, 3 401.51), both P < 0.05]. Spearman correlation analysis demonstrated that the serum POMC level at admission to the ICU was positively correlated with the SOFA score and the occurrence of PIICS (with r values of 0.275 and 0.279, respectively, both P < 0.05). In contrast, the α-MSH level was negatively correlated with the APACHE II score, SOFA score, and the occurrence of PIICS (with r values of -0.291, -0.339, and -0.287, respectively, all P < 0.05). ROC curve analysis demonstrated that both POMC and α-MSH had certain predictive value for the progression of critical patients to PIICS. The predictive value was the greatest when POMC and α-MSH were detected in combination, area under the curve (AUC) was 0.743, with the sensitivity and specificity for predicting PIICS being 87.2% and 50.0%, respectively. CONCLUSIONS:The combined detection of POMC and α-MSH on the first day of ICU admission showed certain predictive value for the progression of critical patients to PIICS.

OBJECTIVE:To explore the possible mechanisms underlying the occurrence and development of sarcopenia in clinical sepsis patients based on proteomic sequencing, and to identify potential targets for early intervention and treatment of sarcopenia in severe infectious states such as sepsis. METHODS:Muscle samples were obtained from two severe trauma patients with sepsis who underwent debridement treatment (sepsis group) hospitalized in the department of critical care medicine of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, and two non-sepsis patients who underwent open surgery (control group) in the department of orthopedics. Both were obtained through routine biopsy procedures. The morphology of muscle tissue was observed under a light microscope using hematoxylin-eosin (HE) staining; mitochondrial status in muscle tissue was observed under transmission electron microscopy. Further proteomic sequencing of muscle tissue was performed to compare and analyze proteins with significantly differentially expressed proteins. A threshold of fold change > 1.5 and P < 0.05 was set for significantly upregulated proteins, and fold change < -0.67 with P < 0.05 for significantly downregulated proteins. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted on the significantly differentially expressed proteins. RESULTS:Compared with the control group, the sepsis group showed significant muscle atrophy under light microscopy, with a markedly reduced cross-sectional area of muscle fibers (μm2: 2 291.77±807.77 vs. 4 570.29±1 687.53, P < 0.05). Electron microscopy revealed mitochondrial edema, vacuolization, and a decreased proportion of normal mitochondria [(16.8±10.0)% vs. (94.4±3.2)%, P < 0.05]. Compared with the control group, proteomic sequencing identified 171 significantly differentially expressed proteins in the sepsis group, including 122 significantly upregulated and 49 significantly downregulated proteins. GO analysis indicated that the top 10 enriched terms for upregulated significantly differentially expressed proteins were primarily related to response to stimulus and membrane-associated processes, including integral component of membrane, intrinsic component of membrane, detection of stimulus, detection of biotic stimulus, response to nutrient, endoplasmic reticulum membrane, endoplasmic reticulum subcompartment, detection of external biotic stimulus, nuclear outer membrane- endoplasmic reticulum membrane network and regulation of reactive oxygen species metabolic process. The top 10 enriched terms for downregulated significantly differentially expressed proteins were mainly associated with catalytic and metabolic processes, including 10-formyltetrahydrofolate catabolic process, folic acid-containing compound catabolic process, pteridine-containing compound catabolic process, 10-formyltetrahydrofolate metabolic process, oxidoreductase activity (acting on the CH-NH group of donors, NAD or NADP as receptors), oxidoreductase activity (acting on the CH-NH group of donors), folic acid-containing compound metabolic process, cellular modified amino acid catabolic process, dicarboxylic acid catabolic process and tetrahydrofolate catabolic process. These findings suggest that differentially expressed proteins in sepsis patients are significantly enriched in processes such as perception of biological stimuli and nutrient metabolism. KEGG pathway analysis revealed that the top 10 enriched pathways for differentially expressed proteins were mainly involved in detoxification and immune-related processes, including peroxisome, mineral absorption, nuclear factor-κB signaling pathway, influenza A, inflammatory bowel disease, nucleocytoplasmic transport, toxoplasmosis, herpes simplex virus 1 infection, ferroptosis and Leishmaniasis, indicating significant activation of peroxisomes and the nuclear factor-κB signaling pathway, and reduced mineral absorption activity in sepsis muscle tissue. CONCLUSIONS:Mitochondrial dysfunction-induced metabolic disorders may be a key factor in sarcopenia during sepsis. Targeting mitochondrial function to restore muscle metabolic homeostasis represents a potential therapeutic strategy for sarcopenia in severe conditions such as sepsis.