Background:Traditional Chinese Medicine (TCM) syndrome differentiation is central to individualized diagnosis, but its relationship with objective biochemical markers remains insufficiently characterized within explicit frameworks for intervention-analog causal inference. Objectives:This study aimed to construct a syndrome load index using confirmatory factor analysis (CFA) and item response theory (IRT), assess measurement invariance, and estimate adjusted intervention-analog associations with lipid and C-reactive protein (CRP) biomarkers. Methods:This single-center retrospective cohort study included 1,472 adults with structured TCM assessments and repeated biochemical measurements over 90 days. Syndrome load was modeled as a continuous latent variable using CFA/IRT. A Gaussian generalized propensity score with stabilized inverse probability of treatment weighting, combined with double machine learning cross-fitting, estimated associations with low-density lipoprotein-cholesterol (LDL-C), triglycerides (TG), and CRP z-scores, as well as corresponding binary abnormality outcomes. Quartiles were used only for descriptive diagnostics. Negative controls, baseline laboratory sensitivity analyses, weight diagnostics, and E-value analyses assessed robustness. Results:CFA/IRT models demonstrated good fit (CFI = 0.96, RMSEA = 0.042) and supported metric/scalar invariance across both sex and age groups. The emulated contrast represented a 1-standard deviation (SD) difference in baseline syndrome load as an analytic intervention analog, rather than a literal randomization of a latent construct. After weighting, all absolute standardized mean differences (SMDs) were <0.10, the effective sample size was 1,289, and no material positivity violations were observed. A 1-SD higher syndrome load was associated with higher TG z-scores (+0.18; 95%CI: 0.12-0.24; approximately +0.20 mmol/L), LDL-C z-scores (+0.11; 95%CI: 0.05-0.18; approximately +0.10 mmol/L), and CRP z-scores (+0.16; 95%CI: 0.09-0.23; approximately +0.31 mg/L), corresponding to 3-5% absolute risk increases in biomarker abnormalities. Baseline laboratory sensitivity analyses yielded attenuated but directionally consistent estimates (TG + 0.16, LDL-C + 0.09, CRP + 0.13 to +0.14 z-score units). Associations were stronger among participants aged ≥65 years, those with diabetes, or those with body mass index (BMI) ≥ 28. Negative controls were null, and E-values ranged from 1.54 to 1.92. Conclusion:Higher syndrome load was consistently associated with dyslipidemia and CRP elevation within an explicit intervention-analog framework. These findings support syndrome objectification and personalized cardiometabolic risk stratification; however, prospective intervention studies are required before concluding that the latent syndrome construct itself is directly modifiable.

This research focuses on the development and application of a novel enzyme‐responsive hydrogel, isoquercitrin‐loaded MMP‐responsive PEG–peptide hydrogel (PEG‐pp‐Iso), for osteochondral defect repair. The hydrogel is synthesized by conjugating isoquercitrin to poly (ethylene glycol) (PEG) and is further enhanced with hydroxyapatite (HAp) to facilitate cartilage and subchondral bone regeneration. To understand the molecular mechanisms behind its regenerative potential, transcriptomic analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, least absolute shrinkage and selection operator (LASSO) regression, and support vector machine‐recursive feature elimination (SVM‐RFE) algorithms, reveals that the CXCL12/CXCR4‐CDC42 signaling axis plays a crucial role in regulating bone marrow mesenchymal stem cells (BMSCs) migration, chondrogenic differentiation, and immune modulation. In vitro, PEG‐pp‐Iso effectively enhances the antioxidant activity, proliferation, migration, and chondrogenic differentiation of BMSCs, as evidenced by increased SOX9 and COL II expression. The inhibition of the CXCL12/CXCR4‐CDC42 axis significantly reduces these effects, confirming its importance in promoting cartilage repair. In vivo, PEG‐pp‐Iso hydrogels promote the migration of BMSCs to osteochondral defect sites, enhances cartilage matrix formation, and improve immune microenvironment regulation by increasing anti‐inflammatory macrophages and reducing pro‐inflammatory ones. These results highlight the potential of PEG‐pp‐Iso in promoting osteochondral regeneration and offer a novel approach to osteochondral defect repair through modulation of immune responses and stem cell activity.

Major adverse kidney events within 30 days (MAKE30) are associated with poor outcomes in patients with sepsis-associated acute kidney injury (SA-AKI). This study aimed to develop and validate a nomogram-based prediction model for MAKE30 in SA-AKI patients. Clinical and laboratory data were collected from SA-AKI patients admitted to eight tertiary Grade-A hospitals in Shanghai between January 2021 and October 2022, forming the development cohort. External validation was performed using data from SA-AKI patients treated at Ruijin Hospital between January 2017 and December 2019. A predictive nomogram was constructed using LASSO regression followed by multivariate logistic regression. Model performance was assessed using area under the curve (AUC), calibration plots, decision curve analysis (DCA), and clinical impact curves (CIC). The model was subsequently validated in the external validation cohort. A total of 531 SA-AKI patients were included, with 372 in the development cohort and 159 in the validation cohort. The incidence of MAKE30 was 55.6

Sepsis survivors face substantial risks of late mortality following discharge, underscoring the critical need for early prediction and targeted interventions for this vulnerable population. Early identification of those at high risk of mortality following discharge may optimize healthcare resource allocation. We sought to feed common clinical available data to a deep learning algorithm for predicting short to long-term mortality in sepsis survivors. This retrospective study, using a real-world database (MIMIC-IV database), screened adult critically ill patients with sepsis (as defined by Sepsis-3) admitted to the ICU with stays exceeding four days and who were discharged alive. Static features including patient characteristics, comorbidities, laboratory tests at ICU admission, and each dynamic SOFA component score over the first four days post-ICU admission were collected. We developed a deep learning-based combined model (DL-CMT) for post-discharge mortality prediction using multidimensional and time-series data. Comparisons were made with a multilayer perceptron and two machine learning models of random forest and eXtreme Gradient Boosting (XGBoost). 7532 patients fulfilled the inclusion criteria, and the observed mortality rates were 30.7

BACKGROUND:This study intends to examine any possible correlation between monocyte-to-lymphocyte ratio (MLR) and cardiovascular diseases (CVD). METHODS:Data from the 1999-2020 National Health and Nutrition Examination Survey (NHANES) in the USA were analyzed. Heart attacks, angina pectoris, congestive heart failure (CHF), coronary heart disease (CHD), and stroke were all covered by CVD. The independent relationships between these cardiovascular events and MLR levels, as well as other inflammatory indices (system inflammation response index (SIRI), aggregate index of systemic inflammation (AISI), and C-reactive protein-to-albumin ratio (CAR)), were investigated. Furthermore, interaction tests and subgroup analysis were performed. Diagnostic capacities were also predicted and compared using receiver operating characteristic (ROC) curves. RESULTS:Males made up 49.63% of the 46,289 people who were recruited in this study. The prevalence of CVD and its events were as follows: CHF at 2.99%, CHD at 3.72%, angina pectoris at 2.57%, heart attacks at 3.94%, and stroke at 3.48%, with CVD itself at 7.98%. MLR and CVD were positively correlated. Specifically, smooth curve fittings also found a non-linear relationship between MLR and CVD. Moreover, higher MLR levels were linked to increased rates of CHF, CHD, and strokes. SIRI was also found to have a positive correlation with CVD. MLR outperformed other inflammatory indices (SIRI, AISI, and CAR) in terms of discriminative capacity and accuracy in predicting CVD, CHF, CHD, angina pectoris, heart attack, and stroke, according to ROC analysis. CONCLUSIONS:Compared with other inflammatory indicators (SIRI, AISI, and CAR), MLR appears to be a better inflammatory index for predicting CVD, CHF, CHD, angina pectoris, heart attack, and stroke. American adults with elevated MLR and SIRI should be aware of the possible harm caused by CVD. Causal inference is, however, limited by the cross-sectional design and dependence on self-reported data. Further longitudinal studies are needed to validate these findings.

Background:Nerve transplantation, as a classical nerve repair technique, has received extensive attention in recent years. However, the rapid development of this field has also brought challenges such as knowledge fragmentation and the blurring of research hotspots. Therefore, at present, the future research direction of this field is not clear. Through the research method of bibliometrics, this study investigates the research hotspots and development trends in this field, and fills the research gap in this field. Methods:The publications in the core database of Web of Science (WoS) were collected, and the included publications were analyzed by bibliometric methods after the screening exclusion process. The basic information of the publications was analyzed, and the future development direction and research hotspots were predicted and visualized. Results:A total of 847 publications were included in the research, in the past 10 years, the number of publications in this field has nearly doubled (49 publications), and the number of publications in this field will continue to grow in the next 15 years. In terms of national contribution, the United States is the largest contributor (289 publications), and in terms of institutional contribution, Fudan University is the largest contributor (47 publications). Conclusion:This is the first bibliometric analysis in the field of nerve transplantation, which included all publications in this field in the past decade. Our results illuminate the contributions of countries and institutions, international cooperation, interdisciplinary relationships, and future research directions. This research will point out the future development path of nerve transplantation.

Objective: This study aimed to investigate the effects of pancreatic enzyme replacement therapy (PERT) on infection level, nutrition condition and prognosis of patients with sepsis. Method: According to the fecal elastase-1 (FE1) level, 68 sepsis patients who were diagnosed with pancreatic exocrine insufficiency (PEI) from 2014.11 to 2015. 12 in our hospital were randomly divided into two groups: regular nutritional support (RNS) group or PERT group. A total of 15 patients were dropout for various reasons.Finally, 25 patients were enrolled in PERT group and 28 in RNS group. APACHEII score, SOFA score, inflammatory biomarkers including C-reaction protein (CRP), white blood cell (WBC), procalcitonin (PCT), nutrition markers including prealbumin (PA), transferrin (TFN), retinol binding protein (RBP), creatinine/height index (CHI) were recorded at the day 1 (D1), day7 (D7) and day14 (D14) since they were admitted in ICU. These data were compared between and within the two groups chronologically. Also, the duration of vasoactive drug using (DVAD), mechanical ventilation (DMV), length of stay in ICU (LOS) and survival rate within 14 days were compared between the two groups. Results: There were no differences in general information (Age and gender) between PERT and RNS groups. Compared with the RNS group, CRP, WBC and PCT declined significantly at D14 in the PERT group. Especially, CRP declined significantly over time in both groups. In addition, compared with the RNS group, in the PERT group at D14, nutrition markers, including PA, TFN, RBP and CHI increased significantly, APACHEII score and SOFA score decreased significantly. And DVAD, DMV and LOS were significantly shortened in PERT group, but the survival rate within 14 days was not significantly changed. Conclusion: The PERT can improve infection level, nutrition condition and prognosis of patients with sepsis. And the underlying mechanism may be related to improve pancreatic exocrine insufficiency of these patients.

INTRODUCTION:The peptidyl-propyl cis-trans isomerase F (Ppif) gene encodes cyclophilin D. Its involvement suggests that sepsis-induced pancreatic injury may relate to mitochondrial membrane pore transition proteins, offering potential targets for pancreatic functional protection. This study aimed to determine whether sepsis leads to pancreatic injury and whether knockout (KO) of Ppif protects against sepsis-induced pancreatic injury. METHODS:A septic mouse model was established using cecal ligation and puncture (CLP). Mice were divided into four groups: sham, CLP, Ppif KO-sham, and Ppif KO-CLP. Serum amylase and interleukin (IL)-6 levels were measured in blood and pancreatic tissues 24 h post CLP. Pancreatic tissues were analyzed using hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, and electron microscopy. RESULTS:In the CLP-induced sepsis model mice, serum IL-6, serum amylase, pancreatic tissue pathological scores, and terminal deoxynucleotidyl transferase dUTP nick-end labeling apoptosis indices were elevated. Compared with wild-type CLP mice, Ppif KO mice exhibited lower levels of serum IL-6 and amylase, pancreatic tissue pathological scores, and apoptosis indices, indicating that KO of Ppif had a protective effect against septic pancreatic injury. Electron microscopy of tissues from CLP mice revealed basement membrane irregularities, nuclear shrinkage, mitochondrial swelling, cristae deformation, and endoplasmic reticulum structural disorder. In Ppif KO CLP mice, pancreatic acinar cells exhibited more autophagosomes. CONCLUSIONS:Our study demonstrates that fecal peritonitis triggers a systemic inflammatory response, which subsequently induces pancreatic injury, and that KO of Ppif may mitigate this pathological injury.

BACKGROUND:Malnutrition is associated with poor outcomes. Exocrine pancreatic insufficiency (EPI) may be an overlooked factor contributing to malnutrition. Early nutritional support improves the prognosis of critically ill patients. The effect of pancreatic enzyme preparations on nutritional status and prognosis in critically ill patients requires further study. METHODS:An exploratory, single-center, randomized controlled trial was conducted in critically ill adult patients. A total of 768 patients admitted to the Department of Critical Care Medicine between November 2021 and August 2022 were screened, and 317 patients who met the inclusion criteria were randomized into the pancreatic enzyme replacement therapy (PERT) group or the non-pancreatic enzyme replacement therapy (NOT PERT) group. Neither group received a specific enteral nutrition formula. The formula was selected according to the patient's condition to provide the required calories and protein. The primary outcome was the change in the cross-sectional area of the rectus femoris muscle (RFCSA). Secondary outcomes included changes in rectus femoris muscle echogenicity, retinol-binding protein, and prealbumin levels; duration of mechanical ventilation; APACHE II scores; and 14-day and 28-day mortality. This trial was registered in ChiCTR under identifier 2100052385. RESULTS:RFCSA decreased over time. PERT combined with enteral nutrition appeared to slow the decline in RFCSA but had no significant effect on rectus femoris muscle echogenicity. PERT had no significant effect on retinol-binding protein, prealbumin, or the duration of mechanical ventilation. No significant differences were observed in APACHE II scores, 14-day mortality, or 28-day mortality. CONCLUSIONS:PERT may serve as an effective adjunct to nutritional support in critically ill patients.

The role of chlorhexidine in oral care for mechanically ventilated elderly patients remains debated, particularly regarding its impact on oral microbiota and clinical outcomes. To compare oral microbiota composition and prognosis among elderly mechanically ventilated patients receiving oral care with either chlorhexidine solution or normal saline. Sixty intubated patients (≥ 65 years) were randomized to receive oral care with 0.12

The stability and sustainability of economic growth have always been a hot topic of concern in the academic and practical circles around the world. The purpose of this study is to examine the stability and sustainability of China's economic growth. For over 200 economies around the world, ensuring the stability and sustainability of their economic development in the face of sudden and catastrophic events is a great challenge. The COVID-19 epidemic in 2020 is just an emergency to test the economic development of each economy. The method adopted in this study is to observe the economic growth of more than 200 countries and regions in the world in 2020, visually measure the economic growth of each economy after being impacted by the COVID-19 epidemic, and then further explain the reason for the robustness of China's economic growth with the help of shock theory, statistical methods, including variance coefficient, nonlinear econometric model, shock entropy and other quantitative indicators. This study found that although the impact of the COVID-19 epidemic on China's economic growth is huge on the whole, the resilience of China's economic growth is significant, and the original trend of economic growth has not changed because of the impact of the COVID-19 epidemic. Its average variance coefficient is only 0.42, and the shock entropy is almost 0. The conclusion is that China's economic development is not only robust, but also sustainable. The practical significance of this study is that the perfect industrial economic structure and the Chinese style COVID-19 epidemic prevention and control model can still maintain the existing track of economic development at a certain cost of economic development, ensuring that the overall trend of economic growth remains strong, which lays a solid foundation for economic and social development after the COVID-19 epidemic.

BACKGROUND:Elderly patients undergoing lung resection are particularly susceptible to postoperative adverse respiratory events (AREs), due to age-related physiological decline and a higher incidence of residual neuromuscular blockade (RNMB). Sugammadex is a selective relaxant binding agent that enables rapid and complete reversal of aminosteroid neuromuscular blocking agents such as rocuronium, offering potential advantages over traditional acetylcholinesterase inhibitors like neostigmine. However, evidence directly comparing the impact of sugammadex versus neostigmine on clinically relevant respiratory outcomes, particularly AREs in elderly patients undergoing lung resection remains limited. METHODS AND ANALYSIS:This is a prospective, double-blinded, randomized controlled clinical trial involving 530 elderly patients (≥65 years old) scheduled for video-assisted thoracoscopic lung surgery requiring one-lung ventilation. Patients will be 1:1 randomized to receive sugammadex or neostigmine for neuromuscular blockade reversal. The primary outcome is a composite of AREs occurring in the post-anaesthesia care unit (PACU). Secondary outcomes include time from neuromuscular to extubation, the composite of ARE and rescue measures, PACU length of stay, postoperative pulmonary and extra-pulmonary complications, unplanned intensive care unit (ICU) admission, chest drainage tube duration, hospital length of stay, and mortality. All patients will be followed up until 30 days after surgery. The primary analysis will be conducted on a modified intention-to-treat basis. DISCUSSION:This trial is designed to address a critical gap in perioperative care for elderly patients undergoing lung resection by directly comparing sugammadex and neostigmine in terms of clinically meaningful respiratory outcomes. While previous studies have primarily focused on pharmacokinetic profiles or surrogate markers such as train-of-four recovery time, evidence regarding the impact of these agents on postoperative AREs remains limited. Given the growing elderly surgical population and the high incidence of RNMB and pulmonary complications in this group, the findings of this study will offer valuable insight into optimizing neuromuscular blockade reversal strategies. TRIAL REGISTRATION:This study is registered at Chinese clinical trial registry (ChiCTR2400094005).

OBJECTIVE:To identify cellular senescence-associated genes in lung squamous cell carcinoma (LUSC) and explore their relationship with tumour microenvironment, immunotherapy response, and prognosis. STUDY DESIGN:An observational study. Place and Duration of the Study:  Department of Thoracic Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China, from September to October 2023. METHODOLOGY:Prognostic genes and clinical information of LUSC were derived from the Cancer Genome Atlas (TCGA). Subsequently, R packages were used to obtain differentially expressed genes (DEGs) associated with cellular senescence prognosis. In addition, univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to construct cellular senescence-related gene signatures to determine the degree of risk. Sensitivity to immune checkpoint inhibitors (ICI) was evaluated according to the median risk score, which served as an independent prognostic factor. RESULTS:By univariate Cox regression analysis of gene expression data and overall survival data in the TCGA-LUSC cohort, 11 DEGs associated with prognostic cellular senescence were identified. The ageing prognostic models include genes of IGFBP1, SERPINE1, SIX1, and TRPM8. Tumour immune dysfunction and exclusion (TIDE) score and tumour mutation burden (TMB) score were better in the low-risk group, with advantages in terms of prognostic and immunotherapy response rate. CONCLUSION:The results suggest that senescence-related determinants are involved in the tumour microenvironment through senescence-related secretory phenotypes and can be used as reliable biomarkers for LUSC immunotherapy and prognosis. KEY WORDS:Cellular senescence, Lung squamous cell carcinoma, Tumour microenvironment, Immunotherapy, Prognosis.

Sepsis, a severe systemic infection triggered by the invasion of bacterial, viral, fungal, and other pathogens into human tissues, frequently results in substantial damage to the heart, which is one of the primary organs affected. This myocardial injury is strongly linked to poor patient outcomes in sepsis. Recent research has identified key factors such as mitochondrial dysfunction, metabolic disturbances, cell death, and dysregulated inflammatory responses as critical contributors to the pathogenesis of sepsis-induced myocardial injury (SIMI). These mechanisms not only enhance our understanding of SIMI but also offer potential therapeutic targets. The review aims to investigate the pathophysiological mechanisms driving myocardial injury in sepsis, particularly from the perspective of mitochondrial dysfunction. It will examine the complex interactions between inflammatory dysregulation, calcium homeostasis disruption, metabolic reprogramming, and mitochondrial dysfunction in the onset and progression of SIMI. By exploring therapeutic approaches focused on restoring mitochondrial function, this research aims to establish a theoretical framework for interventions targeting SIMI, thereby providing a robust foundation for the development of targeted therapies for SIMI.

Eravacycline, a novel tetracycline antibiotic, may be an effective treatment option for Klebsiella pneumoniae infections. We thus conducted an in vitro susceptibility analysis for eravacycline in 211 K. pneumoniae isolates. Eravacycline achieved an overall susceptibility rate of 86% against K. pneumoniae, and the sensitivity rates to carbapenem-susceptible Klebsiella pneumoniae and carbapenem-resistant Klebsiella pneumoniae (CRKP) strains were 100% and 84%, respectively. The combined drug sensitivity test in vitro for eravacycline and polymyxin B demonstrated a synergistic effect in 20% of eravacycline-resistant CRKP strains. IMPORTANCE:Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global priority pathogen due to its limited therapeutic options and high morbidity, which urgently needs new antibiotics that are not affected by common resistance mechanisms. As the next generation of fluorocycline antibiotics, eravacycline can circumvent the tetracycline-specific resistance pathways by its structural modifications, which may be a candidate antibiotic for CRKP infections. The present study evaluated the in vitro activity of eravacycline against CRKP strains, including carbapenemase producers, and explored synergistic interactions with existing antibiotics. By determining the efficacy spectrum and combinatorial potential for eravacycline, this study will directly guide clinical strategies to combat infections caused by CRKP and optimize treatment regimens for high-risk populations.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant global health challenge due to its limited treatment options and high mortality rates. Meanwhile, the prevalence of non-carbapenemase-producing CRKP (NC-CRKP) strains is increasing, but their resistance mechanisms remain less understood compared to those of carbapenemase-producing CRKP (CP-CRKP). In this study, KP-469, an NC-CRKP strain, was found to lack the major porins OmpK35 and Ompk36 but possessed OmpK37, coexisting with ESBL resistance genes CTX-M and SHV. Membrane porin coding sequence alignment revealed a minor deletion in Ompk35 and a 768 bp insertion sequence in the promoter region (IS-PR) of Ompk36, located between the -10 region and the ribosome binding site (RBS). In the KO-469 strain with scarless excision of IS-PR and the constructed pHSG396-promoter-Ompk36 strain that incorporated wild-type Ompk36 promoter into KP-469, the transcription levels of Ompk36 were significantly higher than that in KP-469 strain, and His-tag antibody quantification further confirmed the regular expression of Ompk36 in KO-469. These results demonstrated that IS-PR markedly reduced the transcriptional and translational efficiency of Ompk36 in the KP-469 strain, leading to decreased permeability to meropenem. Moreover, the restored susceptibility to meropenem in the KO-469 strain was validated by in vitro antimicrobial susceptibility tests and an in vivo intraperitoneal infection model constructed in neutrophil-depleted mice. The novel carbapenem resistance mechanism of NC-CRKP caused by the insertion sequence in the OmpK36 promoter will facilitate the development of antibacterial regimens for treating NC-CRKP infections.

Recognition of carbapenem-resistant gram-negative bacteria (CR-GNB) carriage is frequently delayed, which increases the risk of subsequent infection and transmission. Previously, we developed a scoring system to identify CR-GNB carriage upon intensive care unit (ICU) admission. Although the ICU-CARB score showed satisfactory performance, it has not been externally validated. In this study, therefore, we externally validated the ICU-CARB score. In the previous article, we introduced a risk-scoring system that incorporated seven key variables: neurological disease, high-risk department history, length of stay ≥ 14 days, ICU history, invasive mechanical ventilation, gastrointestinal tube placement, and carbapenem usage. To externally validate the ICU-CARB score, we conducted a study involving patients admitted to the ICUs of four tertiary hospitals between January 2021 and December 2023. Patients from three hospitals were grouped into Cohort I (n = 815) and those from the fourth hospital into Cohort II (n = 1602). Model calibration, discrimination, and performance were then assessed. A total of 2417 patients were included, among which 289 (12

Background and purpose: Acute kidney injury (AKI) is a common serious complication in sepsis patients with a high mortality rate. This study aimed to develop and validate a predictive model for sepsis associated acute kidney injury (SA-AKI). Methods: In our study, we retrospectively constructed a development cohort comprising 733 septic patients admitted to eight Grade-A tertiary hospitals in Shanghai from January 2021 to October 2022. Additionally, we established an external validation cohort consisting of 336 septic patients admitted to our hospital from January 2017 to December 2019. Risk predictors were selected by LASSO regression, and a corresponding nomogram was constructed. We evaluated the model's discrimination, precision and clinical benefit through receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA) and clinical impact curves (CIC) in both internal and external validation. Results: AKI incidence was 53.2% in the development cohort and 48.2% in the external validation cohort. The model included five independent indicators: chronic kidney disease stages 1 to 3, blood urea nitrogen, procalcitonin, D-dimer and creatine kinase isoenzyme. The AUC of the model in the development and validation cohorts was 0.914 (95% CI, 0.894-0.934) and 0.923 (95% CI, 0.895-0.952), respectively. The calibration plot, DCA, and CIC demonstrated the model's favorable clinical applicability. Conclusion: We developed and validated a robust nomogram model, which might identify patients at risk of SA-AKI and promising for clinical applications.

Ferroptosis is a novel form of programmed cell death which can exacerbate lung injury in septic acute respiratory distress syndrome (ARDS). Alveolar macrophages, crucial innate immune cells, play a pivotal role in the pathogenesis of ARDS. Ferritinophagy is a process of ferritin degradation mediated by nuclear receptor coactivator 4 (NCOA4) which releases large amounts of iron ions thus promoting ferroptosis. Recent evidence revealed that inhibiting macrophage ferroptosis can effectively attenuate pulmonary inflammatory injury. Melatonin (MT), an endogenous neurohormone, has antioxidant and anti-inflammatory effects and can reduce septic ARDS. However, it is not clear whether MT's pulmonary protective effect is related to the inhibition of macrophage ferritinophagy. Our in vitro experiments demonstrated that MT decreased intracellular malondialdehyde (MDA), Fe2+, and lipid peroxidation levels, increased glutathione (GSH) levels and cell proliferation, and upregulated glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) protein levels in LPS-treated macrophages. Mechanistically, the antiferroptotic effect of MT on LPS-treated macrophages was significantly compromised by the overexpression of NCOA4. Our in vivo experiments revealed that MT alleviated the protein expression of NCOA4 and FTH1 in the alveolar macrophages of septic mice. Furthermore, MT improved lipid peroxidation and mitigated damage in alveolar macrophages and lung tissue, ultimately increasing the survival rates of septic mice. These findings indicate that MT can inhibit ferroptosis in an NCOA4-mediated ferritinophagy manner, thereby ameliorating septic ARDS.

Objective:This study aimed to evaluate the in vitro activity of omadacycline (OMC) and OMC-based combination therapy against carbapenem-resistant Klebsiella pneumoniae (CRKP). Methods:The broth microdilution assay assessed the in vitro susceptibility of CRKP to OMC. The checkerboard assay was performed to evaluate the activity of OMC combined with polymyxin B (PB), amikacin (AN), or meropenem (MEM) against KPC-producing (class A) CRKP strains, and OMC combined with PB, aztreonam (ATM), MEM, or AN against class B and class A plus class B CRKP strains. Synergistic effects of OMC and PB were further evaluated by time-kill assays in the KPC-producing CRKP strains. Results:Broth microdilution assays revealed a notable variation in susceptibility between KPC-producing and class B CRKP strains, with MIC50/90 of 32/32 mg/L and 0.5/8 mg/L, respectively. Although KPC-producing CRKP strains were resistant to OMC, a synergistic effect was observed in 37.5% of KPC-producing CRKP strains when OMC was combined with PB. In the nine KPC-producing CRKP strains, time-kill assays found that cell densities of six strains (66.7%) decreased by 3.61 ± 0.23 log10 CFU/mL compared to the initial inoculum after 2 hours of PB exposure. The cell densities further decreased by an average of 2.38 ± 0.23 log10 CFU/mL when the six strains were exposed to OMC plus PB, confirming their potent synergism. Conclusion:OMC monotherapy is ineffective against KPC-producing CRKP strains, but OMC plus PB has a potent synergistic effect on them, suggesting that OMC plus PB is the preferred combination therapy against KPC-producing CRKP in vitro.