Sepsis-associated acute kidney injury (SA-AKI) is a common and life-threatening complication of sepsis. Increasing evidence suggests that dysregulation of the renin-angiotensin-aldosterone system (RAAS) is involved in its pathogenesis, but the direction of this dysregulation is not uniform. In some patients and experimental settings, elevated renin and angiotensin I levels are accompanied by an inadequate rise in circulating angiotensin II (Ang II), suggesting impaired effective Ang II generation and relative Ang II deficiency. In other contexts, persistent or excessive local Ang II signaling may continue to promote vasoconstriction, inflammation, oxidative stress, and fibrosis. These differences likely reflect the heterogeneity of sepsis across disease stages, models, biological compartments, and measurement methods. Accordingly, RAAS-targeted therapy in SA-AKI should be interpreted within a context-dependent framework: exogenous Ang II may benefit selected patients with impaired effective Ang II generation, whereas ACE2/Ang-(1-7)/Mas-based or anti-angiotensin II type 1 receptor (AT1R) strategies may be more relevant in settings of maladaptive Ang II signaling. These observations support a biomarker- and endotype-guided approach to RAAS-targeted therapy in SA-AKI.

OBJECTIVE:To evaluate the comprehensive protective effects of ulinastatin (UTI) on intestinal structure and function during sepsis and to explore whether UTI restores intestinal motility through mechanisms involving attenuation of interleukin-1β (IL-1β)-mediated inflammation. METHODS:A murine cecal ligation and puncture (CLP) model was established and mice received intravenous UTI. Primary outcomes included 7-day survival, time to first black stool, fecal output, small-intestinal transit, and blinded histopathology. Barrier integrity was assessed by Alcian Blue-Periodic Acid-Schiff staining for goblet-cell mucin and Claudin-1 immunofluorescence; inflammation by IL-1β, tumor necrosis factor (TNF)-α, and IL-6; and enteric nerve integrity by counting HuD-positive neurons and measuring PGP9.5-labeled nerve fibers. To assess direct effects, primary enteric neurons were stimulated with lipopolysaccharide or IL-1β in vitro. An IL-1β-neutralizing antibody (nAb) was used alone or with UTI to interrogate mechanism. RESULTS:UTI improved survival, shortened stool latency, increased pellet output, and enhanced transit after CLP. UTI attenuated intestinal injury, restored goblet-cell mucin production and Claudin-1 expression, and reduced systemic and colonic IL-1β, TNF-α, and IL-6. Moreover, UTI also increased the number of HuD+ enteric neurons and preserved PGP9.5-labeled nerve fiber networks. In vitro, UTI preserved βIII-tubulin-defined neuronal morphology and reduced IL-1β secretion. IL-1β nAb reproduced the protective benefits on enteric nerve and intestinal motility; no significant additive benefits were observed when IL-1β nAb was combined with UTI. CONCLUSION:UTI confers broad and integrated protection of the intestine during sepsis. These findings suggest that IL-1β-mediated inflammatory signaling plays a key role in UTI-induced enteric neuroprotection and restoration of intestinal motility.

A LightGBM model was developed to predict sepsis-induced coagulopathy (SIC) within 72 h of ICU admission using routine clinical data. The model achieved an ROC-AUC of 0.937 (95

BackgroundPatients with pulmonary embolism (PE) and chronic kidney disease (CKD) have a fragile hemostatic balance, yet evidence comparing bleeding risk between direct oral anticoagulants (DOACs) and warfarin in critically ill patients remains limited. We compared overall and major bleeding risks associated with DOACs versus warfarin in ICU patients with PE and CKD.MethodsWe conducted a retrospective cohort study using the MIMIC-IV (v3.1) database. Adult ICU patients with PE and an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 treated with DOACs or warfarin were included. Propensity score matching (PSM) was used as the primary adjustment strategy, with stabilized inverse probability of treatment weighting (IPTW) as sensitivity analysis. Cox proportional hazards models were applied. The primary outcome was any bleeding, and the secondary outcome was major bleeding.ResultsAmong 1,363 patients, 832 received warfarin and 531 received DOACs. After PSM, 1,038 patients were well balanced. In IPTW-weighted analyses, DOAC use was associated with a higher risk of any bleeding compared with warfarin (HR 1.37, 95% CI 1.13-1.66; P = 0.001), while no significant difference was observed for major bleeding (HR 0.97, 95% CI 0.74-1.28; P = 0.84). Results were consistent in the PSM cohort. Renal function did not significantly modify the relative bleeding risk.ConclusionsIn critically ill patients with PE and CKD, DOACs were associated with increased overall bleeding but not major bleeding compared with warfarin. Differentiating non-major from major bleeding is essential when selecting anticoagulant therapy in this population.

The optimal airway strategy during out-of-hospital cardiac arrest (OHCA) remains uncertain. This study investigated the association between prehospital endotracheal intubation (ETI) and return of spontaneous circulation (ROSC) using a regional emergency medical services registry. This retrospective cohort study analyzed 6,162 adult non-traumatic OHCA patients treated by emergency medical services between October 2023 and November 2024. Patients were categorized into an ETI group (n = 1,448) and a basic airway (BA) group (n = 4,714). The primary outcome was prehospital ROSC. Long-term survival and neurological outcomes were not available in the registry. Multivariable logistic regression and propensity score-matched sensitivity analysis were used to evaluate the association between ETI and ROSC while accounting for measured confounders. Airway strategy was selected by on-scene physicians during routine EMS care, and rhythm-stratified unadjusted analyses were performed to describe whether the ETI-ROSC association differed by initial rhythm category. ROSC occurred more frequently in the ETI group than in the BA group (21.1

Cellular senescence has emerged as an important contributor to acute kidney injury (AKI); however, its role in sepsis-associated acute kidney injury (SA-AKI) remains insufficiently characterized. This study aimed to investigate the involvement of cellular senescence in SA-AKI and to determine the contribution of the Toll-like receptor (TLR)/MyD88 signaling pathway. A cecal ligation and puncture (CLP) mouse model was established to induce SA-AKI. Cellular senescence markers and inflammatory indices were evaluated at 24, 48, and 72 h after injury using senescence-associated β-galactosidase (SA-β-Gal) staining, immunofluorescence, and quantitative real-time PCR (qPCR). Integrated transcriptomic and proteomic analyses were performed to identify candidate hub genes involved in SA-AKI. Human Kidney-2 (HK-2) cells were used to assess the role of MyD88 in tubular epithelial cell senescence, and mice with tubular epithelial cell-specific deletion of Myd88 were subsequently used to investigate the in vivo role of MyD88 in SA-AKI. At 72 h after CLP, SA-AKI was associated with a marked increase in SA-β-Gal activity, p21 expression, DNA damage, and inflammatory cytokine production, together with decreased lamin B1 (LAMNB1) expression and reduced proliferative activity, indicating the induction of cellular senescence. Inflammatory cell infiltration was also evident at this time point. Integrated omics analysis identified MyD88 as a key candidate molecule. In HK-2 cells, pharmacological inhibition of MyD88 attenuated lipopolysaccharide-induced cellular senescence and inflammatory responses. Consistently, tubular epithelial cell-specific deletion of Myd88 significantly reduced cellular senescence, inflammatory infiltration, and renal injury following SA-AKI. These findings indicate that cellular senescence in SA-AKI is mediated, at least in part, by the TLR/MyD88 signaling pathway. Targeting this pathway may represent a potential therapeutic strategy for attenuating SA-AKI progression and improving renal outcomes.

BACKGROUND:Coagulation dysfunction is a major contributor to the increased mortality associated with sepsis (Levi et al., 2013; Gando et al., 2019 [1,2]), in which platelet activation, neutrophil activation, and neutrophil extracellular trap (NET) formation play important roles. Recent studies have suggested that HSP47 is involved in venous thromboembolism and platelet/neutrophil activation (Thienel et al., 2023a [3]); however, whether HSP47 contributes to platelet-mediated NET formation and coagulation dysfunction during sepsis remains unclear. OBJECTIVES:This study aimed to investigate the involvement of heat shock protein 47 (HSP47) in platelet activation, NET formation, and coagulation dysfunction during sepsis, and to evaluate the potential effect of pharmacological modulation of HSP47-associated responses. METHODS:A murine model of sepsis was established using cecal ligation and puncture (CLP), and mice were treated with Col003, a functional inhibitor of HSP47-associated responses. Platelet HSP47 signal, histopathological injury, coagulation parameters, platelet activation, granule release, platelet-leukocyte aggregate formation, and NET formation were assessed. Seven-day survival was monitored in the main CLP intervention experiment, and 48 h short-term survival was assessed in the Col003 timing experiment. Additional in vitro experiments using bone marrow-derived neutrophils were performed to explore the involvement of the TLR2-MyD88 pathway in HSP47-associated NET formation. RESULTS:CLP induced an increase in platelet HSP47 signal, coagulation abnormalities, inflammatory cytokine production, platelet activation, platelet granule release, platelet-leukocyte aggregate formation, and NET formation. Col003 treatment attenuated these CLP-associated changes and improved 7-day survival. In the timing experiment, early administration 3 h before CLP showed the most pronounced effects on platelet HSP47 signal, CitH3 expression, and 48 h survival. In platelet-neutrophil co-culture experiments, platelets from CLP mice promoted NET formation, whereas platelets from Col003-treated CLP mice showed a reduced NET-inducing capacity. In vitro pathway-validation experiments further showed that recombinant mouse HSP47 increased TLR2, MyD88, and CitH3 expression in bone marrow-derived neutrophils, while inhibition of TLR2 or MyD88 reduced HSP47-induced CitH3 expression. CONCLUSIONS:These findings suggest that HSP47-associated responses are involved in sepsis-associated coagulation dysfunction and are linked to platelet activation and NET formation. Early Col003 intervention attenuated CLP-induced pathological changes, supporting HSP47-associated pathways as potential targets for further investigation in sepsis-associated coagulopathy. Further studies are needed to determine whether delayed Col003 administration remains effective after sepsis has been established.

Lead poisoning mainly results from inhaling lead-containing dust or aerosols,ingesting contaminated food/water,or contact with lead-based paint.[1]Lead poisoning symptoms include headaches,dizziness,fatigue,memory impairment,sleep disorders,joint and muscle aches,peripheral neuropathy,abdominal pain,bloating,constipation,and anemia.

Rhabdomyolysis-induced acute kidney injury (RM-AKI) is a life-threatening complication with incompletely understood pathogenesis. Recent studies have highlighted the roles of endoplasmic reticulum stress (ERS) and cellular senescence in kidney diseases; however, their involvement in RM-AKI remains unclear. A mouse model of glycerol-induced RM-AKI was established, and kidney injury was assessed at 48 h, 7 days, 14 days, and 28 days. Techniques including transcriptomic sequencing, quantitative PCR, Western blotting, immunofluorescence, SA-β-galactosidase staining, and transmission electron microscopy were employed to detect markers of ERS and cellular senescence at different timepoints. In vitro experiments involved treating HK-2 cells with myoglobin to simulate tubular injury, and siRNA was used to knockdown ATF4 to investigate its molecular mechanisms. Early and sustained activation of ERS accompanied by tubular epithelial cell senescence was observed during RM-AKI. Transcriptomic analysis revealed early enrichment of ERS and senescence-related signaling pathways. The ERS markers GRP78, CHOP, and ATF4, as well as the senescence marker p21, were significantly upregulated. Transmission electron microscopy showed endoplasmic reticulum dilation and mitochondrial swelling, while SA-β-gal staining indicated an increased proportion of senescent cells. In vitro, myoglobin induced ERS and cellular senescence in HK-2 cells, both of which were markedly attenuated by ATF4 knockdown. This study provides the first evidence that ATF4-mediated ERS drives the senescence of renal tubular epithelial cells in RM-AKI. This new finding, identifying ATF4 as a key upstream regulator linking ERS to cellular senescence in this pathological state, reveals a previously unrecognized pathogenic mechanism. Targeting ATF4 and its downstream ERS signaling pathways may represent a promising therapeutic strategy for treating RM-AKI.

Objective:Sepsis is a systemic inflammatory response syndrome triggered by infection, characterized by high clinical heterogeneity and complex immunopathological mechanisms. Immune dysregulation plays a central role in its progression. This study aims to investigate the compositional changes of immune cells, characteristics of intercellular communication, and potential regulatory mechanisms of N⁶-methyladenosine (m6A) modification in sepsis, with a particular focus on the functional remodeling of platelets. Methods:This study integrated single-cell RNA sequencing data (GSE167363 dataset) from sepsis patients with m6A methylation sequencing data of peripheral blood mononuclear cells (PBMCs). Through systematic analysis, we compared the differences in immune cell composition, developmental trajectories, intercellular communication, and m6A modifications among healthy controls, survivors, and non-survivors, and further screened for key m6A-regulated target genes. Results:The analysis revealed that platelets gradually accumulated during the progression of sepsis, while B cells, T cells, and regulatory T cells (Tregs) exhibited a trend toward platelet-like phenotypic remodeling. Cell-cell communication analysis showed a marked decline in communication strength among immune cells as the disease worsened, particularly a significant weakening of the APP-CD74 signaling pathway between platelets and B cells, indicating impaired immune network synergy. m⁶A methylation sequencing revealed distinct remodeling of m⁶A peaks and dysregulation of related regulatory factors in non-survivors. Further integrative analysis identified RPA1 as a key m⁶A-regulated target gene, whose expression was closely associated with APP and co-regulated by multiple m6A-modifying factors. Conclusion:This study reveals disruptions in immune cell interactions and an m6A-dependent mechanism of platelet functional remodeling during sepsis progression. The identification of the key target gene RPA1 offers new insights into the immunopathological mechanisms of sepsis and lays a theoretical foundation for future precision interventions and therapeutic strategies.

The gut microbiota and its metabolites profoundly influence cardiac function, emerging as critical players in the pathophysiology of Sepsis-Induced Cardiomyopathy (SIC). Conversely, therapeutic interventions for SIC and the resultant cardiac alterations can reciprocally modulate gut microbial composition and function. To systematically elucidate this complex bidirectional relationship during SIC, this review delineates two key aspects: the 'forward gut-heart axis', defined as influences originating from the gut microbiota and its metabolites directed towards the cardiovascular system, and the 'reverse gut-heart axis', encompassing the reciprocal effects of cardiovascular drugs and cardiac factors on the gut microbiota. Furthermore, we explore potential therapeutic strategies for SIC centered on the targeted modulation of this intricate gut-heart interplay.

PurposeAcute kidney injury (AKI) secondary to Rhabdomyolysis syndrome represents a life-threatening complication, characterized by notably high incidence and mortality rates. The role of cellular senescence in the progression of AKI has increasingly garnered attention in recent years. Our previous research has demonstrated that remote ischemic postconditioning (RIPC) can attenuate renal cellular senescence and elevation of serum level of interleukin-6 (IL-6) induced by ischemia-reperfusion injury following crush injury. The objective of this study is to investigate the specific role of IL-6 in Rhabdomyolysis-induced AKI (RM-AKI).MethodsWe established a mouse model of RM-AKI by intramuscular injection of glycerol and simulated RM-AKI at the cellular level by treating Hk-2 cells with myoglobin. Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, is a key substance. IL-6, a multifunctional cytokine, plays a crucial role in the occurrence and development of various kidney diseases. It can promote inflammatory responses, cell proliferation, fibrosis, and other processes. TCZ exerts a protective effect on the kidneys by specifically binding to the IL-6 receptor and blocking the signal transduction of IL-6. Additionally, the levels of IL-6 were detected by employing ELISA kits. RNA sequencing analysis was performed on cells treated with myoglobin and tocilizumab. Flow cytometry was utilized to assess cell cycle distribution and the percentage of senescent cells. The expression levels of SERPINE1, GATA2, p53, and p21 were determined by real-time quantitative PCR and Western blot. Additionally, a dual-luciferase reporter gene assay was conducted to validate the binding effect of SERPINE1 and GATA2.ResultsTranscriptome Analysis revealed that genes including GATA2 and SERPINE1 were downregulated in HK-2 cells following tocilizumab treatment. Inhibition of the IL-6 receptor by tocilizumab in these cells led to a reduction in cellular senescence, accompanied by decreased of the cell cycle regulatory proteins P53 and P21 in mRNA and protein levels, while alleviating cell cycle arrest. Additionally, a dual-luciferase reporter assay confirmed that GATA2 binds to the promoter of SERPINE1 (PAI-1), thereby initiating its transcription.ConclusionThe IL-6/GATA2/SERPINE1 pathway mediates cellular senescence after acute kidney injury, and inhibiting IL-6 can alleviate AKI-induced cellular senescence, providing an important basis for exploring new therapeutic strategies.

>Wellens’ syndrome is defined by specific T-wave inversions in the precordial leads of the electrocardiogram （ECG）, which are indicative of acute anterior myocardial ischemia caused by severe proximal stenosis of the left anterior descending （LAD）artery. If not promptly treated, approximately 75%of patients with Wellens’ syndrome may experience extensive anterior wall myocardial infarction or sudden cardiac death within days to weeks. [1,2] Although the characteristic ECG changes associated with Wellens’syndrome are highly suggestive of LAD occlusion, there are rare instances in which similar ECG alterations are observed in the absence of LAD stenosis, a phenomenon referred to as pseudo-Wellens’ syndrome. The precise pathophysiological mechanisms underlying this syndrome remain unclear. Here, we present a patient with a myocardial bridge who presented a typical Wellens’ECG pattern.

Diquat poisoning leads to severe liver injury in clinical settings, whose mechanism is closely associated with oxidative stress. Melatonin possesses antioxidant and cytoprotective properties, but its role in diquat-induced liver injury remains unclear. In this study, we established a mouse model of acute diquat-induced liver injury and determined the LD₅₀ (42.7 mg/kg) through survival analysis. We evaluated liver function, inflammatory cytokines, oxidative stress levels, iron metabolism, and mitochondrial function to assess the protective effects of melatonin. The Nrf2 inhibitor ML385 was employed to validate the role of the Nrf2/HO-1 pathway. Diquat exposure resulted in severe liver dysfunction, inflammation, oxidative stress, iron accumulation, and mitochondrial damage. Melatonin treatment significantly improved these parameters, reversed the abnormal expression of ferroptosis-related proteins, and activated the Nrf2/HO-1 pathway. ML385 inhibited this pathway and attenuated the protective effects of melatonin. In conclusion, our study demonstrates that melatonin alleviates diquat-induced acute liver injury by activating the Nrf2/HO-1 pathway to suppress oxidative stress and ferroptosis, highlighting its potential as a therapeutic strategy.

Sepsis-induced vascular endothelial injury, characterized by ferroptosis and barrier dysfunction, remains a major cause of mortality. This study investigates the role of the stimulator of interferon genes (STING)/ferroptosis suppressor protein 1 (FSP1) pathway in mediating endothelial ferroptosis during sepsis and explores therapeutic interventions. A murine sepsis model was established using cecal ligation and puncture (CLP), along with LPS-stimulated human umbilical vein endothelial cells (HUVECs). STING activation was modulated using inhibitor H-151 and siRNA silencing. Ferroptosis was assessed through lipid peroxidation (MDA, BODIPY C11), Fe2+ accumulation (FerroOrange), and FSP1/GPX4 expression. Vascular permeability was quantified via Evans Blue extravasation and FITC-Dextran assays. STING activation in septic endothelial cells suppressed FSP1 expression, amplifying lipid peroxidation and ferroptosis. CLP mice exhibited elevated vascular leakage, which H-151 reversed. STING inhibition restored FSP1 levels, reduced Fe2+ overload, and preserved VE-cadherin integrity. FSP1 inhibition abolished these protective effects, confirming its necessity in STING-mediated ferroptosis. The STING/FSP1 axis exacerbates septic endothelial injury by driving ferroptosis. Targeting this pathway reduces oxidative stress and vascular dysfunction, highlighting its therapeutic potential for sepsis.

Diabetes insipidus is characterized by polyuria and polydipsia, often resulting from central or nephrogenic causes. In diabetic emergencies, hyperosmolar hyperglycemic state (HHS), severe hypernatremia, and ventricular fibrillation are life-threatening conditions that require prompt intervention. This report describes a 47-year-old male with poorly controlled diabetes mellitus, who developed coma, excessive thirst, polyuria, hyperglycemia (47.29 mmol/L), hypernatremia (195.6 mmol/L), and plasma hyperosmolality (385 mOsm/kg). Despite fluid resuscitation and insulin therapy, refractory hypernatremia persisted, leading to a diagnosis of central diabetes insipidus (CDI). The patient also developed ventricular fibrillation, which was managed with defibrillation. Concurrently, desmopressin and blood purification were administered to address CDI and severe hypernatremia. This case emphasizes the importance of considering CDI when polyuria persists despite glucose control. The occurrence of ventricular fibrillation underscores the necessity of continuous cardiac monitoring in the context of hypovolemia and severe electrolyte imbalance. We propose that diabetes mellitus-related vascular injury impairs blood flow in the hypothalamus-pituitary tract, disrupting arginine vasopressin synthesis and secretion, contributing to CDI in poorly controlled diabetes mellitus.

BACKGROUND AND PURPOSE:Rhabdomyolysis (RM) and rhabdomyolysis-induced acute kidney injury (RM-AKI) are increasingly prevalent, yet specific therapies are lacking.Cellular senescence contributes to the transition of RM-AKI to chronic kidney disease (CKD), in which macrophage-tubular epithelial interactions play a pivotal role. Azathioprine, an immunosuppressant, through its metabolite 6-thio-GTP, inhibits Vav1-mediated Rac2 activation; nevertheless, its potential role in RM-AKI has not been elucidated. This study explores the Vav1/Rac2/NF-κB pathway in macrophage-mediated senescence in RM-AKI and azathioprine's efficacy. EXPERIMENTAL APPROACH:A glycerol-induced RM-AKI mouse model was used. High-throughput RNA sequencing, proteomic profiling, and co-immunoprecipitation were performed to evaluate activation of the Vav1-associated pathway. RAW264.7-TCMK-1 co-cultures verified azathioprine's effects on the pathway and senescence. KEY RESULTS:RM-AKI mice showed renal senescence (elevated p53, p21, p16, SA-β-gal) and activated macrophage Vav1/Rac2/NF-κB. Azathioprine treatment down-regulated Vav1/Rac2 expression, improved renal function, and mitigated histological injury. In vitro, inhibiting the pathway reduced tubular senescence and improved LaminB1 integrity. CONCLUSION AND IMPLICATIONS:Activation of macrophage Vav1/Rac2/NF-κB signaling promotes tubular cell senescence, whereas azathioprine counteracts this process by inhibiting the pathway.

INTRODUCTION:Acute kidney injury (AKI) is a common clinical condition where cellular senescence plays a crucial role in its progression. Previous studies have suggested that DOT1L plays a pivotal role in cellular senescence, yet its specific mechanisms in regulating AKI cellular senescence remain unclear. METHODS:This study utilized a glycerol-induced in vivo AKI model and employed the DOT1L-specific inhibitor EPZ004777 (EPZ) to suppress DOT1L function. Aging staining, periodic acid-Schiff staining, and Masson staining were employed to assess renal aging, injury, and interstitial fibrosis. In vitro experiments utilized doxorubicin-treated human renal tubular epithelial (HK-2) cells to establish an AKI cellular senescence model. EPZ was used to inhibit DOT1L, evaluating its impact on cellular senescence. High-throughput miRNA sequencing was performed to analyze differential expression of miRNAs downstream of DOT1L, and DOT1L overexpression and dual luciferase reporter gene experiments were conducted to explore interactions among DOT1L, miR-222-5p, and Wnt family member 9B (WNT9B). RESULTS:The results demonstrated that in vivo inhibition of DOT1L significantly reduced cellular senescence and improved renal tubular injury and interstitial fibrosis. In the doxorubicin-induced HK-2 cell model, DOT1L inhibition markedly decreased cellular senescence and lowered mRNA and protein levels of senescence markers while alleviating cell cycle arrest. DOT1L inhibition notably upregulated miR-222-5p expression and suppressed WNT9B expression, with opposite effects observed with DOT1L overexpression. CONCLUSION:DOT1L regulates cellular senescence through the miR-222-5p/WNT9B pathway in AKI. These findings suggest that DOT1L may serve as a potential therapeutic target to mitigate the progression of AKI to chronic kidney disease.

Introduction:Previous studies have linked placental weight (PW) to cardiovascular diseases, but the causality and potential mediators underlying this relationship are still unknown. Material and methods:We conducted Mendelian randomization (MR) analysis via summary statistics from genome-wide association studies (GWAS), including PW adjusted for sex, 21 candidate mediators and atherosclerotic cardiovascular disease (ASCVD), which includes coronary heart disease (CHD) and ischemic stroke (IS). Two-step MR was employed to identify and assess the mediation and proportion of potential mediators in the association between PW and ASCVD. Additionally, we conducted a repeated analysis using PW adjusted for gestational age and sex. Results:Univariable MR (UVMR) analysis revealed that for each 1-SD decrease in fetal genotype-determined PW adjusted for sex only, the risk of CHD increased by 24% (95% CI: 1.05-1.46) and the risk of large artery stroke (LAS) increased by 46% (95% CI: 1.13-1.89). Similar results were obtained in repeated analyses. The mediation MR analysis revealed that the causal relationship between fetal genotype-determined PW and CHD risk was primarily mediated by birthweight, type 2 diabetes, and education, each mediating 3.66% to 40.80% of the total effect. The causal relationship between fetal genotype-determined PW and LAS risk was mediated mainly by type 2 diabetes, which accounted for 22.11% of the total effect. Conclusions:This study identified a unidirectional causal relationship between lower PW and a greater ASCVD risk, with factors such as birthweight, type 2 diabetes, and education mediating the association between PW and ASCVD.

Objective: The ultrasonic cardiac output monitor (USCOM), an instrument that monitors the evolution of a patient's hemodynamic status and determines the type of shock, has become an important tool for assessing cardiac pathology and predicting changes in disease, but there are some variations in the instrumental findings for different physical conditions of patients. This article examines whether there are differences in the quality of USCOM waveforms measured in different types of critically ill patients based on clinical characteristics and test parameters. Methods: Baseline data, diagnoses, echocardiograms, ventilation patterns, and USCOM results were retrospectively collected from patients in the emergency intensive care unit. Waveform quality was quantified using the Fremantle score to determine the extent to which age, body mass index (BMI), chronic obstructive pulmonary disease (COPD), respiratory failure, cardiac enlargement, valvular heart disease, and ventilation pattern influenced USCOM waveform quality. Results: Age, body mass index, chronic obstructive pulmonary disease, respiratory failure, right and left heart enlargement, aortic valve disease (excluding aortic stenosis), and ventilation mode did not have a significant effect on USCOM waveform quality in critically ill patients (P > 0.05). Conclusions: Various physical conditions of critically ill patients may have limited effect on the quality of the USCOM waveform, potentially rendering USCOM suitable for early assessment of hemodynamic status during ICU admission.