Sepsis, a life-threatening syndrome, results from a dysregulated immune and hemostatic response, contributing to acute lung injury (ALI) and its progression into acute respiratory distress syndrome (ARDS). The development of septic ALI is complex, involving excessive inflammatory mediator production that damages endothelial and epithelial cells, leading to vascular leakage, edema, and vasodilation-key factors in ALI pathogenesis. Long noncoding RNAs (lncRNAs), over 200 nucleotides in length, play critical roles in various biological processes, including sepsis regulation. They exhibit both promotive and inhibitory effects, influencing sepsis progression and resolution. Despite their significance, comprehensive reviews detailing lncRNA involvement in sepsis-induced ALI remain limited. This review aims to address this gap by summarizing the diverse functions of lncRNAs in septic ALI, emphasizing their potential in diagnosis and treatment. Furthermore, we will explore the molecular mechanisms underlying lncRNA involvement, particularly their miRNA-dependent regulatory pathways. Understanding these interactions may provide novel insights into therapeutic strategies for sepsis-induced ALI.

Infectious complications following prostate biopsy are costly and potentially deadly. Multiple strategies have been devised to avoid infections, including augmented prophylaxis and transperineal biopsy (TPBx). Their uptake and success in reducing population-level infectious outcomes following biopsy are largely unknown. Here, we evaluate contemporary postbiopsy infections and hospital admissions in a large insurance claims dataset.

The Merative MarketScan Database was queried for prostate biopsies from 2012 to 2021. MarketScan contains inpatient and outpatient data on >40 million individuals annually. Our primary endpoint was overall and sepsis-related hospitalizations within 14-days of prostate biopsy, and postbiopsy infections not requiring admission. Multvariable analysis evaluated temporal trends in endpoints.

We identified 301,733 patients undergoing prostate biopsy between 2012 and 2021 among whom 2,587 developed sepsis. The proportion of patients with sepsis decreased from 1.1% in 2017 to 0.7% in 2021, following an increase from 0.6% in 2012 to 1.1% in 2016. This paralleled trends in hospitalizations within 14-days. Postbiopsy infections not requiring hospitalization remained stable across the study period. These temporal trends persisted even after adjustment for patient age, comorbidities, biopsy history, insurance status, and geographic region. Single-agent fluoroquinolone use decreased alongside an increase in multiagent prophylaxis over the study period.

We identified a decrease in postbiopsy all-cause and sepsis-related hospitalization, synchronous with augmented prophylaxis. Our findings suggest population-level improvement in major postbiopsy complications, reversing a trend from historical series.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Current treatments are limited to source control and supportive care, underscoring the urgent need for novel therapeutic interventions. Endogenous molecules released from stressed or damaged cells, known as damage-associated molecular patterns (DAMPs), exacerbate inflammation, organ injury, and mortality in sepsis. In this study, we discovered a novel therapeutic compound, opsonic peptide 18 (OP18), designed to scavenge multiple DAMPs, including extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1) and histone H3, by facilitating their clearance via macrophages. OP18 was developed by identifying a 15-amino acid (aa) binding site within the extracellular domain of Toll-like receptor 4 (TLR4) shared by eCIRP, HMGB1, and histone H3, then extending it with an αvβ3-integrin binding RGD (Arg-Gly-Asp) motif, resulting in an 18-aa peptide. Our data show that OP18 binds strongly to the above DAMPs and interacts with αvβ3-integrin on macrophages, promoting phagocytosis of DAMPs and facilitating their lysosomal degradation. In vitro, OP18 reduced the production of the inflammatory cytokine TNF-α in DAMP-activated macrophages and restored mitochondrial function, as evidenced by improved oxygen consumption rate (OCR) and ATP production. In a lethal sepsis model induced by cecal ligation and puncture (CLP), DAMP levels were significantly elevated, while OP18 treatment markedly reduced the serum DAMP levels. Additionally, OP18-treated septic mice demonstrated reduced blood organ injury markers, decreased proinflammatory cytokine levels, attenuated ALI, and improved survival. These findings establish OP18 as a promising therapeutic molecule that reduces DAMP-induced inflammation, offering a potential strategy to improve outcomes in lethal sepsis.

The endotoxin, which is a highly pathogenic toxin released from the cell wall of gram-negative bacteria after death, can lead to critical diseases such as sepsis and intestinal inflammation. Poly 2-hydroxyethyl methacrylate (HEMA)-glycidyl methacrylate (GMA)/polyethyleneimine (PEI) cryogel membranes employed for endotoxin removal were synthesized via the immobilization of PEI solution with poly(HEMA-GMA) membranes. The concentration of the treated PEI% solution, the concentration of the endotoxin solution, and the ambient temperature influenced the endotoxin binding percentage of poly(HEMA-GMA) cryogel membranes. Maximum endotoxin removal was observed with poly(HEMA-GMA) cryogel membranes treated with a 25 % PEI solution at 25 °C. Additionally, it was noted that poly(HEMA-GMA)/PEI cryogel membranes exhibited increased endotoxin binding with rising endotoxin concentrations. The percentage of endotoxin bound by cryogel membranes in both aqueous solutions and artificial plasma media increases with the endotoxin concentration in the solutions. The Limulus Amebocyte Lysate (LAL) assay results show that the percentages of bound endotoxin in artificial plasma and aqueous solutions are approximately equivalent. The prepared poly(HEMA-GMA)/PEI adsorbent exhibited good reusability and offered high removal ability for endotoxin. The adsorption process can be accurately described by Langmuir adsorption isotherm model.

Sepsis is a severe condition associated with high mortality, and hospital performance is variable. The objective of this study was to develop geospatial sepsis clusters, identify sources of variation between clusters, and test the hypothesis that redistributing sepsis patients from low-performing hospitals to higher-performing hospitals within a cluster will improve sepsis outcomes.

We conducted a cohort study of age-qualifying Medicare beneficiaries using administrative claims data from 2013 to 2015. We calculated risk-standardized mortality for hospitals then used a clustering algorithm to define geospatial cluster boundaries based on care-seeking and interhospital transfer patterns. Finally, we used simulation to model the effect of reallocating sepsis patients to higher-performing hospitals within the same cluster.

None.

We included 1,125,308 patients, and they were grouped into 222 regional clusters. High-performing clusters were located largely in the Midwest, and they tended to be in less urban regions with smaller hospitals. In our simulation, the most impactful strategy was reassigning cases from the lowest-performing hospital in a cluster to the highest-performing hospital in the cluster, which was predicted to prevent 1705 deaths per year in the United States. This aggregate benefit was lower than the 5702 deaths predicted from reducing mortality by 1% absolute in hospitals in the lower half of the performance distribution.

Geospatial clusters provide insight into regional approaches to system-based acute care. In a simulation study, targeted sepsis regionalization appears less effective than local performance improvement in reducing preventable sepsis deaths.

Aims: The present work aimed to examine impact of tanshinone IIA on intestinal barrier in sepsis and to explore the underpinning mechanisms. Materials and Methods: Sepsis induction in Sprague-Dawley (SD) rats was conducted via cecal ligation and puncture (CLP), with subsequent intraperitoneal injection of tanshinone IIA. Intestinal permeability was examined 12 h post-operation using the fluorescein isothiocyanate dextran method. Blood and distal ileum tissue samples were collected for Enzyme-Linked Immunosorbent Assay (ELISA) analysis of oxidative stress and inflammatory markers. Histopathologic examination was performed using hematoxylin and eosin staining and the Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Immunofluorescence and immunoblot were performed for protein detection. In vitro, Caco-2 cells were administered lipopolysaccharide (LPS) followed by tanshinone IIA treatment, and pregnane X receptor (PXR) and cytochrome P450-3A4 (CYP3A4) protein levels were assessed. Results: In sepsis model rats, tanshinone IIA dose-dependently reversed the increased intestinal permeability, bacterial shift rate, ileum Chiu's score, apoptosis level of ileal mucosa, the elevated serum and ileal Malondialdehyde (MDA), Interleukin-1 beta (IL-1β), and Tumor Necrosis Factor-alpha (TNF-α) amounts, and the enhanced ileal expression levels of Proto-oncogene c-Fos (c-Fos) and tryptase proteins. In addition, tanshinone IIA restored the decreased serum and ileal Superoxide Dismutase (SOD) levels and reversed the reduced ileal expression levels of claudin-1, Junctional Adhesion Molecule (JAM), occludin, and ZO-1. In vitro, tanshinone IIA restored PXR and CYP3A4 levels following LPS stimulation. Conclusion: Tanshinone IIA exerts a protective effect in murine CLP-induced sepsis. The underlying mechanism may involve activation of the PXR-CYP3A4 pathway in murine intestinal epithelial cells.

Background: Sepsis is a major global health issue and the leading cause of death in critically ill patients, with rising incidence and associated healthcare costs. Early administration of antibiotic therapy is crucial, but increasing antibiotic resistance poses a threat. Beta-lactam antibiotics, commonly used as a first-line therapy option against sepsis, often demonstrate unpredictable concentrations due to pharmacokinetic and pharmacodynamic changes in critically ill patients. Acute kidney injury (AKI) affects a significant portion of septic patients, and continuous renal replacement therapy can further complicate treatment by reducing antibiotic levels and, consequently, increasing antibiotic resistance risk. Objectives: To develop pharmacokinetic/pharmacodynamic models for beta-lactam antibiotics in septic shock patients undergoing continuous renal replacement therapy (CRRT), with the goal of optimizing antibiotic dosing and then improving treatment outcomes. Methods: Septic shock Caucasian adult patients treated with beta-lactams and who have undergone major surgery in AKI failure that requires CRRT will be eligible with previous informed written consent. CRRT will be performed exclusively using Continuous Venovenous Hemodiafiltration (CVVHDF) modality. Antimicrobial determination analyses will be carried out with LC-MS/MS. Further calculation of pharmacokinetic parameters and determination of PK/PD breakpoints will be made using Monte Carlo simulation. Conclusions: The expected results from this study will lead to a better understanding of the pharmacokinetics of beta-lactam antibiotics in critically ill patients with AKI and septic shock undergoing CVVHDF, allowing for improved therapeutic strategies.

Sepsis is a common condition associated with significant morbidity and mortality. Emergency physicians play a key role in the diagnosis and management of this condition.

This paper evaluates key evidence-based updates concerning the management of sepsis and septic shock for the emergency clinician.

Sepsis is a life-threatening syndrome, and rapid diagnosis and management are essential. Antimicrobials should be administered as soon as possible, as delays are associated with increased mortality. Resuscitation targets include mean arterial pressure ≥ 65 mmHg, mental status, capillary refill time, lactate, and urine output. Intravenous fluid resuscitation plays an integral role in those who are fluid responsive. Balanced crystalloids and normal saline are both reasonable options for resuscitation. Early vasopressors should be initiated in those who are not fluid-responsive. Norepinephrine is the recommended first-line vasopressor, and if hypotension persists, vasopressin should be considered, followed by epinephrine. Administration of vasopressors through a peripheral 20-gauge or larger intravenous line is safe and effective. Steroids such as hydrocortisone and fludrocortisone should be considered in those with refractory septic shock.

An understanding of the recent updates in the literature concerning sepsis and septic shock can assist emergency clinicians and improve the care of these patients.

Sepsis and septic shock are common conditions evaluated and managed in the emergency department (ED), and these conditions are associated with significant morbidity and mortality. There have been several recent updates in the literature, including guidelines, on the evaluation and diagnosis of sepsis and septic shock.

This is the first paper in a two-part series that provides emergency clinicians with evidence-based updates concerning sepsis and septic shock. This first paper focuses on evaluation and diagnosis of sepsis and septic shock.

The evaluation, diagnosis, and management of sepsis have evolved since the first definition in 1991. Current guidelines emphasize rapid diagnosis to improve patient outcomes. However, scoring systems have conflicting data for diagnosis, and sepsis should be considered in any patient with infection and abnormal vital signs, evidence of systemic inflammation (e.g., elevated white blood cell count or C-reactive protein), or evidence of end-organ dysfunction. The clinician should consider septic shock in any patient with infection and hypotension despite volume resuscitation or who require vasopressors to maintain a mean arterial pressure ≥ 65 mmHg. There are a variety of sources of sepsis but the most common include pulmonary, urinary tract, abdomen, and skin/soft tissue. Examples of other less common etiologies include the central nervous system (e.g., meningitis, encephalitis), spine (e.g., spinal epidural abscess, osteomyelitis), cardiac (e.g., endocarditis), and joints (e.g., septic arthritis). Evaluation may include biomarkers such as procalcitonin, C-reactive protein, and lactate, but these should not be used in isolation to exclude sepsis. Imaging is a key component of evaluation and should be based on the suspected source.

There have been several recent updates in the literature including guidelines concerning sepsis and septic shock; an understanding of these updates can assist emergency clinicians and improve the care of these patients.

Sepsis is a common cause of hospitalization among Medicare beneficiaries, often leading to prolonged hospital stays and high costs.

To estimate the impact of registered nurse (RN) staffing and skill mix on hospital lengths of stay and associated costs for Medicare beneficiaries with sepsis.

A retrospective, cross-sectional analysis was conducted using 2018 data from 2,107 acute care hospitals, including 653,496 patients with sepsis.

A one-unit increase in RN hours per patient day and a 1% increase in RN skill mix reduced hospital stays by 2% and 1%, respectively. Enhancing staffing to nine RN hours per patient day and an 80% RN skill mix could save 63,580 inpatient days annually, reducing costs by $152.9 million. Further increases to 11 RN hours and an 85% skill mix could save $331.9 million.

Better RN staffing and skill mix can improve patient outcomes and yield significant cost savings.

Continuous waveform monitoring is standard-of-care for patients at risk for or with critically illness. Derived from waveforms, heart rate, respiratory rate and blood pressure variability contain useful diagnostic and prognostic information; and when combined with machine learning, can provide predictive indices relating to severity of illness and/or reduced physiologic reserve. Integration of predictive models into clinical decision support software (CDSS) tools represents a potential evolution of monitoring.

We perform a review and analysis of the multidisciplinary steps required to develop and rigorously evaluate predictive clinical decision support tools based on monitoring.

Development and evaluation of waveform-based variability-derived predictive models involves a multistep, multidisciplinary approach. The stepwise processes involves data science (data collection, waveform processing, variability analysis, statistical analysis, machine learning, predictive modelling), CDSS development (iterative research prototype evolution to commercial tool), and clinical research (observational and interventional implementation studies, followed by feasibility then definitive randomized controlled trials), and poses unique challenges (including technical, analytical, psychological, regulatory and commercial).

The proposed roadmap provides guidance for the development and evaluation of novel predictive CDSS tools with potential to help transform monitoring and improve care.

In recent years, we have witnessed both artificial intelligence obtaining remarkable results in clinical decision support systems (CDSSs) and explainable artificial intelligence (XAI) improving the interpretability of these models. In turn, this fosters the adoption by medical personnel and improves trustworthiness of CDSSs. Among others, counterfactual explanations prove to be one such XAI technique particularly suitable for the healthcare domain due to its ease of interpretation, even for less technically proficient staff. However, the generation of high-quality counterfactuals relies on generative models for guidance. Unfortunately, training such models requires a huge amount of data that is beyond the means of ordinary hospitals. In this paper, we therefore propose to use federated learning to allow multiple hospitals to jointly train such generative models while maintaining full data privacy. We demonstrate the superiority of our approach compared to locally generated counterfactuals. Moreover, we prove that generative models for counterfactual generation that are trained using federated learning in a suitable environment perform only marginally worse compared to centrally trained ones while offering the benefit of data privacy preservation. Finally, we integrate our method into a prototypical CDSS for treatment recommendation for sepsis patients, thus providing a proof of concept for real-world application as well as insights and sanity checks from clinical application.

Despite considerable research efforts, inflammatory diseases remain a heavy burden on human health, causing significant economic losses annually. Histone deacetylases (HDACs) play a significant role in regulating inflammation (via histone and non-histone protein deacetylation) and chromatin structure and gene expression regulation. Herein, we present a detailed description of the different HDACs and their functions and analyze the role of HDACs in inflammatory diseases, including pro-inflammatory cytokine production reduction, immune cell function modulation, and anti-inflammatory cell activity enhancement. Although HDAC inhibitors have shown broad inflammatory disease treatment potentials, their clinical applicability remains limited because of their non-specific effects, adverse effects, and drug resistance. With further research and insight, these inhibitors are expected to become important tools for the treatment of a wide range of inflammatory diseases. This review aims to explore the mechanisms and application prospects of HDACs and their inhibitors in multiple inflammatory diseases.

Sepsis poses one of the biggest public health problems, necessitating the search for new therapeutic alternatives. For centuries, propolis has been widely used in folk medicine to treat various inflammatory and infectious diseases. Given its extensive use, it has excellent potential as an adjuvant treatment for patients with sepsis.

This study evaluated prophylactic treatment with standardized propolis extract (EPP-AF®) and followed the prognosis of sepsis induced by ligation and cecal ligation and puncture (CLP).

Initially, for survival assessment, Swiss mice were separated into five groups: Sham (false operated), control (PBS), ATB (received antibiotic, 8 mg/kg), P10 (received EPP-AF®, 10 mg/kg), and P100 (received EPP-AF®, 100 mg/kg). The animals received PBS, antibiotic, or EPP-AF® by the subcutaneous route 6 h before the CLP procedure. Animal survival was assessed every 12 h for five days when all of them were euthanized.

We show that the treatment with EPP-AF® significantly increased the life expectancy of animals with sepsis compared to the control group. Interestingly, prophylactic treatment with EPP-AF® showed no effect on the number of colony-forming units in the peritoneum, blood, or lung. However, there was a decrease in cellular influx in the peritoneum. This alteration was unrelated to the number of bone marrow cells or the differential counting of peripheral blood cells. The coagulogram remained unchanged, including the number of platelets and prothrombin time-activated partial thromboplastin time. However, the inflammatory infiltrate and bleeding in the lung tissue were lower in the animals that received EPP-AF®.

Thus, it was possible to conclude that prophylactic treatment with EPP-AF® preserved the lung parenchyma, resulting in an increased lifespan of mice with sepsis. It can be a helpful adjuvant in prophylactic treatment with antibiotics in presurgical conditions.

Sepsis can have severe implications on lung function, leading to acute lung injury (ALI), a major contributor to sepsis-related mortality. Anisodamine hydrobromide (Ani HBr), a bioactive constituent derived from the root of Scopolia tangutica Maxim, a plant endemic to China, has demonstrated efficacy in treating septic shock. We aim to explore whether Ani HBr can alleviate sepsis-triggered ALI and elucidate the fundamental mechanisms involved.

The protective effects of Ani HBr were assessed in two models: in vitro, lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and in vivo, cecal ligation puncture (CLP)-induced sepsis. To measure the cell viability of RAW264.7 cells after Ani HBr treatment, we used the CCK-8 assay. We quantified the levels of pro-inflammatory cytokines expression using ELISA. We also measured the expression of pyrotosis indicators by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence.

Our study demonstrates that Ani HBr can alleviate pulmonary edema, bleeding, and excessive inflammation induced by CLP. Additionally, it exhibits protective effects against cytotoxicity induced by LPS in RAW264.7 macrophage cells. Furthermore, Ani HBr downregulates the mRNA and protein levels of NLRP3, Caspase-1, GSDMD, IL-18, and IL-1β in both animal models and cell cultures, thereby inhibiting pyroptosis in a similar mechanism to AC-YVAD-CMK (AYC)'s blockade of Caspase-1. Moreover, Ani HBr suppresses the production and release of proinflammatory cytokines.

These findings suggest that Ani HBr could serve as a protective agent against sepsis-induced ALI by suppressing pyroptosis.

Acute lung injury is one of the most serious complications of sepsis, which is a common critical illness in clinic. This study aims to investigate the role of caspase-3/ gasdermin-E (GSDME)-mediated pyroptosis in sepsis-induced lung injury in mice model. Cecal ligation (CLP) operation was used to establish mice sepsis-induced lung injury model. Lung coefficient, hematoxylin and eosin staining and transmission electron microscopy were used to observe the lung injury degree. In addition, caspase-3-specific inhibitor Z-DEVD-FMK and GSDME-derived inhibitor AC-DMLD-CMK were used in CLP model, caspase-3 activity, GSDME immunofluorescence, serum lactate dehydrogenase (LDH) and interleukin-6 (IL-6) levels, TUNEL staining, and the expression levels of GSDME related proteins were detected. The mice in CLP group showed the increased expressions of cleaved-caspase-3 and GSDME-N terminal, destruction of lung structure, and the increases of LDH, IL-6, IL-18 and IL-1β levels, which were improved in mice treated with Z-DEVD-FMK or AC-DMLD-CMK. In conclusion, caspase-3/GSDME mediated pyroptosis is involved in the occurrence of sepsis-induced lung injury in mice model, inhibiting caspase-3 or GSDME can both alleviate lung injury.

Sepsis is a life-threatening condition but predicting its development and progression remains a challenge.

This study aimed to assess the impact of infection site on sepsis development among emergency department (ED) patients.

Data were collected from a single-center ED between January 2016 and December 2019. Patient encounters with documented infections, as defined by the Systematized Nomenclature of Medicine-Clinical Terms for upper respiratory tract (URI), lower respiratory tract (LRI), urinary tract (UTI), or skin or soft-tissue infections were included. Primary outcome was the development of sepsis or septic shock, as defined by Sepsis-1/2 criteria. Secondary outcomes included hospital disposition and length of stay, blood and urine culture positivity, antibiotic administration, vasopressor use, in-hospital mortality, and 30-day mortality. Analysis of variance and various different logistic regression approaches were used for analysis with URI used as the reference variable.

LRI was most associated with sepsis (relative risk ratio [RRR] 5.63; 95% CI 5.07-6.24) and septic shock (RRR 21.2; 95% CI 17.99-24.98) development, as well as hospital admission rates (odds ratio [OR] 8.23; 95% CI 7.41-9.14), intensive care unit admission (OR 4.27; 95% CI 3.84-4.74), in-hospital mortality (OR 6.93; 95% CI 5.60-8.57), and 30-day mortality (OR 7.34; 95% CI 5.86-9.19). UTIs were also associated with sepsis and septic shock development, but to a lesser degree than LRI.

Primary infection sites including LRI and UTI were significantly associated with sepsis development, hospitalization, length of stay, and mortality among patients presenting with infections in the ED.

A dysregulated host response to infection causes organ dysfunction in sepsis and septic shock, two potentially fatal diseases. They continue to be major worldwide health burdens with high rates of morbidity and mortality despite advancements in medical care. The goal of this thorough review was to present a thorough summary of the current body of knowledge about the prevalence of sepsis and septic shock worldwide. Using widely used computerized databases, a comprehensive search of the literature was carried out, and relevant studies were chosen in accordance with predetermined inclusion and exclusion criteria. A narrative technique was used to synthesize the data that were retrieved. The review's conclusions show how widely different locations and nations differ in terms of sepsis and septic shock's incidence, prevalence, and fatality rates. Compared to high-income countries (HICs), low- and middle-income countries (LMICs) are disproportionately burdened more heavily. We talk about risk factors, comorbidities, and difficulties in clinical management and diagnosis in a range of healthcare settings. The review highlights the need for more research, enhanced awareness, and context-specific interventions in order to successfully address the global burden of sepsis and septic shock.

Sepsis is a life-threatening process due to organ dysfunction resulting from severe infections. Mesenchymal stromal cells (MSCs) are being investigated as therapy for sepsis, along with conditioning regimens to improve their function. Carbon monoxide (CO) gas, which is cytoprotective at low doses, induces autophagy and is a mediator of inflammation. We evaluated CO-induced autophagy in human MSCs (hMSCs), and its impact on cell function in murine cecal ligation and puncture. Conditioning of hMSCs with CO ex vivo resulted in enhanced survival and bacterial clearance in vivo, and neutrophil phagocytosis of bacteria in vitro. Decreased neutrophil infiltration and less parenchymal cell death in organs were associated with increased macrophage efferocytosis of apoptotic neutrophils, promoting resolution of inflammation. These CO effects were lost when the cells were exposed to autophagy inhibition prior to gas exposure. When assessing paracrine actions of CO-induced autophagy, extracellular vesicles (EVs) were predominantly responsible. CO had no effect on EV production, but altered their miRNA cargo. Increased expression of miR-145-3p and miR-193a-3p by CO was blunted with disruption of autophagy, and inhibitors of these miRNAs led to a loss of neutrophil phagocytosis and macrophage efferocytosis. Collectively, CO-induced autophagy enhanced hMSC function during sepsis via paracrine actions of MSC-derived EVs.

Under Medicare's fee-for-service and bundled payment models, the basic unit of hospital payment for inpatient hospitalizations is determined by the Medicare Severity Diagnosis Related Group (MS-DRG) coding system. Primary total joint arthroplasties (hip and knee) are coded under MS-DRG code 469 for hospitalizations with a major complication or comorbidity and MS-DRG code 470 for those without a major complication or comorbidity. However, these codes do not account for the indication for surgery, which may influence the cost of care.Questions/purposes We sought to (1) quantify the differences in hospital costs associated with six of the most common diagnostic indications for THA (osteoarthritis, rheumatoid arthritis, avascular necrosis, hip dysplasia, posttraumatic arthritis, and conversion arthroplasty), (2) assess the primary drivers of cost variation using comparisons of hospital charge data for the diagnostic indications of interest, and (3) analyze the median length of stay, discharge destination, and intensive care unit use associated with these indications.

This study used the 2019 Medicare Provider Analysis and Review Limited Data Set. Patients undergoing primary elective THA were identified using MS-DRG codes and International Classification of Diseases, Tenth Revision, Procedure Coding System codes. Exclusion criteria included non-fee-for-service hospitalizations, nonelective procedures, patients with missing data, and THAs performed for indications other than the six indications of interest. A total of 713,535 primary THAs and TKAs were identified in the dataset. After exclusions were applied, a total of 135,194 elective THAs were available for analysis. Hospital costs were estimated using cost-to-charge ratios calculated by the Centers for Medicare and Medicaid Services. The primary benefit of using cost-to-charge ratios was that it allowed us to analyze a large national dataset and to mitigate the random cost variation resulting from unique hospitals' practices and patient populations. As an investigation into matters of health policy, we believe that assessing the surgical cost borne by the "average" hospital was most appropriate. To analyze estimated hospital costs, we performed a multivariable generalized linear model controlling for patient demographics (gender, age, and race), preoperative health status, and hospital characteristics (hospital setting [urban versus rural], geography, size, resident-to-bed ratio, and wage index). We assessed the principal drivers of cost variation by analyzing the median hospital charges arising from 30 different hospital revenue centers using descriptive statistics. Length of stay, intensive care use, and discharge to a nonhome location were analyzed using multivariable binomial logistic regression.

The cost of THA for avascular necrosis was 1.050 times (95% confidence interval 1.042 to 1.069; p < 0.001), or 5% greater than, the cost of THA for osteoarthritis; the cost of hip dysplasia was 1.132 times (95% CI 1.113 to 1.152; p < 0.001), or 13% greater; the cost of posttraumatic arthritis was 1.220 times (95% CI 1.193 to 1.246; p < 0.001), or 22% greater; and the cost of conversion arthroplasty was 1.403 times (95% CI 1.386 to 1.419; p < 0.001), or 40% greater. Importantly, none of these CIs overlap, indicating a discernable hierarchy of cost associated with these diagnostic indications for surgery. Rheumatoid arthritis was not associated with an increase in cost. Medical or surgical supplies and operating room charges represented the greatest increase in charges for each of the surgical indications examined, suggesting that increased use of medical and surgical supplies and operating room resources were the primary drivers of increased cost. All of the orthopaedic conditions we investigated demonstrated increased odds that a patient would experience a prolonged length of stay and be discharged to a nonhome location compared with patients undergoing THA for osteoarthritis. Avascular necrosis, posttraumatic arthritis, and conversion arthroplasty were also associated with increased intensive care unit use. Posttraumatic arthritis and conversion arthroplasty demonstrated the largest increase in resource use among all the orthopaedic conditions analyzed.

Compared with THA for osteoarthritis, THA for avascular necrosis, hip dysplasia, posttraumatic arthritis, and conversion arthroplasty is independently associated with stepwise increases in resource use. These cost increases are predominantly driven by greater requirements for medical and surgical supplies and operating room resources. Posttraumatic arthritis and conversion arthroplasty demonstrated substantially increased costs, which can result in financial losses in the setting of fixed prospective payments. These findings underscore the inability of MS-DRG coding to adequately reflect the wide range of surgical complexity and resource use of primary THAs. Hospitals performing a high volume of THAs for indications other than osteoarthritis should budget for an anticipated increase in costs, and orthopaedic surgeons should advocate for improved MS-DRG coding to appropriately reimburse hospitals for the financial and clinical risk of these surgeries.

Level IV, economic and decision analysis.

Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI. However, strategies to screen more effective EV-miRNAs as therapeutic targets are yet to be elucidated. In this study, functional EV-miRNAs were identified based on multiomics analysis of single-cell RNA sequencing of targeted organs and serum EV (sEV) miRNA profiles in patients with sepsis. The proportions of neutrophils and macrophages were increased significantly in the lungs of mice receiving sEVs from patients with sepsis compared with healthy controls. Macrophages released more EVs than neutrophils. MiR-125a-5p delivery by sEVs to lung macrophages inhibited Tnfaip3, while miR-221-3p delivery to lung neutrophils inhibited Fos. Macrophage membrane nanoparticles (MM NPs) loaded with an miR-125a-5p inhibitor or miR-221-3p mimic attenuated the response to lipopolysaccharide (LPS)-induced ALI. Transcriptome profiling revealed that EVs derived from LPS-stimulated bone marrow-derived macrophages (BMDMs) induced oxidative stress in neutrophils. Blocking toll-like receptor, CXCR2, or TNFα signaling in neutrophils attenuated the oxidative stress induced by LPS-stimulated BMDM-EVs. This study presents a novel method to screen functional EV-miRNAs and highlights the pivotal role of macrophage-derived EVs in ALI. MM NPs, as delivery systems of key sEV-miRNA mimics or inhibitors, alleviated cellular responses observed in sepsis-induced ALI. This strategy can be used to reduce septic organ damage, particularly lung damage, by targeting EVs.

Conversion THA, which we defined for this study as THA with concomitant removal of preexisting orthopaedic hardware, has been associated with increased hospital costs and perioperative complications compared with primary THA. Yet, conversion THA is classified as a primary procedure under the Medicare Severity Diagnosis-Related Group coding scheme, and hospitals are reimbursed based on the resource use expected for a routine primary surgery. Prior authors have argued for conversion THA to be reclassified as a revision procedure. Although prior research has focused on comparisons between conversion THAs and primary arthroplasties, little is known about the resource use of conversion THA compared with that of revision THA.

(1) Do inpatient hospital costs, estimated using cost-to-charge ratios, differ between conversion THA and revision THA? (2) Do the median length of stay, intensive care unit use, and likelihood of discharge to home differ between conversion and revision THA?

This was a retrospective study of the Medicare Provider Analysis and Review Limited Data Set for 2019. A total of 713,535 primary and 74,791 revision THAs and TKAs were identified initially. Exclusion criteria then were applied; these included non-fee-for-service hospitalizations, nonelective admissions, and patients with missing data. Approximately 37% (263,545 of 713,535) of primary and 34% (25,530 of 74,791) of revision arthroplasties were excluded as non-fee-for-service hospitalizations. Two percent (13,159 of 713,535) of primaries and 11% (8159 of 74,791) of revisions were excluded because they were nonelective procedures. Among the remaining 436,831 primary and 41,102 revision procedures, 31% (136,748 of 436,831) were primary THAs and 36% (14,774 of 41,102) were revision THAs. Two percent (2761 of 136,748) of primary THAs involved intraoperative removal of hardware and were classified as conversion THAs. After claims with missing data were excluded, there were 2759 conversion THAs and 14,764 revision THAs available for analysis. Propensity scores were generated using a multivariate logistic regression model using the following variables as covariates: gender, age, race, van Walraven index, hospital setting, geography, hospital size, resident-to-bed ratio, and wage index. After matching, 2734 conversion THAs and 5294 revision THAs were available for analysis. The van Walraven index, which is a weighted score of patient preoperative comorbidities, was used to measure patient health status. Hospital costs were estimated by multiplying cost-to-charge ratios obtained from the 2019 Impact File by total hospital charges. This methodology enabled the use of a large national database to mitigate the random effects of individual hospitals' unique practices and patient populations. Multivariable regression was performed after matching to determine the independent effects of surgery type (that is, conversion versus revision THA) on hospital cost, length of stay greater than 2 days, intensive care unit use, and discharge to home.

There was no difference in the estimated hospital cost between conversion THA and revision THA (β = 0.96 [95% confidence interval 0.90 to 1.01]; p = 0.13). Patients undergoing conversion THA had increased odds of staying in the hospital for more than 2 days (odds ratio 1.12 [95% CI 1.03 to 1.23]; p = 0.01), increased odds of using the intensive care unit (OR 1.24 [95% CI 1.03 to 1.48]; p = 0.02), and decreased odds of being discharged to home (OR 0.74 [95% CI 0.67 to 0.80]; p < 0.001).

The inpatient hospital cost of conversion THA is no different from that of revision THA, although patients undergoing conversion surgery have modestly increased odds of prolonged length of stay, intensive care unit use, and discharge to a nonhome location. These findings support the conclusion that reclassification of conversion THA is warranted. Orthopaedic surgeons must advocate for the reclassification of conversion THA using data-backed evidence or run the risk that orthopaedic procedures will be given decreased reimbursement.

Level III, economic and decision analysis.

The present study aimed to investigate the protective action and mechanism of songorine on sepsis-induced acute lung injury (ALI).

The sepsis-induced ALI mouse and cell models were established by lipopolysaccharide (LPS) induction. Lung injury was assayed by hematoxylin and eosin staining, lung injury score, and lung wet-to-dry (W/D) weight ratio. Apoptosis in lung tissues was evaluated by TUNEL assay, and the expression of apoptosis-related markers (Bcl2, Bax, and caspase-3) was measured by western blotting. Levels of pro-inflammatory factors and oxidative stress markers in the bronchoalveolar lavage fluid (BALF) of mice were measured by ELISA and RT-qPCR. The expression of PI3K/AKT/NRF2 pathway-related proteins was analyzed by western blotting.

Songorine treatment at 40 mg/kg mitigated sepsis-induced ALI, characterized by improved histopathology, lung injury score, and lung W/D weight ratio (p < 0.05). Moreover, songorine markedly attenuated sepsis-induced apoptosis in lung tissues; this was evidenced by an increase in Bcl2 levels and a decrease in Bax and caspase-3 levels (p < 0.01). Also, songorine reduced levels of proinflammatory cytokines (TNF-α, IL-6, IL-1β and MPO) and oxidative stress regulators (SOD and GSH) in the BALF of LPS-induced sepsis mice and RAW264.7 cells (p < 0.05). In addition, songorine upregulated the PI3K/AKT/NRF2 pathway-related proteins in LPS-induced sepsis mice and RAW264.7 cells (p < 0.05). Furthermore, LY294002 (a PI3K inhibitor) treatment reversed the protective effect of songorine on sepsis-induced ALI.

Songorine inhibits oxidative stress-related inflammation in sepsis-induced ALI via the activation of the PI3K/AKT/NRF2 signaling pathway.

Metallo-β-lactamases (MBLs) represent a prevalent resistance mechanism in Gram-negative bacteria, rendering last-line carbapenem-related antibiotics ineffective. Here, a bioresponsive sliver peroxide (Ag2 O2 )-based nanovesicle, named Ag2 O2 @BP-MT@MM, is developed as a broad-spectrum MBL inhibitor for combating MBL-producing bacterial pneumonia. Ag2 O2 nanoparticle is first orderly modified with bovine serum albumin and polydopamine to co-load meropenem (MER) and [5-(p-fluorophenyl)-2-ureido]-thiophene-3-carboxamide (TPCA-1) and then encapsulated with macrophage membrane (MM) aimed to target inflammatory lung tissue specifically. The resultant Ag2 O2 @BP-MT@MM effectively abrogates MBL activity by displacing the Zn2+ cofactor in MBLs with Ag+ and displays potent bactericidal and anti-inflammatory properties, specific targeting abilities, and great bioresponsive characteristics. After intravenous injection, the nanoparticles accumulate prominently at infection sites through MM-mediated targeting . Ag+ released from Ag2 O2 decomposition at the infection sites effectively inhibits MBL activity and overcomes the resistance of MBL-producing bacteria to MER, resulting in synergistic elimination of bacteria in conjunction with MER. In two murine infection models of NDM-1+ Klebsiella pneumoniae-induced severe pneumonia and NDM-1+ Escherichia coli-induced sepsis-related bacterial pneumonia, the nanoparticles significantly reduce bacterial loading, pro-inflammatory cytokine levels locally and systemically, and the recruitment and activation of neutrophils and macrophages. This innovative approach presents a promising new strategy for combating infections caused by MBL-producing carbapenem-resistant bacteria.

Background: Circular RNAs have been reported to be involved in regulating the progression of sepsis and sepsis-associated damage. Herein, this work investigated whether circ_0033530 had roles in the process of septic acute lung injury (sepsis-ALI) and its associated mechanism. Methods: Lipopolysaccharide (LPS)-stimulated human lung fibroblasts MRC-5 were used to mimic the cell model of sepsis-ALI in vitro . Levels of genes and proteins were detected by quantitative real-time polymerase chain reaction and Western blotting. Functional experiments were conducted using 5-ethynyl-2'-deoxyuridine assay, Cell Counting Kit-8 assay, flow cytometry, and enzyme-linked immunosorbent assay. The interaction between miR-1184 and circ_0033530 or toll-like receptor 4 (TLR4) was confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. Results: Circ_0033530 expression was lower in sepsis patients and LPS-induced fibroblasts than those in healthy control and untreated cells. Functionally, knockdown of circ_0033530 protected fibroblasts against LPS-induced proliferation arrest, apoptosis, and inflammatory response. Mechanistically, circ_0033530 acted as a sponge for miR-1184, and TLR4 RNA was targeted by miR-1184, indicating the circ_0033530/miR-1184/TLR4 axis. Further rescue experiments showed that circ_0033530 silencing-mediated growth inhibition and inflammation on fibroblasts were attenuated by miR-1184 downregulation or TLR4 upregulation. Conclusion: Circ_0033530 knockdown alleviated LPS-induced proliferation arrest, apoptosis, and inflammation in lung fibroblasts by miR-1184/TLR4 axis, and provided molecular theoretical basis for circ_0033530 on the pathogenesis of sepsis-ALI.

Objective The objective of this study is to compare the outcomes of hospital mortality, the requirement of invasive ventilation, vasopressor requirement, duration of vasopressor requirement, and duration of intensive care unit (ICU) stay among the different causes of sepsis and to determine which cause of sepsis had the most severe outcomes. Methods A retrospective chart review was done in critically ill adult patients who were admitted with sepsis to the ICU from July 2017 until July 2019. Acute Physiology and Chronic Health Evaluation (APACHE) IV scores were calculated on patients admitted to ICU on day one of ICU admission. Each patient was then evaluated for outcomes of hospital mortality, need for invasive ventilation, requirement of vasopressors, duration of vasopressors, and duration of ICU stay. The outcomes were then compared between the different sources of sepsis to determine which source of sepsis had the highest severity. Results In total, 176 patients were included in the study. Ninety-three patients were admitted with respiratory sepsis, 26 patients were admitted with gastrointestinal sepsis, 31 patients were admitted with urosepsis, and 26 patients were admitted with other miscellaneous causes of sepsis. The hospital mortality was highest in the respiratory sepsis group at 32%, with a trend towards statistical significance with a P value of 0.057. ICU stay duration was highest in patients with respiratory sepsis at six days, with a statistically significant P value of < 0.001. The need for invasive ventilation was highest in patients with respiratory sepsis at 64%, with a statistically significant P value of < 0.001. The requirement of vasopressor support was highest in patients with respiratory sepsis at 47% and the duration of vasopressors was highest in both respiratory and gastrointestinal sepsis at three days, however, there was no statistical significance. Conclusion Among the different origins of sepsis, the patients with respiratory sepsis had the most severe outcomes, with the highest need for invasive ventilation and the highest ICU stay duration.

Sepsis-induced acute lung injury (ALI) accounts for about 40% of ALI, accompanied by alveolar epithelial injury. The study aimed to reveal the role of circular RNA_0114428 (circ_0114428) in sepsis-induced ALI.

Human pulmonary alveolar epithelial cells (HPAEpiCs) were treated with lipopolysaccharide (LPS) to mimic a sepsis-induced ALI cell model. RNA expression of circ_0114428, miR-574-5p and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) was detected by qRT-PCR. Protein expression was checked by Western blotting. Cell viability, proliferation and apoptosis were investigated by cell counting kit-8, 5-Ethynyl-29-deoxyuridine (EdU) and flow cytometry analysis, respectively. The levels of pro-inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). Oxidative stress was analyzed by lipid peroxidation Malondialdehyde (MDA) and Superoxide Dismutase (SOD) activity detection assays. The interplay among circ_0114428, miR-574-5p and ROCK2 was identified by dual-luciferase reporter, RNA pull-down and RNA immunoprecipitation assays.

Circ_0114428 and ROCK2 expression were significantly increased, but miR-574-5p was decreased in blood samples from sepsis patients and LPS-stimulated HPAEpiCs. LPS treatment led to decreased cell viability and proliferation and increased cell apoptosis, inflammation and oxidative stress; however, these effects were relieved after circ_0114428 knockdown. Besides, circ_0114428 acted as a miR-574-5p sponge and regulated LPS-treated HPAEpiC disorders through miR-574-5p. Meanwhile, ROCK2 was identified as a miR-574-5p target, and its silencing protected against LPS-induced cell injury. Importantly, circ_0114428 knockdown inhibited ROCK2 production by interacting with miR-574-5p.

Circ_0114428 knockdown protected against LPS-induced HPAEpiC injury through miR-574-5p/ROCK2 axis, providing a novel therapeutic target in sepsis-induced ALI.

Sepsis is a significant public health concern, particularly affecting individuals above 70 years in developed countries. This is a crucial fact due to the increasing aging population, their heightened vulnerability to sepsis, and the associated high mortality rates. However, the morbidity and long-term outcomes are even more notable. While many patients respond well to timely and appropriate interventions, it is imperative to enhance efforts in identifying, documenting, preventing, and treating sepsis. Managing sepsis in older patients poses greater challenges and necessitates a comprehensive understanding of predisposing factors and a heightened suspicion for diagnosing infections and assessing the risk of sudden deterioration into sepsis. Despite age often being considered an independent risk factor for mortality and morbidity, recent research emphasizes the pivotal roles of frailty, disease severity, and comorbid conditions in influencing health outcomes. In addition, it is important to inquire about the patient's preferences and establish a personalized treatment plan that considers their potential for recovery with quality of life and functional outcomes. This review provides a summary of the most crucial aspects to consider when dealing with an old critically ill patient with sepsis.

Peripherally inserted central catheters (PICCs) are increasingly recognized as an alternative to centrally inserted central catheters (CICCs) in critical care, yet the data regarding the safety and feasibility of this choice in septic shock management is growing but still lacking. In this study, we aimed to determine the feasibility, safety, and impact on outcomes of using dedicated vascular access specialist (VAS) teams to insert PICCs versus CICCs on patients admitted to the ICU with septic shock.

Retrospective cohort study.

Mayo Clinic Rochester Medical ICU and Mayo Clinic Arizona Multidisciplinary ICU from 2013 to 2016.

All adult patients hospitalized with diagnosis of septic shock excluding patients who declined authorization for review of their medical records, mixed shock states, and readmissions.

None.

Comprehensive data regarding septic shock diagnosis and resuscitation were abstracted from electronic medical records. A total of 562 patients with septic shock were included in the study; 215 patients were resuscitated utilizing a PICC and 347 were resuscitated using a CICC. On univariate analysis, the time to central line insertion and time to vasopressor initiation were found to be reduced in those who received PICC at time of ICU admission versus CICC. Other favorable outcomes were also observed in those who received PICC versus CICC including shorter ICU length of stay and lower unadjusted hospital mortality. A multivariable analysis for hospital mortality showed that after adjusting for important covariates, neither the time to central line insertion nor the time to vasopressor initiation was associated with a lower hospital mortality.

Across two tertiary referral centers within the same enterprise, use of a dedicated VAS team for insertion of PICCs for initial resuscitation in patients with septic shock was feasible and associated with shorter time to central venous access and initiation of vasopressors; however, adjusted hospital mortality was not different between the two groups.

Sepsis is a life-threatening disease with high morbidity and mortality, characterized by an inadequate systemic immune response to an initial stimulus. Whether the use of ondansetron (OND) during intensive care unit (ICU) stay is associated with the prognosis of sepsis patients remains unclear.

Critically ill patients with sepsis were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Multivariate logistic regression and Cox regression analyses were used to explore the association between OND use and clinical outcomes after adjusting for confounders. Kaplan-Meier survival curve was used for survival analysis. Propensity score matching (PSM) and subgroup analysis were performed to further confirm the results.

The OND-medication group showed reduced in-hospital mortality, 28-day and 90-day mortalities. The OR for in-hospital mortality was 0.80 (0.64-0.99) and HRs for 28-day mortality and 90-day mortality were 0.77 (0.64-0.92) and 0.83 (0.70-0.98), respectively. After PSM, the clinical outcomes remained consistent. In-hospital mortality was lower in the OND-medication group (28.1% vs. 35.8%, P= 0.044), as well as 28-day mortality (23.4% vs. 32.1%, P=0.022) and 90-day mortality (27.4% vs. 35.8%, P=0.035). The protective effect of OND in sepsis patients was relatively robust, independent of age, septic shock, vasopressin and mechanical ventilation. Additionally, the OND users had longer lengths of stay in ICU (6.9(3.1-13.2) vs. 5.1(2.5-11.0), P = 0.026) while no statistical differences were found in lengths of stay in hospital (P = 0.333).

OND exposure might be associated with lower in-hospital, 28-day, and 90-day mortality rates in critically ill patients with sepsis. This study indicated that OND might help improve the prognosis of patients with sepsis.

Sepsis-associated acute kidney injury is associated with high morbidity and mortality in critically ill patients. Cell-free hemoglobin (CFH) is released into the circulation of patients with severe sepsis and the levels of CFH are independently associated with mortality. CFH treatment increased cytotoxicity in the human tubular epithelial cell line HK-2. To better model the intact kidney, we cultured human kidney organoids derived from induced pluripotent stem cells. We treated human kidney organoids grown using both three-dimensional and transwell protocols with CFH for 48 h. We found evidence for increased tubular toxicity, oxidative stress, mitochondrial fragmentation, endothelial cell injury and injury-associated transcripts compared to those of the untreated control group. To evaluate the protective effect of clinically available small molecules, we co-treated CFH-injured organoids with ascorbate (vitamin C) or acetaminophen for 48 h. We found significantly decreased toxicity, preservation of endothelial cells and reduced mitochondrial fragmentation in the group receiving ascorbate following CFH treatment. This study provides direct evidence that ascorbate or ascorbic acid protects human kidney cells from CFH-induced damage such as that in sepsis-associated acute kidney injury.

The interhospital transfer (IHT) of patients with sepsis to higher-capability hospitals may improve outcomes. Little is known about patient and hospital factors associated with sepsis IHT.

We evaluated patterns of hospitalization and IHT and determined patient and hospital factors associated with the IHT of adult patients with sepsis.

Retrospective cohort study.

A total of 349,938 adult patients with sepsis at 329 nonfederal hospitals in California, 2018-2019.

We evaluated patterns of admission and outward IHT between low sepsis-, intermediate sepsis-, and high sepsis-capability hospitals. We estimated odds of IHT using generalized estimating equations logistic regression with bootstrap stepwise variable selection.

Among the cohort, 223,202 (66.4%) were initially hospitalized at high-capability hospitals and 10,870 (3.1%) underwent IHT. Nearly all transfers (98.2%) from low-capability hospitals were received at higher-capability hospitals. Younger age (< 65 yr) (adjusted odds ratio [aOR] 1.54; 95% CI, 1.40-1.69) and increasing organ dysfunction (aOR 1.22; 95% CI, 1.19-1.25) were associated with higher IHT odds, as were admission to low-capability (aOR 2.79; 95% CI, 2.33-3.35) or public hospitals (aOR 1.35; 95% CI, 1.09-1.66). Female sex (aOR 0.88; 95% CI, 0.84-0.91), Medicaid insurance (aOR 0.59; 95% CI, 0.53-0.66), home to admitting hospital distance less than or equal to 10 miles (aOR 0.92; 95% CI, 0.87-0.97) and do-not-resuscitate orders (aOR 0.48; 95% CI, 0.45-0.52) were associated with lower IHT odds, as was admission to a teaching hospital (aOR 0.83; 95% CI, 0.72-0.96).

Most patients with sepsis are initially hospitalized at high-capability hospitals. The IHT rate for sepsis is low and more likely to originate from low-capability and public hospitals than from high-capability and for-profit hospitals. Transferred patients with sepsis are more likely to be younger, male, sicker, with private medical insurance, and less likely to have care limitation orders. Future studies should evaluate the comparative benefits of IHT from low-capability hospitals.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and is characterized by multiple biological and clinical features. N6-methyladenosine (m6A) modification is the most common type of RNA modifications in eukaryotes and plays an important regulatory role in various biological processes. Recently, m6A modification has been found to be involved in the regulation of immune responses in sepsis. In addition, several studies have shown that m6A modification is involved in sepsis-induced multiple organ dysfunctions, including cardiovascular dysfunction, acute lung injury (ALI), acute kidney injury (AKI) and etc. Considering the complex pathogenesis of sepsis and the lack of specific therapeutic drugs, m6A modification may be the important bond in the pathophysiological process of sepsis and even therapeutic targets. This review systematically highlights the recent advances regarding the roles of m6A modification in sepsis and sheds light on their use as treatment targets for sepsis.

This study was conducted to investigate the relationship between atrial fibrillation and the clinical prognosis of patients with sepsis in intensive care unit. A total of 21,538 sepsis patients were enrolled in the study based on the Medical Information Mart for Intensive Care IV database, of whom 6,759 had AF. Propensity score matching was used to compare the clinical characteristics and outcomes of patients with and without AF. Besides, the inverse probability of treatment weighting, univariate and multivariate Cox regression analyzes were performed. Of the 21,538 patients, 31.4% had AF. The prevalence of AF increased in a step-by-step manner with growing age. Patients with AF were older than those without AF. After PSM, 11,180 patients remained, comprising 5,790 matched pairs in both groups. In IPTW, AF was not associated with 28-day mortality [hazard ratio (HR), 1.07; 95% confidence interval (CI), 0.99-1.15]. In Kaplan-Meier analysis, it was not observed difference of 28-day mortality between patients with and without AF. AF could be associated with increased ICU LOS, hospital LOS and need for mechanical ventilation; however, it does not remain an independent short-term predictor of 28-day mortality among patients with sepsis after PSM with IPTW and multivariate analysis.

Sepsis is a significant global health issue causing organ failure and high mortality. The number of sepsis cases has recently increased in Thailand making it crucial to comprehend the factors behind these infections. This study focuses on exploring the spatial autocorrelation between socio-economic factors and health service factors on the one hand and sepsis mortality on the other. We applied global Moran's I, local indicators of spatial association (LISA) and spatial regression to examine the relationship between these variables. Based on univariate Moran's I scatter plots, sepsis mortality in all 77 provinces in Thailand were shown to exhibit a positive spatial autocorrelation that reached a significant value (0.311). The hotspots/ high-high (HH) clusters of sepsis mortality were mostly located in the central region of the country, while the coldspots/low-low (LL) clusters were observed in the north-eastern region. Bivariate Moran's I indicated a spatial autocorrelation between various factors and sepsis mortality, while the LISA analysis revealed 7 HH clusters and 5 LL clusters associated with population density. Additionally, there were 6 HH and 4 LL clusters in areas with the lowest average temperature, 4 HH and 2 LL clusters in areas with the highest average temperature, 8 HH and 5 LL clusters associated with night-time light and 6 HH and 5 LL clusters associated with pharmacy density. The spatial regression models conducted in this study determined that the spatial error model (SEM) provided the best fit, while the parameter estimation results revealed that several factors, including population density, average lowest and highest temperature, night-time light and pharmacy density, were positively correlated with sepsis mortality. The coefficient of determination (R2) indicated that the SEM model explained 56.4% of the variation in sepsis mortality. Furthermore, based on the Akaike Information Index (AIC), the SEM model slightly outperformed the spatial lag model (SLM) with an AIC value of 518.1 compared to 520.

Vitamin D, as a common micronutrient, has been widely used in critically ill patients. However, whether supplementation of vitamin D in adult patients with sepsis can improve their prognosis remains controversial.

Data from the Mart for Intensive Care IV database was used in this retrospective cohort study, and adult patients with sepsis were enrolled. Critically ill patients, admitted to intensive care units (ICUs) between 2008 and 2019 at the Beth Israel Deaconess Medical Center (BIDMC), were divided into the vitamin D supplementation group and non-vitamin D supplementation group. The primary outcomes were defined as all-cause in-hospital, 28-day, and 90-day mortality rates after admission to the ICU. A 1:1 propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and overlap weighting (OW) analyses were used to minimize selection bias and balance the baseline demographic characteristics. Regression and survival analyses were performed to assess the association between vitamin D supplementation and clinical outcomes in patients with sepsis.

In total, 3539 patients with sepsis were enrolled as study participants; of these, 315 were supplemented with vitamin D during their ICU stay. In-hospital, 28-day, and 90-day mortality rates were significantly lower in patients with sepsis supplemented with vitamin D. Multivariate regression analysis showed vitamin D supplementation as a potential protective factor for in-hospital mortality with an odds ratio (OR) = 0.70 (0.51-0.96) after adjusting for all confounders. The hazard ratios (HRs) for 28-day and 90-day mortality were 0.65 (0.50-0.85) and 0.70 (0.55-0.90), respectively. The survival analysis showed that the vitamin D supplementation group had a higher survival probability within 28 and 90 days (p-value < 0.05). These results remained relatively stable post PSM, IPTW, and OW. However, we found no evidence that vitamin D supplementation could shorten the length of stay in the ICU or hospital.

Vitamin D supplementation during an ICU stay was associated with improved prognosis in patients with sepsis, as evidenced by lower in-hospital, 28-day, and 90-day mortality rates and lower disease severity-related scores, but showed no influence on the length of stay in the hospital or ICU.

Purpose: Young adults receive severe sepsis treatment across pediatric and adult care settings. However, little is known about young adult sepsis outcome differences in pediatric versus adult hospital settings. Material and Methods: Using Truven MarketScan database from 2010-2015, we compared in-hospital mortality and hospital length of stay in young adults ages 18-26 treated for severe sepsis in Pediatric Intensive Care Units (PICUs) versus Medical ICUs (MICUs)/Surgical ICUs (SICUs) using logistic regression models and accelerated time failure models, respectively. Comorbidities were identified using Complex Chronic Conditions (CCC) and Charlson Comorbidity Index (CCI). Results: Of the 18 900 young adults hospitalized with severe sepsis, 163 (0.9%) were treated in the PICU and 952 (5.0%) in the MICU/SICU. PICU patients were more likely to have a comorbid condition compared to MICU/SICU patients. Compared to PICU patients, MICU/SICU patients had a lower odds of in-hospital mortality after adjusting for age, sex, Medicaid status, and comorbidities (adjusting for CCC, odds ratio [OR]: 0.50, 95% CI 0.29-0.89; adjusting for CCI, OR: 0.51, 95% CI 0.29-0.94). There was no difference in adjusted length of stay for young adults with severe sepsis (adjusting for CCC, Event Time Ratio [ETR]: 1.14, 95% CI 0.94-1.38; adjusting for CCI, ETR: 1.09, 95% CI 0.90-1.33). Conclusions: Young adults with severe sepsis experience higher adjusted odds of mortality when treated in PICUs versus MICU/SICUs. However, there was no difference in length of stay. Variation in mortality is likely due to significant differences in the patient populations, including comorbidity status.

Cell-free hemoglobin is a pathophysiological driver of endothelial injury during sepsis and acute respiratory distress syndrome (ARDS), but the precise mechanisms are not fully understood. We hypothesized that hemoglobin (Hb) increases leukocyte adhesion and endothelial activation in human lung microvascular endothelial cells (HLMVEC). We stimulated primary HLMVEC, or leukocytes isolated from healthy human donors, with Hb (0.5 mg/mL) and found that leukocyte adhesion to lung endothelium in response to Hb is an endothelial-dependent process. Next, we stimulated HLMVEC with Hb over time (1, 3, 6, and 24 h) and found increased transcription and release of inflammatory cytokines (IL-1β, IL-8, and IL-6). In addition, Hb exposure variably upregulated transcription, total protein expression, and cell-surface localization of adhesion molecules E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Since VCAM-1 was most upregulated by Hb, we further tested mechanisms for Hb-mediated upregulation of VCAM-1 in HLMVEC. Although upregulation of VCAM-1 was not prevented by hemoglobin scavenger haptoglobin, heme scavenger hemopexin, or inhibition of nod-like receptor protein 3 (NLRP3) signaling, blocking Toll-like receptor 4 (TLR4) with small molecule inhibitor TAK-242 (1 µM) prevented upregulation of VCAM-1 in response to Hb. Consistently, Hb increased nuclear factor-κB (NF-κB) activation and intracellular reactive oxygen species (ROS), which were both prevented by TLR4 inhibition. Together, these data demonstrate that Hb increases leukocyte-endothelial adhesion and activates HLMVEC through TLR4 signaling, indicating a potential mechanism for Hb-mediated pulmonary vascular injury during inflammatory and hemolytic conditions.

Sepsis is defined as a life-threatening dysfunction due to a dysregulated host response to infection. It is a common and complex syndrome and is the leading cause of death in intensive care units. The lungs are most vulnerable to the challenge of sepsis, and the incidence of respiratory dysfunction has been reported to be up to 70%, in which neutrophils play a major role. Neutrophils are the first line of defense against infection, and they are regarded as the most responsive cells in sepsis. Normally, neutrophils recognize chemokines including the bacterial product N-formyl-methionyl-leucyl-phenylalanine (fMLP), complement 5a (C5a), and lipid molecules Leukotriene B4 (LTB4) and C-X-C motif chemokine ligand 8 (CXCL8), and enter the site of infection through mobilization, rolling, adhesion, migration, and chemotaxis. However, numerous studies have confirmed that despite the high levels of chemokines in septic patients and mice at the site of infection, the neutrophils cannot migrate to the proper target location, but instead they accumulate in the lungs, releasing histones, DNA, and proteases that mediate tissue damage and induce acute respiratory distress syndrome (ARDS). This is closely related to impaired neutrophil migration in sepsis, but the mechanism involved is still unclear. Many studies have shown that chemokine receptor dysregulation is an important cause of impaired neutrophil migration, and the vast majority of these chemokine receptors belong to the G protein-coupled receptors (GPCRs). In this review, we summarize the signaling pathways by which neutrophil GPCR regulates chemotaxis and the mechanisms by which abnormal GPCR function in sepsis leads to impaired neutrophil chemotaxis, which can further cause ARDS. Several potential targets for intervention are proposed to improve neutrophil chemotaxis, and we hope that this review may provide insights for clinical practitioners.