Disseminated Intravascular Coagulopathy (DIC) and Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) are critical care syndromes that frequently coexist in critically ill patients, but mechanisms underlying their shared pathways are not well understood.

This review discusses the pathophysiology of DIC and PICS and explores the shared mechanisms behind DIC and PICS and their implications for clinical management.

DIC and PICS share a common pathophysiological foundation of endothelial dysfunction, coagulation dysregulation, and inflammation, leading to a vicious cycle of microvascular injury and systemic inflammation, culminating in organ dysfunction. DIC has also been identified as an independent risk factor for PICS. Anticoagulation therapies such as antithrombin, recombinant human soluble thrombomodulin (rhTM), and heparin attenuates inflammation, a mechanism underlying both syndromes, thereby improving outcomes in PICS.

DIC and PICS share critical pathophysiological pathways that exacerbate outcomes in critically ill patients. Recognizing these interconnections is essential for developing targeted therapies. Standardizing PICS definitions and advancing research to clarify mechanisms, interplay, and causality between DIC and PICS are crucial next steps.

Sepsis is a life-threatening multiple organ dysfunction resulting from a dysregulated host response to infection, and patients with sepsis always exhibit a state of immune disorder characterized by both overwhelming inflammation and immunosuppression. The aging of immune system, namely "immunosenescence", has been reported to be correlated with high morbidity and mortality in elderly patients with sepsis. Initially, immunosenescence was considered as a range of age-related alterations in the immune system. However, increasing evidence has proven that persistent inflammation or even a short-term inflammatory challenge during sepsis could trigger accelerated aging of immune cells, which might further exacerbate inflammatory cytokine storm and promote the shift towards immunosuppression. Thus, premature immunosenescence is found in young sepsis individuals, which further aggravates immune disorders and induces the progression of sepsis. Furthermore, in old sepsis patients, the synergistic effects of both sepsis and aging may cause immunosenescence-associated alterations more significantly, resulting in more severe immune dysfunction and a worse prognosis. Therefore, it is necessary to explore the potential therapeutic strategies targeting immunosenescence during sepsis.

Management of persistent inflammation, immunosuppression, and catabolism syndrome (PICS) after sepsis remains challenging for patients in the intensive care unit, experiencing poor quality of life and death. However, immune-cell signatures in patients with PICS after sepsis remain unclear.

We determined immune-cell signatures of PICS after sepsis at single-cell resolution. Murine cecal ligation and puncture models of PICS were applied for validation.

Immune functions of two enriched monocyte subpopulations, Mono1 and Mono4, were suppressed substantially in patients with sepsis and were partially restored in patients with PICS after sepsis and exhibited immunosuppressive and pro-apoptotic effects on B and CD8T cells. Patients with PICS and sepsis had reduced naive and memory B cells and proliferated plasma cells. Besides, naive and memory B cells in patients with PICS showed an active antigen processing and presentation gene signature compared to those with sepsis. PICS patients with better prognoses exhibited more active memory B cells and IGHA1-plasma cells. CD8TEMRA displayed signs of proliferation and immune dysfunction in the PICS-death group in contrast with the PICS-alive group. Megakaryocytes proliferation was more pronounced in patients with PICS and sepsis than in healthy controls, with notable changes in the anti-inflammatory and immunomodulatory effects observed in patients with PICS and verified in mice models.

Our study evaluated PICS after sepsis at the single-cell level, identifying the heterogeneity present within immune-cell subsets, facilitating the prediction of disease progression and the development of effective intervention.

This work was supported by the National Natural Science Foundation of China, Shanghai Municipal Health Commission "Yiyuan New Star" Youth Medical Talent Cultivating Program, and Shanghai Clinical Research Center for Anesthesiology.

Epidemiological evidence has revealed an associative link between sepsis survivorship and increased risk of dementia, particularly Alzheimer's disease (AD). Paradoxically, population studies show females are less susceptible to sepsis but more vulnerable to post-sepsis dementia. Here, we examined the temporal impacts of sepsis in the context of AD by using an AD-amyloidosis model (TgCRND8) and their wild-type littermates and assessing outcomes at 7 days and 3 months post-sepsis in male and female mice. Following 7-days recovery, the microglia and astrocytes in AD-model mice were largely refractile to the systemic immune stimuli. Notably, the female AD-model mice accumulated higher hippocampal amyloid-beta (Aβ) burden and upregulated AD-type transcriptomic signature at this time. On the other hand, male AD-model mice showed no Aβ changes. At this time, the wild-type post-septic males, but not females, displayed robust astrocytosis, with nominal microgliosis. By 3 months post-sepsis, microgliosis was specifically elevated in wild-type females, indicating a prolonged central immune response. At this time, both male and female AD-model mice showed exacerbated Aβ and anxiety indices. Gene network analysis revealed a stronger immune response in females, while the male response was linked to estrogen receptor (ESR) signaling, with ERα protein upregulated in the brains of post-septic AD-model males. Together, our data highlights a sex-dimorphic temporal response in post-sepsis neuroinflammation, with ESR signaling playing a key role in males, while Aβ burden is affected similarly in both males and females.

Swertianolin is one of the main components of Gentianaceae Swertia plants, a traditional Chinese medicine used for the treatment of infection, fever, viral hepatitis, and pneumonia. An expansion of myeloid-derived suppressor cells (MDSCs) contributes to sepsis induced immunosuppression. We investigated the mechanism by which Swertianolin regulates MDSCs in a mouse model of sepsis.

Severe sepsis was induced in mice using caecal ligation and puncture. These mice received an intraperitoneal injection of Swertianolin. MDSCs were isolated and analyzed by flow cytometry; serum concentrations of immunosuppressive factors were detected by ELISA; and mitogen-activated protein kinase and nuclear factor-κB (NFκB) were detected by Western blots.

We found that Swertianolin reduced the number of MDSCs in the marrow and the spleen while increased the number of CD4+ T cells in the spleen of mice with sepsis in comparison to controls (p < 0.05). Swertianolin reduced lung damage and improved the survival rate in mice with secondary infection of Legionella pneumophila (p < 0.05). Swertianolin inhibited the phosphorylation of p38 and nuclear translocation of p65 in MDSCs (p < 0.05), leading to decreased production of IL-10 and nitric oxide (both p < 0.05).

Swertianolin may improve immunosuppressive function of MDSCs and increased T cell activity by inhibiting p38 phosphorylation and NF-κB activation.

Growing evidence indicates that preoperative hyperinflammation is an independent risk factor for postoperative sarcopenia and poor prognosis in patients with colon cancer. However, inflammation fluctuates with tumor burden and immune status after surgery, and its role in muscle degradation remains unclear. This study aimed to explore the impact of different inflammatory trajectories on muscle wasting.

This retrospective study included 193 patients who are diagnosed with stage II or III colon cancer between 2015 and 2021. The preoperative and postoperative neutrophil-to-lymphocyte ratio (NLR) and prognostic immunological and nutritional index (PINI) were used to assess inflammation, and the subjects divided into four groups: a group with consistently low inflammation (G1), a group with initially high but postoperative decreased inflammation (G2), a group with initially low but postoperative increased inflammation (G3), and a group with consistently high inflammation (G4). Logistic regression identified risk factors for postoperative sarcopenia, while multivariate linear regression assessed the impact of inflammation on skeletal muscle index (SMI%) and density loss rate (SMD%). Cox models calculated overall survival (OS) and recurrence-free survival (RFS).

For all the assessed markers, the SMI% and SMD% in G4 significantly increased compared to G1 (P < 0.05), while G2 and G3 showed no significant change at 12 months (P > 0.05). Elevated inflammation was an independent risk factor for postoperative sarcopenia (P < 0.05). Postoperative sarcopenia and PINI in G4 independently influenced OS and RFS.

Only patients with persistent postoperative inflammation, not all patients with preoperative inflammation, are at increased risk for muscle wasting and poor prognosis. These findings suggest that modulating postoperative inflammation could reduce muscle loss and improve survival; these findings guide the future development of anti-inflammatory therapies for suitable populations.

This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.

Most trauma patients require intensive care treatment and are susceptible to developing persistent inflammation and immunosuppression, potentially leading to multi organ dysfunction syndrome (MODS) and dependence on long term care facilities. T cells undergo changes in numbers and function post trauma. T cell dysfunction in polytraumatized patients was characterized using functional immunomonitoring to predict individual clinical outcome. Moreover, the potential to reverse T cell dysfunction using Interleukin (IL)-7 was examined.

Blood samples were drawn from healthy individuals and prospectively enrolled polytrauma patients (Injury Severity Score ≥ 18) on admission, 8, 24 and 48 hours, 5 and 10 days after. CD3/28-stimulated cytokine production of T cells in whole blood was assessed via Enzyme Linked Immuno Spot (ELISpot). T cell subsets were quantified via counting and flow cytometry. Unfavorable physical performative outcome was defined as death or new functional disability necessitating long term care. Secondary outcomes were the development of MODS and in-hospital mortality. IL-7 was added ex vivo to test reversibility of cytokine disturbances.

34 patients were enrolled. The different outcome groups showed no difference in injury severity. Patients with favorable physical performative outcome revealed higher functional T cell specific Interferon γ (IFN-γ) and IL-17 (8 hours) and lower IL-10 production (day 5) and higher CD8 T cell concentrations. Patients without MODS development showed a higher IFN-γ (day 10), higher IL-2 (8 hours) and higher IL-17 production (admission, day 5). There were no differences regarding in-hospital mortality. Systemic blood IFN-γ, IL-2 and IL-10 concentrations only correlated with MODS (24 hours). Systemic CD8 T cell numbers correlated with functional IFN-γ production. Whole blood stimulation with IL-7 increased functional T cell IFN-γ release.

Our study reveals an early characteristic overall T cell dysfunction of pro-inflammatory (IFN-γ, IL-2, IL-17) and immunosuppressive (IL-10) subtypes in polytraumatized patients. Our data indicates that rather the functional capacity of T cells to release cytokines, but not systemic cytokine concentrations can be used to predict outcome post trauma. We assume that the early stimulation of pro- and anti-inflammatory T cells benefits polytraumatized patients. Potentiation of functional IFN-γ release might be achieved by IL-7 administration.

Hypernatremia represents a significant electrolyte imbalance associated with numerous adverse outcomes, particularly in cases of intensive care unit (ICU)-acquired hypernatremia (IAH). Nevertheless, its relevance in patients with septic shock remains uncertain.

To identify independent risk factors and their predictive efficacy for IAH to improve outcomes in patients with septic shock.

In the present retrospective single-center study, a cohort of 157 septic shock patients with concurrent hypernatremia in the ICU at The First Affiliated Hospital of Soochow University, between August 1, 2018, and May 31, 2023, were analyzed. Patients were categorized based on the timing of hypernatremia occurrence into the IAH group (n = 62), the non-IAH group (n = 41), and the normonatremia group (n = 54).

In the present study, there was a significant association between the high serum sodium concentrations, excessive persistent inflammation, immunosuppression and catabolism syndrome and chronic critical illness, while rapid recovery had an apparent association with normonatremia. Moreover, multivariable analyses revealed the following independent risk factors for IAH: Total urinary output over the preceding three days [odds ratio (OR) = 1.09; 95%CI: 1.02-1.17; P = 0.014], enteral nutrition (EN) sodium content of 500 mg (OR = 2.93; 95%CI: 1.13-7.60; P = 0.027), and EN sodium content of 670 mg (OR = 6.19; 95%CI: 1.75-21.98; P = 0.005) were positively correlated with the development of IAH. Notably, the area under the curve for total urinary output over the preceding three days was 0.800 (95%CI: 0.678-0.922, P = 0.001). Furthermore, maximum serum sodium levels, the duration of hypernatremia, and varying sodium correction rates were significantly associated with 28-day in-hospital mortality in septic shock patients (P < 0.05).

The present findings illustrate that elevated serum sodium level was significantly associated with a poor prognosis in septic shock patients in the ICU. It is highly recommended that hypernatremia be considered a potentially important prognostic indicator for the outcome of septic shock.

The management of peri-operative pain is one of the pillars of anaesthesia and is of particular importance in patients undergoing surgery for solid malignant tumours. Amongst several options, the most commonly employed analgesic regimens involve opioids, NSAIDs and regional anaesthesia techniques with different local anaesthetics. In recent years, several research reports have tried to establish a connection between peri-operative anaesthesia care and outcome after cancer surgery. Experimental studies have indicated that certain pain management substances may influence cancer progression, mainly by modifying the tumour's response to surgical stress and peri-operative inflammation. However, these promising in-vitro and in-vivo data have yet to be confirmed by randomised clinical trials. The reason for this might lie with the nature of tumour biology itself, and in the diversity of patient and tumour phenotypes. In a translational approach, future research should therefore concentrate on patient and tumour-related factors or biomarkers, which might either influence the tumour and its microenvironment or predict potential responses to interventions, including the choice of the analgesic. This might not only be relevant for the daily practice of clinical anaesthesia, but would also be of great importance for patients undergoing cancer surgery, who might be able to receive an individualised anaesthetic regimen based on their phenotypic profile.

Many patients now survive their initial critical events but subsequently develop chronic critical illness (CCI). CCI is characterized by prolonged hospital stays, poor outcomes, and significant long-term mortality. The incidence of chronic critical illness (CCI) is estimated to be 34.4 cases per 100,000 population. The incidence varies significantly with age, peaking at 82.1 cases per 100,000 in individuals aged 75-79. The one-year mortality rate among CCI patients approaches 50%. A subset of these patients enters a state of persistent inflammation, immune suppression, and ongoing catabolism, a condition termed persistent inflammation, immunosuppression, and catabolism syndrome (PICS) in 2012. In recent years, some progress has been made in treating PICS. For instance, recent advancements such as the persistent expansion of MDSCs (myeloid-derived suppressor cells) and the mechanisms underlying intestinal barrier dysfunction have provided new directions for therapeutic strategies, as discussed below. Persistent inflammation, a key feature of PICS, has received comparatively little research attention. In this review, we examine the potential pathophysiological changes and molecular mechanisms underlying persistent inflammation and its role in PICS. We also discuss current therapies about inflammation and offer recommendations for managing patients with PICS.

Sepsis induces profound derangements in the immune system, including lymphopenia, which correlates with immunosuppression and poor prognosis. However, most evaluations of immunosuppression in sepsis patients rely on static, sporadic lymphocyte counts, lacking dynamic modeling over the disease course. This study aimed to apply latent class mixed modeling on longitudinal lymphocyte counts to uncover heterogeneous trajectory phenotypes in sepsis patients and assess their predictive value for clinical outcomes.

Four lymphocyte trajectory phenotypes were identified in the retrospective cohort (n=2,149) and externally validated (n=2,388): high-declining (α, 3.8%), stable-medium (β, 69.3%), high-increasing (γ, 3.2%), and stable-low (δ, 23.8%). The α phenotype exhibited the highest disease severity and mortality (25.9%) compared with other phenotypes in both cohorts. In the prospective cohort (n=1,056), all lymphocyte subset counts differed among phenotypes on admission (P <.001) and were lower in non-survivors (P<.05). Multivariable regression demonstrated that age, Acute Physiology and Chronic Health Evaluation-II score, heart rate, natural killer cell count, infection source, and lymphocyte trajectory phenotype were independent predictors of 28-day mortality. A nomogram combining these variables provided individualized risk estimations.

The lymphocyte trajectories delineated novel dynamic phenotypes associated with divergent sepsis outcomes. Incorporating longitudinal trajectory modeling and lymphocyte subsets may improve prognostic risk assessment and guide the selection of immunotherapies tailored to specific immune phenotypes in sepsis patients.

https://www.chictr.org.cn/showproj.aspx?proj=18277, identifier ChiCTR-40 ROC-17010750.

Sepsis remains a significant cause of morbidity and mortality worldwide. Although many more patients are surviving the acute event, a substantial number enters a state of persistent inflammation and immunosuppression, rendering them more vulnerable to infections. Modulating the host immune response has been a focus of sepsis research for the past 50 years, yet novel therapies have been few and far between. Although many septic patients have similar clinical phenotypes, pathways affected by the septic event differ not only between individuals but also within an individual over the course of illness. These differences ultimately impact overall immune function and response to treatment. Defining the immune state, or endotype, of an individual is critical to understanding which patients will respond to a particular therapy. In this review, we highlight current approaches to define the immune endotype and propose that these technologies may be used to "prescreen" individuals to determine which therapies are most likely to be beneficial.

This study sought to elucidate the potential association between serum cortisol level and clinical outcomes in patients diagnosed with Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PIICS).

This prospective observational study, initiated in January 2023 and concluded in July 2023 enrolled 42 patients diagnosed with PIICS admitted to the intensive care unit (ICU) at Training and Research Hospital. For the purpose of analysis, serum cortisol levels were categorized as low (<15 μg/dL) and high (>15 μdL). To facilitate data organization and subsequent analysis, measurements were categorized into three time intervals following ICU admission: T1 (days 14-21), T2 (days 21-28), and T3 (days >28). Statistical analysis was performed using IBM-SPSS 28. A significance level of p < 0.05 was set to determine statistically significant differences between groups.

Cortisol measured at T3 were significantly lower (p < 0.05) compared to T2. In contrast, SOFA scores were significantly higher (p < 0.05). No statistically significant differences were observed between the low and high cortisol level groups at T1, T2 and T3 in terms of gender, APACHE-2 score, SOFA score, ICU length of stay (days), duration of mechanical ventilation (days), mortality rate, or mechanical ventilation requirement at discharge. Patients in the low cortisol group at T3 exhibited a significantly higher mean age compared to those in the high cortisol group (p < 0.05).

Cortisol levels in ICU patients may change over time. That cortisol levels tend to decrease as the length of stay increases, in older patients, and in PIICS patients with elevated SOFA scores.

Sepsis is a life-threatening condition caused by severe infection. The efficacy of intravenous immunoglobulin (IVIG) as adjunctive therapy on mortality remains controversial. Moreover, IVIG may favorably affect sepsis-induced immunosuppression like persistent inflammation, immunosuppression, and catabolism syndrome (PICS).

This study was a retrospective cohort study using inpatient claims database provided by Medical Data Vision, which included approximately 190,000 episodes of intensive care unit admissions in Japanese acute care hospitals between April 2008 and September 2021. We used a propensity score-matched analysis to compare outcomes between the IVIG and control groups. Primary outcomes were 28-day mortality, while secondary outcomes included in-hospital mortality, the Barthel Index at discharge, length of hospital stay and laboratory data (albumin, C-reactive protein (CRP), and lymphocyte count) on days 14 and 28.

Of the 17,626 patients enrolled, 15,159 (786 in the IVIG group and 14,373 in the control group) were included in the analysis. Propensity score matching generated 758 matched pairs. Before matching, 28-day mortality and in-hospital mortality were lower in the control group; however, in the matched cohort, 28-day mortality was significantly lower in the IVIG group than in the control group (90/758 [11.9%] vs 124/758 [16.4%]; risk difference [95% confidence intervals (CI)], -4.5% [-8.0% to -1.0%]; P = 0.015). In-hospital mortality in the matched cohort was also significantly more favorable in the IVIG group (137/758 [18.1%] vs 177/758 [23.4%]; risk difference [95%CI], -5.3% [-9.3% to -1.2%]; P = 0.013). Favorable outcomes in terms of albumin on days14 and 28 and CRP levels on day 28 were observed in the IVIG group.

The administration of IVIG was associated with a reduction in sepsis mortality and favorable outcomes in laboratory parameters and the functional status. These results will contribute to the ongoing debate on the efficacy of IVIG for sepsis. The results obtained herein suggest the benefit of IVIG, particularly in mitigating PICS. Further research, including prospective studies, is warranted to confirm these results and examine long-term outcomes.

Early identification of individuals at risk of functional impairment after trauma is crucial for the timely clinical decision-making and intervention to improve reintegration into the society. This study aimed to develop and validate models for predicting new-onset functional impairment after trauma using predictors that are routinely collected within 2 days of hospital admission.

In this multicenter retrospective cohort study of acute care hospitals in Japan, we identified adult patients with trauma with independence in carrying out activities of daily living before hospitalization, treated in the intensive or high-dependency care unit, and survived for at least 2 days between April 2008 and September 2023. The primary outcome was functional impairment defined as Barthel Index ≤60 at hospital discharge. In the internal validation data set (between April 2008 and August 2022), using the routinely collected 129 candidate predictors within 2 days of admission, we trained and tuned the four conventional and machine learning models with repeated random subsampling cross-validation. We measured the performance of these models in the temporal validation data set (between September 2022 and September 2023). We also computed the importance of each predictor variable in our model.

We identified 8,529 eligible patients. Functional impairment at discharge was observed in 41% of the patients (n = 3,506/8,529). In the temporal validation data set, all four models showed moderate discrimination ability, with areas under the curve above 0.79, and extreme gradient boosting showing the best performance (0.83). In the variable importance analyses, age was the most important predictor, followed by consciousness, severity score, cervical spinal cord injury, mild dementia, and serum albumin level at admission.

We successfully developed early prediction models for patients with trauma with new-onset functional impairment at discharge that achieved high predictive performance using routinely collected data within 2 days of hospital admission.

Prognostic and Epidemiological; Level III.

Normal coagulation TEG values on admission negatively correlate with overall risk of multiple organ failure, but less is known about association between coagulation and late-resolving multiple organ failure (LRMOF) risk. Here, the relationship between TEG parameters and development of LRMOF was investigated.

We conducted a retrospective assessment of patients at high postinjury multiple organ failure risk at our center. The primary outcome was LRMOF.

Analysis included 742 patients. Demographics were 76% male, mean age of 41, mean ISS of 23, 34% hypercoagulability, and 16% developed LRMOF. Patients with normal admission TEG developed LRMOF at significantly lower unadjusted rates than patients with coagulation disturbances (9 vs 16%-19%, P = 0.029); however, multivariable logistic regression demonstrated that neither coagulation profile nor individual admission TEG parameters showed association with LRMOF.

In this series, we found no significant relationship between coagulation status and LRMOF development.

The GDF15 protein, a member of the TGF-β superfamily, is a stress-induced multifunctional protein with many of its functions associated with the regulation of the immune system. GDF15 signaling provides a defence against the excessive inflammation induced by diverse stresses and tissue injuries. Given that the aging process is associated with a low-grade inflammatory state, called inflammaging, it is not surprising that the expression of GDF15 gradually increases with aging. In fact, the GDF15 protein is a core factor secreted by senescent cells, a state called senescence-associated secretory phenotype (SASP). Many age-related stresses, e.g., mitochondrial and endoplasmic reticulum stresses as well as inflammatory, metabolic, and oxidative stresses, induce the expression of GDF15. Although GDF15 signaling is an effective anti-inflammatory modulator, there is robust evidence that it is a pro-aging factor promoting the aging process. GDF15 signaling is not only an anti-inflammatory modulator but it is also a potent immunosuppressive enhancer in chronic inflammatory states. The GDF15 protein can stimulate immune responses either non-specifically via receptors of the TGF-β superfamily or specifically through the GFRAL/HPA/glucocorticoid pathway. GDF15 signaling stimulates the immunosuppressive network activating the functions of MDSCs, Tregs, and M2 macrophages and triggering inhibitory immune checkpoint signaling in senescent cells. Immunosuppressive responses not only suppress chronic inflammatory processes but they evoke many detrimental effects in aged tissues, such as cellular senescence, fibrosis, and tissue atrophy/sarcopenia. It seems that the survival functions of GDF15 go awry in persistent inflammation thus promoting the aging process and age-related diseases.

Sepsis (defined as sepsis 3.0) is a life-threatening organ dysfunction caused by a dysregulated host response to a variety of pathogenic microorganisms. Characterized by high morbidity and mortality, sepsis has become a global public health problem. However, there is a lack of appropriate diagnostic and therapeutic strategies for sepsis and current management rely on the limited treatment strategies. Recently, nanomedicines targeting and controlling the release of bio-active agents have shown excellent potency in sepsis management, with improved therapeutic efficacy and reduced adverse effects. In this review, we have summarized the advantages of nanomaterials. Also, the preparation and efficacy of the main categories of anti-sepsis nanomedicines applied in sepsis management are described in detail, including antibiotic-coated nanomaterials, antimicrobial peptides-coated nanomaterials, biomimetic nanomaterials, nanomaterials targeting macrophages and natural products loaded nanomaterials. These advances in nanomedicines establish the huge potential for nanomaterials-based sepsis management, especially in the improved pharmaceutical and pharmacological properties, enhanced therapeutic efficacy, controllable drug-targeting and reduced side effects. To further facilitate clinical translation of anti-sepsis nanomedicines, we propose that the issues involving safety, regulatory laws and cost-effectiveness should receive much more attention in the future.

Severe acute pancreatitis (SAP) is characterized by high mortality rates and various complications, including skeletal muscle atrophy, which significantly exacerbates its outcomes. Despite its clinical relevance, the mechanistic understanding of the relationship between skeletal muscle and the pancreas in SAP remains limited. Our study aimed to elucidate this "organ crosstalk" and its potential implications.

We established an SAP mouse model through pancreatic duct ligation (PDL) and evaluated pancreatic necrosis, skeletal muscle atrophy, and myonectin expression levels. Recombinant myonectin protein was administered in vivo and in vitro to assess its effects on acinar cell necrosis. Mechanistic insights were gained through RNA-seq data analysis and experimental validation. Serum samples from AP patients and healthy controls were collected to investigate the correlation between serum myonectin levels and disease severity.

The mouse model exhibited severe pancreatic necrosis, skeletal muscle atrophy, and elevated myonectin levels, with myonectin administration exacerbating model severity. We identified iron accumulation-induced ferroptosis as a key pathway contributing to myonectin-mediated acinar cell necrosis. A total of 22 healthy controls and 52 patients with varying degrees of AP were included in the serum samples and clinical data (36.5% females, age 49.79 ± 16.53). Analysis of serum samples revealed significantly higher myonectin levels in AP patients, correlating with disease severity (R = 0.28, P = 0.041).

Our findings underscore the significant role of myonectin in SAP progression and its potential as a prognostic marker for disease severity in AP patients. This study contributes to a deeper understanding of the pathophysiology of SAP and highlights potential therapeutic targets for intervention.

Sepsis remains a major global health challenge, yet specific diagnostic biomarkers are still lacking. This study aims to investigate the causal relationship between B7 homologue 3 (B7-H3) and sepsis susceptibility, severity, and clinical outcomes using Mendelian randomization (MR) analysis, in order to evaluate its potential as a biomarker.

Genetic data related to sepsis (including overall sepsis, sepsis-related mortality with 28 days, severe sepsis, and severe sepsis with 28-day mortality) were extracted from genome-wide association study (GWAS) datasets. Single nucleotide polymorphisms (SNPs) associated with B7-H3 were selected as instrumental variables. The inverse-variance weighted (IVW) was used as the primary approach for causal effect estimation, while weighted median (WME) and MR-Egger regression served as supplementary methods. Additionally, a constrained maximum likelihood-model average (cML-MA) approach was employed to enhance the reliability of causal effect estimation. Cochran's Q test was conducted to assess heterogeneity, and MR-PRESSO along with the MR-Egger intercept method were used to detect horizontal pleiotropy. Sensitivity analyses were performed using the leave-one-out method. A reverse MR analysis was performed with sepsis as the exposure and B7-H3 as the outcome to exclude potential reverse causation.

IVW analysis indicated a significant positive causal association between B7-H3 and sepsis susceptibility, severity, and clinical outcomes. A genetically predicted 1-standard deviation (SD) increase in B7-H3 levels was associated with a 10.4% increased risk of sepsis (OR=1.104, 95% CI 1.021 to 1.194, P=0.013), a 26.2% increased risk of sepsis-related 28-day mortality (OR=1.262, 95% CI 1.078 to 1.476, P=0.004), a 22.3% increased risk of severe sepsis (OR=1.223, 95% CI 1.023 to 1.463, P=0.027), and a 60.2% increased risk of severe sepsis with 28-day mortality (OR=1.602, 95% CI 1.119 to 2.294, P=0.010). The causal effect direction remained consistent across IVW, WME, MR-Egger, and cML-MA analyses, reinforcing the robustness and reliability of the results. Cochran's Q test showed no heterogeneity (P>0.05), while MR-PRESSO and MR-Egger intercept tests indicated no evidence of horizontal pleiotropy (both P>0.05). The leave-one-out analysis showed that removing individual SNPs did not significantly alter the causal estimates. Reverse MR analysis showed no causal association between sepsis and B7-H3.

B7-H3 may serve as an important biomarker for sepsis, as it is closely associated with sepsis susceptibility, severity, and clinical outcomes.

Candida albicans, a common commensal and opportunistic fungal pathogen in humans, can occasionally progress to disseminated candidiasis which is a serious condition with a high morbidity and fatality rate. The emergence of drug-resistant fungal strains compels us to look for an efficient treatment solution. Our earlier studies have demonstrated that the unique antimicrobial peptide AMP-17 from Musca domestica has a strong antifungal impact on C. albicans in vitro. Here, we verified the therapeutic effects of AMP-17 on systemic candidiasis in vivo and the peptide interacts with fluconazole, a common antifungal medication, to treat systemic candidiasis. In the disseminated candidiasis model of Galleria mellonella and mice challenged with C. albicans, AMP-17 increased the survival rates of infected larvae and mice to 66.7 and 75%, respectively. Furthermore, the peptide lowered the load of C. albicans in the infected larvae and the kidneys of the mice by nearly 90%. Additional histological examination and measurements of plasma cytokines showed that the injection of AMP-17 markedly reduced the inflammatory response and balanced cytokine expression. Furthermore, checkerboard micro dilution experiments demonstrated that AMP-17 and fluconazole worked in synergy to inhibit C. albicans in the biofilm mode. According to morphological studies, AMP-17 and fluconazole together decreased the production of hyphae throughout the C. albicans biofilm formation process, loosening the mature biofilms' structure and lowering the amount of carbohydrates in the extracellular matrix (ECM) of the biofilms. Taken together, these results showed that AMP-17 would be a viable treatment for systemic candidiasis and might be a different approach to combating Candida biofilm, either by itself or in conjunction with fluconazole.

We compared epidemiology of intra-abdominal infection (IAI) between immunocompromised and non-immunocompromised ICU patients and identified risk factors for mortality. We performed a secondary analysis on the "AbSeS" database, a prospective, observational study with IAI patients from 309 ICUs in 42 countries. Immunocompromised status was defined as either neutropenia or prolonged corticosteroids use, chemotherapy or radiotherapy in the past year, bone marrow or solid organ transplantation, congenital immunodeficiency, or immunosuppressive drugs use. Mortality was defined as ICU mortality at any time or 28-day mortality for those discharged earlier. Associations with mortality were assessed by logistic regression. The cohort included 2589 patients of which 239 immunocompromised (9.2 %), most with secondary peritonitis. Among immunocompromised patients, biliary tract infections were less frequent, typhlitis more frequent, and IAIs were more frequently healthcare-associated or early-onset hospital-acquired compared with immunocompetent patients. No difference existed in grade of anatomical disruption, disease severity, organ failure, pathogens, and resistance patterns. Septic shock was significantly more frequent in the immunocompromised population. Mortality was similar in both groups (31.1% vs. 28.9 %; p = 0.468). Immunocompromise was not a risk factor for mortality (OR 0.98, 95 % CI 0.66-1.43). Independent risk factors for mortality among immunocompromised patients included septic shock at presentation (OR 6.64, 95 % CI 1.27-55.72), and unsuccessful source control with persistent inflammation (OR 5.48, 95 % CI 2.29-12.57). In immunocompromised ICU patients with IAI, short-term mortality was similar to immunocompetent patients, despite the former presented more frequently with septic shock, and septic shock and persistent inflammation after source control were independent risk factors for death.

The prevalence of persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has an upward trend in sepsis patients and can be associated with poor outcomes. Thyroid hormones are expected to be correlated with inflammation, immunity, and metabolism. Thus, the purpose of this study was to evaluate the effect of thyroid hormones on the occurrence of PICS and then further explore the optimal level of them in sepsis.

This retrospective observational study used the online database Medical Information Mart for Intensive Care (MIMIC)-IV. Univariate and multivariate logistic regression analyses were employed to determine correlations between thyroid hormone levels and PICS. A combination of independent PICS development factors was established with accuracy assessed using the area under the receiver operating characteristic curve (AUC-ROC).

Patients were divided into PICS (n=205) and non-PICS (n=671) groups. The third quartiles of triiodothyronine (T3) (60-80ng/dl) and thyroxine (T4) (5.5-6.8ug/dl) had the lowest PICS incidence and the adjusted odds ratio (OR) was 0.33 (T3, p=0.009) and 0.39 (T4, p=0.006), respectively, compared with the first quartiles of T3 and T4. For patients with a pre-existing T3 deficiency, severe deficiency (T3 <60ng/dl) and a high Sequential Organ Failure Assessment (SOFA) score were significantly related to PICS incidence. The AUC for these combined parameters in predicting PICS occurrence was 0.748 (all patients) and 0.861 (patients without thyroid disease).

A mild T3 deficiency (60-80ng/dl) was significantly associated with the lowest risk-adjusted PICS occurrence in patients with sepsis. A severe T3 deficiency (<60ng/dl) and a high SOFA score were independent risk factors for PICS occurrence.

Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection. It is the primary cause of death in the intensive care unit, posing a substantial challenge to human health and medical resource allocation. The pathogenesis and pathophysiology of sepsis are complex. During its onset, pro-inflammatory and anti-inflammatory mechanisms engage in intricate interactions, possibly leading to hyperinflammation, immunosuppression, and long-term immune disease. Of all critical outcomes, hyperinflammation is the main cause of early death among patients with sepsis. Therefore, early suppression of hyperinflammation may improve the prognosis of these patients. Nafamostat mesilate is a serine protease inhibitor, which can inhibit the activation of the complement system, coagulation system, and contact system. In this review, we discuss the pathophysiological changes occurring in these systems during sepsis, and describe the possible targets of the serine protease inhibitor nafamostat mesilate in the treatment of this condition.

Polytrauma is a complex condition associated with poor outcomes and high mortality rates resulting from severe damage and complicated complications. This study sought to ascertain the incidence of chronic complications in polytrauma patients, as well as the early immune changes and risk factors.

A multicenter, prospective and observational cohort study was conducted at the emergency surgery or traumatic intensive care unit (TICU) of the Advanced Trauma Center from August 2020 to July 2023. A total of 2033 consecutive trauma patients were included in the study. In the first 1, 7, and 14 days after admission, flow cytometry and immunoassay kits were used to examine cytokine release and lymphocyte count.

Trauma patients were reported 33.8% (687/2033) chronic complication rates, with monotrauma patients reported 8.1% (55/683) and polytrauma patients reported 59.4% (802/1350). And the four most frequent chronic complications in polytrauma patients were chronic musculoskeletal pain (30.4%), post-traumatic osteoarthritis (27.2%), chronic wound (21.6%), and chronic lung injury (14.1.%) .There were significant differences in lymphocyte ratios and cytokine levels, at 1, 7, and 14 day of admission between chronic complication groups (CCP) and not chronic complication groups (N-CCP) in polytrauma. Polytrauma patients with characteristics of higher ratio of Ts7d ratio (95% CI: 2.01-6.21), Treg14d (95% CI: 1.12-5.43) and level of IL-67d (95% CI: 1.22-4.43), TNF-α7d (95% CI: 1.05-3.83), IL-1014d (95% CI: 2.01-6.84) were found to have a higher likelihood of experiencing a chronic complication. Conversely, a higher ratio of Tc1d (95% CI: 0.53-0.86), Th1d (95% CI: 0.64-0.95) and Th/Ts14d (95% CI: 0.21-0.64) were identified as independent protective factors against a chronic complication event.

Polytrauma patients exhibit a notable prevalence of chronic complications. Some immune and inflammatory indicators can be observed early in combination after injury to predict the risk of chronic complications after polytrauma.

Lactate significantly impacts immune cell function in sepsis and septic shock, transcending its traditional view as just a metabolic byproduct. This review summarizes the role of lactate as a biomarker and its influence on immune cell dynamics, emphasizing its critical role in modulating immune responses during sepsis. Mechanistically, key lactate transporters like MCT1, MCT4, and the receptor GPR81 are crucial in mediating these effects. HIF-1α also plays a significant role in lactate-driven immune modulation. Additionally, lactate affects immune cell function through post-translational modifications such as lactylation, acetylation, and phosphorylation, which alter enzyme activities and protein functions. These interactions between lactate and immune cells are central to understanding sepsis-associated immune dysregulation, offering insights that can guide future research and improve therapeutic strategies to enhance patient outcomes.

There is a continuous cycle of activation and contraction in the immune response against pathogens and other threats to human health in life. This intrinsic yin-yang of the immune response ensures that inflammatory processes can be appropriately controlled once that threat has been resolved, preventing unnecessary tissue and organ damage. Various factors may contribute to a state of perpetual immune activation, leading to a failure to undergo immune contraction and development of cytokine storm syndromes. A literature review was performed to consider how the trajectory of the immune response in certain individuals leads to cytokine storm, hyperinflammation, and multiorgan damage seen in cytokine storm syndromes. The goal of this review is to evaluate how underlying factors contribute to cytokine storm syndromes, as well as the symptomatology, pathology, and long-term implications of these conditions. Although the recognition of cytokine storm syndromes allows for universal treatment with steroids, this therapy shows limitations for symptom resolution and survival. By identifying cytokine storm syndromes as a continuum of disease, this will allow for a thorough evaluation of disease pathogenesis, consideration of targeted therapies, and eventual restoration of the balance in the yin-yang immune response.

Multiple organ failure (MOF) remains a significant challenge for the acute care surgeon, often leading to poor patient outcomes. This comprehensive review explores the etiology, pathophysiology, clinical presentation, diagnosis, management strategies, prognosis, and prevention strategies associated with MOF and chronic critical illness. Understanding the intricate etiology and pathophysiology of MOF and chronic critical illness is essential for effectively managing these syndromes and developing targeted treatment strategies aimed at mitigating the underlying inflammatory, immune, and microvascular disturbances, in order to redirect patients onto a trajectory of recovery.

Sepsis is a complex condition of inflammatory and immune dysregulation, triggered by severe infection. In survivors, chronic inflammation and immune dysregulation linger, facilitating the emergence of infections. CD8 dysfunction contributes to immunosuppression in sepsis survivors. We devised an animal model that enabled us to identify and analyze CD8-intrinsic defects induced by sepsis. We adoptively transferred CD45.1 CD8 OT-I T cells into CD45.2 congenic mice and subjected them to cecal ligature and puncture, to induce abdominal sepsis. One month later, we isolated the transferred CD8 cells. Surface marker expression confirmed they had not been activated through the TCR. CD8 OT-I T cells isolated from septic (or sham-operated) mice were transferred to second recipients, which were challenged with OVA-expressing Listeria monocytogenes. We compared effector capacities between OT-I cells exposed to sepsis and control cells. Naive mice that received OT-I cells exposed to sepsis had higher bacterial burden and a shorter survival when challenged with OVA-expressing L. monocytogenes. OT-I cells isolated from septic mice produced less IFN-γ but had conserved activation, expansion potential, and cytotoxic function. We observed lower transcript levels of IFN-γ and of the long noncoding RNA Ifng-as1, a local regulator of the epigenetic landscape, in cells exposed to sepsis. Accordingly, local abundance of a histone modification characteristic of active promoter regions was reduced in sepsis-exposed CD8 T cells. Our results identify a mechanism through which inflammation in the context of sepsis affects CD8 T cell function intrinsically.

Early enteral nutrition (EN) is recommended for patients with critical illness to maintain intestinal immunity. However, the optimal timing of the commencement of EN remains unclear, particularly after cardiovascular surgery.

We herein focused on Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) as a predisposing immunodeficiency and investigated its association with very early EN (VEEN) (<24 h) in patients who underwent cardiovascular surgery.

In this retrospective study, we used an administrative claims database with laboratory examinations between 2008 and 2021 to identify adult patients admitted to the intensive care unit after cardiovascular surgery. Patients who received EN the day after surgery were assigned to the EN <24 h group, whereas those who received EN on day 2 or day 3 were assigned to the control group. The primary outcome was a composite of the incidence of PICS and mortality on day 14 after surgery. We defined PICS as patients who were hospitalized for >14 day and meeting ≥2 of the following conditions: a lymphocyte count <800/μL, albumin <3.0 g/dL, and C-reactive protein >2.0 mg/dL. We compared the 2 groups using propensity score analysis.

A propensity score matching generated 2082 pairs. The primary outcome was significantly lower in the EN <24 h group than in the control group on days 14 {risk difference [95% confidence interval (CI)]: -3.1% [-5.9%, -0.3%]} and 28 (risk difference [95% CI]: -2.1% [-3.7%, -0.4%]). Mortality did not significantly differ between the 2 groups. The length of hospital stay was significantly shorter in the EN <24 h group: the difference (95% CI) was -2.2 (-3.7, -0.7) d.

Among patients who underwent cardiovascular surgery, VEEN provided on the day after surgery was associated with a lower incidence of PICS and a shorter length of hospital stay than EN provided 2 day or 3 day after surgery.

Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has been proposed as an endotype of chronic critical illness (CCI). The aim of this systematic review is to synthesise the available evidence of risk factors, biomarkers, and biological mechanisms underlying PICS.

MEDLINE, CENTRAL, and EMBASE were searched on June 2, 2023. Our population of interest was adult intensive care unit survivors. The exposure group was patients with PICS and the comparator group was patients with no PICS, CCI, or rapid recovery. Mean differences were pooled for each biomarker using a random effects DerSimonian-Laird method. Risk of bias assessment was done using the Newcastle-Ottawa Scale.

Six papers were included. Five were single-centre retrospective cohort studies, and one was a prospective cohort study, with sample sizes ranging from 22 to 391 patients. Two studies showed an increased incidence of PICS with age, and two studies showed an association between PICS and Charlson Comorbidity Index scores. PICS was associated with requiring mechanical ventilation in four studies. Meta-analysis showed a 34.4 mg L-1 higher C-reactive protein (95% confidence interval [CI] 12.7-56.2 mg L-1; P<0.01), a 4.4 g L-1 lower albumin (95% CI 0.5-8.3 g L-1; P<0.01), and a 0.36×109 L-1 lower lymphocyte count (95% CI 0.25-0.47×109 L-1; P=0.01) in the PICS compared with the non-PICS group. There are a large variety of other potential biomarkers but limited validation studies. The overall quality of evidence is limited, and these results should be interpreted accordingly.

While older patients and those with co-morbidities could be at greater risk for PICS, acquired risk factors, such as injury severity, are potentially more predictive of PICS than intrinsic patient characteristics. There are many potential biomarkers for PICS, but limited validation studies have been conducted. Persistent myeloid-derived suppressor cell expansion, the continual release of danger-associated molecular patterns and pathogen-associated molecular patterns propagating inflammation, and bioenergetic failure are all mechanisms underlying PICS that could offer potential for novel biomarkers and therapeutic interventions.

International Prospective Register of Systematic Reviews (PROSPERO; CRD42023427749).

To evaluate the long-term efficacy and cost-efficiency of blood purification (BP) in severe acute pancreatitis (SAP) through single-center data.

A total of 155 SAP patients were collected and followed up for 6 months. The participants were divided into control (49 cases) and BP group (106 cases) according to whether they received BP treatment or not. The primary outcomes were 6-month mortality, length of hospital stay, and hospitalization costs. Propensity score matching (PSM) analysis was performed based on various factors such as gender, age, etiology, SOFA score, JSS score, and creatinine value on day 1.

There were significant differences in all baseline data between BP and control groups (p<0.05). However, there was a significant difference in the mortality, length of hospital stay, hospital costs and infection aggravation rate the in outcome data for 6-months (all p<0.05). BP was not considered a death factor in any adjusted models, with p-values ranging from 0.81 to 0.93. The results of subgroup analysis after PSM showed that BP mode had no significant impact on prognostic indicators, but the length of ICU stay and total costs were significantly increased (all p<0.001). There was no significant difference in mortality among the cases that did not require early intervention after 6 months (p=0.487). However, the patients in BP group had longer ICU stays (p=0.001) and higher hospitalization costs (p<0.001) compared to the control group.

The utilization of BP therapy did not decrease the 6-month mortality in SAP patients. Additionally, BP therapy has a significant impact on the duration of ICU stay or hospitalization expenses. However, the effectiveness and cost-efficiency of this therapy are unsatisfactory, and early intervention does not enhance survival benefits. Furthermore, there was no substantial variation in survival benefits between continuous veno-venous hemofiltration (CVVH) alone and compound BP.

Sepsis is a life-threatening condition that requires rapid assessment to reduce mortality. This study investigates the relationship between the Neutrophil-to-Monocyte/Lymphocyte Ratio (NMLR) upon ICU admission and 28-day mortality in sepsis patients.

A retrospective analysis was performed using clinical data from sepsis patients in the Medical Information Mart for Intensive Care IV (MIMIC-IV). Multivariate logistic regression, sensitivity analyses, and Restricted Cubic Spline (RCS) models were employed to explore the relationship between ICU admission NMLR and 28-day mortality. Kaplan-Meier method and inverse probability weighting (IPW) were used to adjust for confounders and estimate survival outcomes. Receiver operating characteristic (ROC) curve evaluating the predictive value of NLMR for 28-day mortality in ICU sepsis patients. Subgroup analyses considered factors like age, sex, race, comorbidities, and disease severity.

In total, 8,710 patients were included. Increased NMLR was associated with higher 28-day all-cause mortality, confirmed by multiple logistic regression models. In Model 3, after adjusting for confounders, each standard deviation increase in NMLR was associated with a 1.5% increase in 28-day mortality risk. Kaplan-Meier and IPW survival analyses showed higher 28-day all-cause mortality in patients with elevated NMLR levels at ICU admission compared to those with lower levels (p < 0.0001, p = 0.031). RCS models suggested a potential non-linear relationship between NMLR and 28-day mortality. ROC curve for the NMLR model, with an AUC of 0.658 (95% CI: 0.642-0.673). Sensitivity analyses confirmed the association even after excluding patients with myocardial infarction and severe liver disease.

Elevated NMLR at ICU admission is significantly associated with increased 28-day all-cause mortality in sepsis patients, suggesting its potential as an early prognostic indicator for risk assessment and intervention.

Decreased monocytic HLA-DR expression is the most studied biomarker of immune competency in critically ill and autoimmune disease patients. However, the underlying regulatory mechanisms remain largely unknown. One probable HLA-DR dysregulation is through microRNAs. The aim of this study was to investigate the effects of specific microRNAs on HLA-DR expression in human monocytic cells. Four up- and four down-HLA-DR-regulating microRNAs were identified, with hsa-miR-let-7f-2-3p showing the most significant upregulation and hsa-miR-567 and hsa-miR-3972 downregulation. Anti-inflammatory glucocorticoid medication Dexamethasone-decreased HLA-DR was significantly restored by hsa-miR-let-7f-2-3p and hsa-miR-5693. Contrarily, proinflammatory cytokines IFN-γ and TNF-α-increased HLA-DR were significantly reversed by hsa-miR-567. Clinically, paired plasma samples from patients before and one day after cardiac surgery revealed up-regulated expression of hsa-miR-5693, hsa-miR-567, and hsa-miR-3972, following the major surgical trauma. In silico approaches were applied for functional microRNA-mRNA interaction prediction and candidate target genes were confirmed by qPCR analysis. In conclusion, novel monocytic HLA-DR microRNA modulators were identified and validated in vitro. Moreover, both the interaction between the microRNAs and anti- and proinflammatory molecules and the up-regulated microRNAs identified in cardiac surgery highlight the potential clinical relevance of our findings.

Early enteral nutrition (EEN) potentially improves immune-related outcomes via the maintenance of intestinal immunity; however, the effects of EEN on clinical outcomes, including infectious complications, are controversial. Therefore, we herein investigated whether EEN affected persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which represents the immunocompromised state after critical illness.

This retrospective cohort study utilized the administrative claims database of inpatients and laboratory findings. Patients admitted to and treated in the intensive care unit (ICU) for more than 3 consecutive days were included. The primary outcome, a composite of PICS or mortality on day 14 after admission, was compared between the EEN group, which received enteral nutrition (EN) on the first 3 days (day 0, 1, or 2), and the late enteral nutrition (LEN) group, which did not receive EN on the first 3 days, but then received EN on days 3 through 7, using a propensity score-matched analysis. Secondary outcomes included the composite outcome on day 28, in-hospital mortality, the Barthel index, and laboratory data. Patients who met at least two of the following conditions were diagnosed with PICS: CRP >2.0 mg/dL, albumin <3.0 g/dL, and a lymphocyte count <800/μL.

A total of 7530 matched pairs were generated after propensity score matching. The primary outcome was significantly lower in the EEN group (risk difference -3.0%, 95% confidence interval (CI) -4.5 to -1.4%), whereas mortality did not significantly differ. The 28-day composite outcome was similar in the 2 groups (risk difference -1.5%, 95% CI -2.8% to -0.2%, no significant difference in mortality). There was no significant difference in in-hospital mortality between the EEN and LEN groups; however, the Barthel index at discharge was higher in the EEN group (the medians, 50 vs 45, P = 0.001). Laboratory data showed lower Albumin and CRP on day 14 in the EEN group, but no other significant differences.

In patients admitted to the ICU, EEN was associated with a lower incidence of PICS on days 14 and 28, but was not associated with mortality. This positive association was not observed in sepsis, cardiac diseases, or gastrointestinal diseases.

Enhanced critical care delivery has led to improved survival rates in critically ill patients, yet sepsis remains a leading cause of multiorgan failure with variable recovery outcomes. Chronic critical illness, characterised by prolonged ICU stays and persistent end-organ dysfunction, presents a significant challenge in patient management, often requiring multifaceted interventions. Recent research, highlighted in a comprehensive review in the British Journal of Anaesthesia, focuses on addressing the pathophysiological drivers of chronic critical illness, such as persistent inflammation, immunosuppression, and catabolism, through targeted therapeutic strategies including immunomodulation, muscle wasting prevention, nutritional support, and microbiome modulation. Although promising avenues exist, challenges remain in patient heterogeneity, treatment timing, and the need for multimodal approaches.