Pre- and post-operative immune status has gained interest in recent years, as it has been shown to be related to postoperative complications and recovery. The change in immune status has also been known to constitute a large part of the surgical stress response, and it has been speculated that immunomodulatory treatment by glucocorticoids may impact it. Profiling of the impact of specific surgeries and medications on immune status are therefore needed.

We characterized the postoperative blood immune proteome in 83 patients receiving either placebo (n = 20) or IV 24 mg dexamethasone (n = 60) preoperative before total knee arthroplasty (TKA). The primary outcome was the effect of dexamethasone on total knee arthroplasty surgical stress by comparing postoperative immune proteome in the dexamethasone group and the placebo group. Secondary outcomes were the surgical stress by total knee arthroplasty by comparing pre- to postoperative immune proteome in the placebo group, and the combined effect of surgical stress and dexamethasone by comparing pre- to postoperative immune proteome in the dexamethasone group. Characterization was performed with the Olink Explorer Inflammation panel on blood samples from the biobank for future research collected during the randomized, clinical DEX-2-TKA Trial. Protein change was reported as log2-fold-change and p-values were corrected a.m. Benjamini-Hochberg.

The surgical stress (placebo) was characterized by a 4.7 log2-fold-change of IL6 (adjusted p-value < 0.01) and up-regulation of central immune signaling pathways and bone marrow mobilization. The combined effect of surgery and dexamethasone showed a less pro-inflammatory profile: IL6 2.5 log2-fold-change (adjusted p-value < 0.01), with decreased signaling for osteoclast activity and innate, immune cell reaction. The effect of dexamethasone showed upregulation of CSF3 (1.55 log2-fold-change, adjusted p-value < 0.01) and an inhibitory effect on both innate and adaptive immune response, immune cell reactivity and formation of extracellular matrix.

Preoperative dexamethasone indicated anti-inflammatory properties on both innate and adaptive immune response, while surgery was pro-inflammatory. the combination of total knee arthroplasty and dexamethasone inhibited pathways for osteoclast-activity, indicating possible implications on aseptic prosthesis loosening. Dexamethasone showed strong modulation of the surgical stress response following total knee arthroplasty and future studies must explore the clinical associations of these findings.

NCT03506789.

Early blood product resuscitation is often essential for optimal trauma care. However, the effects of different products on the underlying trauma-induced coagulopathy and immune dysfunction are not well described. Here, we use high-dimensional analysis and causal modeling in a longitudinal study to explore the circulating proteomic response to plasma as a distinct component versus low-titer O whole blood (LTOWB), which contains plasma. We highlight the differential impacts of plasma and LTOWB on immune mediator levels and the distinct capacity of plasma to modulate coagulation by elevating fibrinogen and factor XIII and reducing platelet factor 4. A higher proportion of plasma in prehospital resuscitation is associated with improved admission time coagulation parameters in patients with severe shock and elevated brain injury markers and reduced post-admission transfusion volumes in those suffering from traumatic brain injury (TBI) and blunt injury. While LTOWB offers broad hemostatic benefits, our findings demonstrate specific advantages of plasma and support individualized transfusion strategies.

Trauma remains a leading cause of morbidity and mortality in part due to secondary multi-organ injury. However, our ability to predict the downstream pathophysiology and adverse outcomes of trauma is limited. Here, we select a panel of microRNAs (miRNAs) biomarker candidates based on plasma RNA-Seq analysis of trauma patients and the unique pro-inflammatory nucleotide motif structures identified via a machine learning-guided computer exhaustive search algorithm. We test the panel of plasma miRNAs for their association with various trauma pathophysiological markers and their ability to predict organ injury and immune responses to trauma. We find a marked elevation of these plasma miRNAs as well as multiple inflammatory and organ injury factors at time of admission in a cohort of 48 blunt trauma patients. The plasma levels of these miRNA biomarkers are highly associated with multiple pathophysiological markers known for organ injury, coagulopathy, endothelial activation, and innate inflammation. AUROC analyses indicate that these miRNA biomarkers possess strong abilities to distinguish trauma severity, brain and liver injuries, metabolic acidosis, coagulopathy, and innate inflammation. These observations offer insights into potential values of the selected plasma miRNAs in prediction of trauma pathophysiological risk and clinical outcomes.

In wound study and dressing development, a lack of a suitable animal model that can recapitulate the complex pathophysiology of human chronic wounds has been a major hurdle. Chronic wounds are defined as wounds that heal with a significant delay, usually over a period >2-3 months, but no current animal wound model has such a longischemia. After a longexploration, our group has developed an animal wound model with ischemia and nerve damage lasting for at least 6 months. This model can be easily combined with other conditions such as diabetes and aging for wound mechanistic study and critical testing of dressings. This report presents the method that has significant utility in evaluating therapies that could become the future standard for screening all new wound dressings.

Traumatic spinal injuries are associated with a high risk of morbidity and mortality. The aim of this study is to investigate which variables best predict adverse outcomes in patients who had surgery for isolated traumatic spinal injury without spinal cord injury.

The American College of Surgeons Trauma Quality Improvement Program database was used to identify adult (18 years or older) surgically managed patients with an isolated traumatic spinal injury, without spinal cord injury admitted between 2013 and 2021. An isolated injury was defined as a spine Abbreviated Injury Scale score ≥2 and an Abbreviated Injury Scale score ≤1 in the remaining body regions, as well as corresponding International Classification of Diseases, Ninth and Tenth Revision, codes. The predictive value of demographic, clinical, and comorbidity data was evaluated using logistic regression models and ranked using the permutation importance method.

A total of 39,457 patients were included in the study, of whom 554 died during hospitalization. The most important variables for predicting in-hospital mortality were age, sex, Glasgow Coma Scale on admission, Orthopedic Frailty Score, and cervical spine injury. The most important variables for predicting complications were age, cervical spine injury, the need for cervical spine surgery, Revised Cardiac Risk Index, and alcohol use disorder. Finally, age, cervical spine injury, sex, Glasgow Coma Scale on admission, and Orthopedic Frailty Score had the highest relative importance when predicting failure to rescue. Models based on the five most important variables for each outcome demonstrated an excellent predictive ability for in-hospital mortality (area under the receiver operating characteristic curve [AUROC], 0.84; 95% confidence interval [CI], 0.82-0.86) and failure to rescue (AUROC [95% CI], 0.86 [0.84-0.87]) as well as an acceptable predictive ability for complications (AUROC [95% CI], 0.72 [0.71-0.73]).

The most important factors identified to predict mortality, complications, and failure to rescue in traumatic spinal injury patients without spinal cord injury who undergo surgery were patients' age, sex, frailty, cervical spine injury that necessitated surgical intervention, and cardiovascular risk.

Prognostic and Epidemiological; Level III.

The field of bone regeneration has primarily focused on investigating fracture healing and nonunion in isolated musculoskeletal injuries. Compared to isolated fractures, which frequently heal well, fractures in patients with multiple bodily injuries (polytrauma) may exhibit impaired healing. While some papers have reported the overall cytokine response to polytrauma conditions, significant gaps in our understanding remain in how fractures heal differently in polytrauma patients. We aimed to characterize fracture healing and the temporal local and systemic immune responses to polytrauma in a murine model of polytrauma composed of a femur fracture combined with isolated chest trauma. We collected serum, bone marrow from the uninjured limb, femur fracture tissue, and lung tissue over 3 weeks to study the local and systemic immune responses and cytokine expression after injury. Immune cell distribution was assessed by flow cytometry. Fracture healing was characterized using microcomputed tomography (microCT), histological staining, immunohistochemistry, mechanical testing, and small angle X-ray scattering. We detected more innate immune cells in the polytrauma group, both locally at the fracture site and systemically, compared to other groups. The percentage of B and T cells was dramatically reduced in the polytrauma group 6 h after injury and remained low throughout the study duration. Fracture healing in the polytrauma group was impaired, evidenced by the formation of a poorly mineralized and dysregulated fracture callus. Our data confirm the early, dysregulated inflammatory state in polytrauma that correlates with disorganized and impaired fracture healing.

Background: Septic shock is a complex syndrome characterized by signs of intense systemic inflammation and a profound dysregulation of the immune response. Large-scale gene expression analysis is a valuable tool in this scenario because sepsis affects various cellular components and signaling pathways. Results: In this article, we provide an overview of the transcriptomic studies that investigated human sepsis from 2007 to 2024, highlighting their major contributions. Conclusions: The field, however, still faces substantial limitations and several challenges. To advance further, we believe that standardization of sample collection and data analysis, preservation of cell and tissue architecture, and integration with other omics techniques are crucial for a broader understanding of this lethal disease.

Preclinical evidence suggests that young plasma has beneficial effects on multiple organ systems in aged mice. Whether young plasma exerts beneficial effects in an aging human population remains highly controversial. Despite lacking data, young donor plasma infusions have been promoted for age-related conditions. Given the preclinical evidence that young plasma exerts beneficial effects by attenuating inflammation, this study examined whether administering a young plasma protein fraction to an elderly population would exert anti-inflammatory and immune modulating effects in humans, using surgery as a tissue injury model.

This double-blind, placebo-controlled study enrolled and randomized 38 patients undergoing major joint replacement surgery. Patients received four separate infusions of a plasma protein fraction derived from young donors, or placebo one day before surgery, before and after surgery on the day of surgery, and one day after surgery. Blood specimens for proteomic and immunological analyses were collected before each infusion. Based on the high-content assessment of circulating plasma proteins with single-cell analyses of peripheral immune cells, proteomic signatures and cell-type-specific signaling responses that separated the treatment groups were derived with regression models.

Elastic net regression models revealed that administration a young plasma protein fraction significantly altered the proteomic (AUC = 0.796, p = 0.002) and the cellular immune response (AUC 0.904, p < 0.001) to surgical trauma resulting in signaling pathway- and cell type-specific anti-inflammatory immune modulation. Affected proteomic pathways regulating inflammation included JAK-STAT, NF-kappa B, and MAPK (p < 0.001). These findings were confirmed at the cellular level as the MAPK and JAK/STAT signaling responses were diminished and IkB, the negative regulator of NFkB, was elevated in adaptive immune cells.

Reported findings provide a first proof of principle in humans that a young plasma protein fraction actively regulates inflammatory and immune responses in an elderly population. They provide a solid rationale for elucidating active principles in young plasma that may be of therapeutic benefits for a range of age-related pathologies.

ClinicalTrials.gov, NCT03981419.

Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection. β-Glucan treatment reduces the morbidity and mortality against IAV infection, independent of host resistance. The enhanced survival is the result of increased recruitment of neutrophils via RoRγt+ T cells in the lung tissue. β-Glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of immature neutrophils utilizing a mitochondrial oxidative metabolism and producing interleukin-10. Collectively, our data indicate that β-glucan reprograms hematopoietic stem cells to generate neutrophils with a new 'regulatory' function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.

The recovery of patients after severe burns is a long and complex process. Genomic analysis of white blood cells from burn and trauma patients revealed excessive and prolonged innate immune activation in patients with complicated outcomes. However, translating this knowledge into practical biomarkers has not been possible yet. Although several biomarkers for monitoring burn patients have been proposed, their ability to accurately distinguish between inflammation stemming from initial tissue destruction, infections, and organ failure complications is limited. Here, we focused on monocytes, critical innate immune cells in the response to burn injured tissues. We measured the monocyte anisocytosis (quantified as monocyte distribution width (MDW), a recently emerged marker of sepsis) throughout the recovery of patients from the time of burn injury until the end of the hospital stay. We observed that MDW increases in patients during the first week after major burns. Among the patients with major burns who survive, MDW starts decreasing in the second week and normalizes by the end of the hospital stay. The duration of hospital stay appears to be proportional to how fast MDW decreases during the second week after the injury. We also found that MDW decreases significantly in most patients after excision and debridement surgeries but not after allo- and auto-graft surgeries. Moreover, high MDW values correlated with a higher rate of positive microbiology blood culture samples and respiratory infections. These findings underscore the importance of monitoring MDW as a potential biomarker for the risk of complications during burn patient recovery.

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.

Background: Blunt thoracic trauma possesses unique physiopathological traits due to the complex interaction of immune and coagulation systems in the lung tissue. Hemogram-based ratios such as neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), neutrophil-to-lymphocyte × platelet (NLPR) ratios have been studied as proxies for immune dysregulation and survival in trauma. We hypothesized that blunt thoracic trauma patients exhibit distinct patterns of coagulation and inflammation abnormalities identifiable by the use of readily available hemogram-derived markers. Methods: The present study represents a retrospective observational analysis that included 86 patients with blunt thoracic trauma from a single high-volume level one trauma center. The primary outcome was mortality prediction in blunt thoracic trauma patients using these derived biomarkers. Secondary outcomes included phenotypes of the immune response and coagulopathy and the prediction of non-fatal adverse events. Results: A U-shaped distribution of mortality was found, with high rates of early deaths in patients with an NLPR value of <3.1 and high rates of late deaths in patients with NLPR > 9.5. A subgroup of blunt thoracic trauma patients expressing moderate inflammation and inflammation-induced hypercoagulation objectified as NLPR between 3.1 and 9.5 may have a survival benefit (p < 0.0001). The NLPR cut-off for predicting early deaths and the need for massive transfusion was 3.1 (sensitivity = 80.00% and specificity = 71.05%). Conclusions: These findings suggest that blunt thoracic trauma patients exhibit distinct phenotypes of the immune response and coagulopathy from the early stages. A controlled, balanced interaction of immune, coagulation, and fibrinolytic systems might effectively achieve tissue repair and increase survival in thoracic trauma patients and should be subject to further research.

Severe traumatic brain injury (TBI) is a devastating injury with a mortality of ∼ 25-30 %. Despite decades of high-quality research, no drug therapy has reduced mortality. Why is this so? We argue two contributing factors for the lack of effective drug therapies include the use of specific-pathogen free (SPF) animals for translational research and the flawed practice of single-nodal targeting for drug design. A revolution is required to better understand how the whole body responds to TBI, identify new markers of its progression, and discover new system-acting drugs to treat it. In this review, we present a brief history of TBI, discuss its system's pathophysiology and propose a new research strategy for the 21st century. TBI progression develops from injury signals radiating from the primary impact, which can cause local ischemia, hemorrhage, excitotoxicity, cellular depolarization, immune dysfunction, sympathetic hyperactivity, blood-brain barrier breach, coagulopathy and whole-body dysfunction. Metabolic reprograming of immune cells drives neuroinflammation and secondary injury processes. We propose if sympathetic hyperactivity and immune cell activation can be corrected early, cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored, and secondary injury minimized with improved patient outcomes. The therapeutic goal is to switch the injury phenotype to a healing phenotype by restoring homeostasis and maintaining sufficient tissue O2 delivery. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat TBI and have shown that it blunts the CNS-stress response, supports cardiovascular function and reduces secondary injury. Future research will investigate its suitability for human translation.

One in five deaths worldwide is associated with sepsis, which is defined as organ dysfunction caused by a dysregulated host response to infection. An increased understanding of the pathophysiology of sepsis could provide improved approaches for early detection and treatment. Here we describe the development and validation of a mechanistic mathematical model of the inflammatory response, making use of a combination of in vitro and human in vivo data obtained from experiments where bacterial lipopolysaccharide (LPS) was used to induce an inflammatory response. The new model can simulate the responses to both acute and prolonged inflammatory stimuli in an experimental setting, as well as the response to infection in the clinical setting. This model serves as a foundation for a sepsis simulation model with a potentially wide range of applications in different disciplines involved with sepsis research.

An estimated 180,000 burn deaths occur each year, and the immune system plays a vital role in wound healing and burn complications, including inflammatory reactions and oxidative stress. This paper aims to explore the basic knowledge and dynamic hotspots in burns and immunology research with bibliometric methods.

Through systematic retrieval, we ensured all the documents complied with our retrieval strategy and were included in the Science Citation Index-Expanded of the Web of Science Core Collection. Using bibliometric methodologies, the general information was delineated; and foundational knowledge, as well as dynamic research hotspots, were ascertained through VOSviewer, CiteSpace, and R-bibliometrix.

8758 publications were identified from January 1st, 2000, to June 17th, 2024. The most productive and collaborative country was the USA; Harvard University was the most productive affiliation; and the most productive author was David N. Herndon. According to source analysis, the highest-impact journal is Burns. Historically, "expression" was the most frequently occurring word. "Delivery" was the most frequently occurring word in recent years.

The domain of burns and immunology has reached a zenith, with a modest decline in publication output over the past two years, yet it continues to evolve robustly. The focal points of inquiry have evolved from the initial appraisal of immunotherapeutic interventions for critical burn injuries to the elucidation of immune cell mechanisms in burn patients. Future research trajectory is poised to innovate therapeutic modalities, encompassing anti-inflammatory, antioxidant, and targeted drug delivery systems, to enhance precision in immune modulation.

Postoperative cognitive decline (POCD) is the predominant complication affecting patients over 60 years old following major surgery, yet its prediction and prevention remain challenging. Understanding the biological processes underlying the pathogenesis of POCD is essential for identifying mechanistic biomarkers to advance diagnostics and therapeutics. This study aimed to provide a comprehensive analysis of immune cell trajectories differentiating patients with and without POCD and to derive a predictive score enabling the identification of high-risk patients during the preoperative period.

Twenty-six patients aged 60 years old and older undergoing elective major orthopedic surgery were enrolled in a prospective longitudinal study, and the occurrence of POCD was assessed 7 days after surgery. Serial samples collected before surgery, and 1, 7, and 90 days after surgery were analyzed using a combined single-cell mass cytometry and plasma proteomic approach. Unsupervised clustering of the high-dimensional mass cytometry data was employed to characterize time-dependent trajectories of all major innate and adaptive immune cell frequencies and signaling responses. Sparse machine learning coupled with data-driven feature selection was applied to the presurgery immunological dataset to classify patients at risk for POCD.

The analysis identified cell-type and signaling-specific immune trajectories differentiating patients with and without POCD. The most prominent trajectory features revealed early exacerbation of JAK/STAT and dampening of inhibitory κB and nuclear factor-κB immune signaling responses in patients with POCD. Further analyses integrating immunological and clinical data collected before surgery identified a preoperative predictive model comprising one plasma protein and 10 immune cell features that classified patients at risk for POCD with excellent accuracy (AUC=0.80, P =2.21e-02 U -test).

Immune system-wide monitoring of patients over 60 years old undergoing surgery unveiled a peripheral immune signature of POCD. A predictive model built on immunological data collected before surgery demonstrated greater accuracy in predicting POCD compared to known clinical preoperative risk factors, offering a concise list of biomarker candidates to personalize perioperative management.

Background: Major trauma, as well as traumatic hemorrhagic shock go along with early damage to the endothelial glycocalyx (EG). Shed glycocalyx constituents can activate the innate immune system and aggravate secondary injury. Subsequently, we investigated the relationship between glycocalyx shedding and the occurrence of coagulopathy, multiple organ failure (MOF) and outcome in our cohort after severe trauma. Methods: We included multiple trauma patients, as defined by Injury Severity Score (ISS). Polytraumatized patients must have arrived in our level 1 trauma center within 60 min after trauma. Retrospectively, patients were assigned to predefined clinical conditions, based on injury severity (ISS ≥ 16 points), multiple organ failure (MOF score ≥ 6 points), need for massive transfusion (≥10 RBC units/first 24 h), coagulopathy (prothrombin time < 70% at 0 h) and survival (90-day survival). Syndecan-1 (Sdc-1) and hyaluronan (HA) plasma concentrations were evaluated immediately (0 h), 6 h and 12 h after trauma. Results: 49 patients (mean ISS 35.7 ± 12.1 SD, mean age 45.78 ± 15.6 SD) were included in this study. A total of 37 patients (75.5%) survived, while 12 patients died within the observation period of 90 days after trauma (24.5%). A total of 77% of all patients suffered multiple organ failure (MOF score ≥ 6, n = 30). Initial prothrombin time at 0 h was <70% in 31 patients. Plasma concentrations of circulating both glycocalyx constituents showed a significant increase over the first 12 h after trauma (p = 0.001; p = 0.008). Patients with multiple organ failure showed significantly increased hyaluronan concentrations at all three time points (p = 0.007/0.006/<0.001), and the syndecan-1 levels were significantly elevated 12 h after trauma in the MOF group (p = 0.01). Patients with coagulopathy on admission exhibited significantly higher hyaluronan levels at 12 h (p = 0.042). Non-survivors showed significantly increased syndecan-1 levels at 12 h after trauma (p = 0.024). Conclusions: Glycocalyx shedding occurs immediately after major trauma. Coagulopathy is associated with significantly increased plasma hyaluronan. Further, significant changes in plasma concentrations within the first 12 h help to identify subgroups at risk for developing MOF and death.

Since previous studies have suggested that the RNAs of human endogenous retrovirus (HERV) might be involved in regulating innate immunity, it is important to investigate the HERV transcriptome patterns in innate immune cell types such as CD14 + monocytes. Using single cell RNA-seq datasets from resting or stimulated PBMCs mapped to 3,220 known discrete autonomous proviral HERV loci, we found individual-specific variation in HERV transcriptomes between HERV loci in CD14 + monocytes. Analysis of paired datasets from the same individual that were cultured in vitro with LPS or without (i.e. control) revealed 36 HERV loci in CD14 + monocytes that were detected only after activation. To extend our analysis to in vivo activated CD14 + monocytes, we used two scRNA-seq datasets from studies that had demonstrated activation of circulating CD14 + monocytes in patients with physical trauma or patients hospitalized with COVID-19 infections. For direct comparison between the trauma and COVID-19 datasets, we first analyzed 1.625 billion sequence reads from a composite pangenome control of 21 normal individuals. Comparison of the sequence read depth of HERV loci in the trauma or COVID-19 samples to the pangenome control revealed that 39 loci in the COVID-19 and 11 HERV loci in the trauma samples were significantly different (Mann-Whitney U test), with 9 HERV loci shared between the COVID-19 and trauma datasets. The capacity to compare HERV loci transcriptome patterns in innate immune cells, like CD14 + monocytes, across different pathological conditions will lead to greater understanding of the physiological role of HERV expression in health and disease.

Background : Trauma and blood loss are frequently associated with organ failure, immune dysfunction, and a high risk of secondary bacterial lung infections. We aim to test if plasma metabolomic flux and monocyte bioenergetics are altered in association with trauma and related secondary infections. Methods : Plasma samples were collected from trauma patients at three time points: days 0, 3, and 7 postadmission. Metabolites (140) were measured in plasma from trauma survivors ( n = 24) and healthy control individuals (HC, n = 10). Further analysis within the trauma cohort included subsets of trauma/infection-negative (TIneg, n = 12) and trauma/infection-positive patients (TIpos, n = 12). The bioenergetic profile in monocytes was determined using mitochondrial and glycolytic stress tests. Results : In the trauma cohort, significant alterations were observed in 29 metabolites directly affecting 11 major metabolic pathways, while 34 metabolite alterations affected 8 pathways in 9, versus TIneg patients. The most altered metabolic pathways included protein synthesis, the urea cycle/arginine metabolism, phenylalanine, tyrosine, tryptophan biosynthesis, and carnitine compound family. In monocytes from trauma patients, reduced mitochondrial indices and loss of glycolytic plasticity were consistent with an altered profile of plasma metabolites in the tricarboxylic acid cycle and glycolysis. Conclusions : Our study highlights that the metabolic profile is significantly and persistently affected by trauma and related infections. Among trauma survivors, metabolic alterations in plasma were associated with reduced monocyte bioenergetics. These exploratory findings establish a groundwork for future clinical studies aimed at enhancing our understanding of the interplay between metabolic/bioenergetic alterations associated with trauma and secondary bacterial infections.

Whether DNA methylation changes follow human physical trauma is uncertain. We aimed to investigate if severe trauma was associated with DNA methylation changes. In a prospective, observational, clinical study, we included severely injured adults and adults undergoing elective surgery (controls). Blood was obtained from trauma patients (n = 60) immediately- and 30-45 days post-trauma, and from surgical patients (n = 57) pre-, post-, and 30-45 days post-surgery. Epigenome-wide DNA methylation profiling was performed and analyzed for significant differentially methylated CpGs and -regions (DMRs) within and between groups. Within the trauma group we identified 10,126 significant differentially methylated CpGs and 1169 DMRs. No significant differential methylation was found in the surgical group. In the trauma group, differentially methylated sites were enriched in genes and pathways involved in blood coagulation and inflammatory response. Severe trauma was associated with profound alterations in the DNA methylome of circulating leucocytes, and differential methylation was located in trauma-relevant genes.

The aim of this study was to investigated the effects of forsythiaside A (FA) on acute lung injury (ALI). The lung tissue pathological was detected by hematoxylin-eosin staining (HE) staining. Wet weight/dry weight (w/d) of the lung in mice was measured. Cytokine such as interleukin 1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were also detected. Compared with the vector group, the protein expression levels of TRAF6 and TAK1 the RNF99 group were significantly reduced. Ubiquitinated TRAF6 protein was increased after knockdown of RNF99. Finally, it was found that FA significantly ameliorated ALI via regulation of RNF99/TRAF6/NF-κB signal pathway. In conclusion, RNF99 was an important biomarker in ALI and FA alleviated ALI via RNF99/ TRAF6/NF-κB signal pathway.

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.

Sepsis is an insidious and frequent condition of severe inflammation due to infections. Several biomarkers have been established for initial screening, but the non-specific nature of the existing biomarkers has led to the investigation of more sensitive and specific tools, such as microRNAs (miRs). These non-coding RNAs are involved in several diseases, including sepsis, due to their roles in cellular homeostasis. Herein, a literature overview was attempted to distinguish the most prominent miRs identified in septic conditions and their usefulness in diagnosis, prognosis and even classification of sepsis. miRs implicated in the regulation of pro and anti-inflammatory mechanisms, such as MIR-146a, MIR-155, MIR-181b, MIR-223-5p, MIR-494-3p, MIR-2055b, MIR-150 and MIR-143 have been pinpointed as acceptable testing tools. Furthermore, the use of miRs as screening panels, specific for septic parameters, such as type of causal infection, inflammation immune pathways affected (NF-kB, STAT/JACK), organs inflicted, as well as parallel screening of certain miRs alongside other long non-coding RNAs (LNCs), as co-regulators of sepsis progression. Overall, miRs exhibit benefits in terms of specificity and sensitivity, as well as practical ease of use and test stability. Furthermore, miRs could offer valuable insights into the molecular basis of disease causality and provide valuable therapeutic information.

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.

Jumonji domain-containing protein D3 (JMJD3) is a 2-oxoglutarate-dependent dioxygenase that specifically removes transcriptional repression marks di- and tri-methylated groups from lysine 27 on histone 3 (H3K27me2/3). The erasure of these marks leads to the activation of some associated genes, thereby influencing various biological processes, such as development, differentiation, and immune response. However, comprehensive descriptions regarding the relationship between JMJD3 and inflammation are lacking. Here, we provide a comprehensive overview of JMJD3, including its structure, functions, and involvement in inflammatory pathways. In addition, we summarize the evidence supporting JMJD3's role in several inflammatory diseases, as well as the potential therapeutic applications of JMJD3 inhibitors. Additionally, we also discuss the challenges and opportunities associated with investigating the functions of JMJD3 and developing targeted inhibitors and propose feasible solutions to provide valuable insights into the functional exploration and discovery of potential drugs targeting JMJD3 for inflammatory diseases.

Traumatic perioperative conditions may trigger early systemic responses, activate leukocytes and reprogram the immune system. We hypothesize that leukocyte activation may not revert to pre-surgical states, and that protracted activation may emerge with increased risks of comorbidities. We tested this concept by examining the transcriptomes of monocytes and T cells in a representative observational cohort of patients (n = 13) admitted for elective cardiac surgery. Transcriptomes in T cells and monocytes were compared from before surgery (t0), and monocytes were analyzed longitudinally after acute (t24hr), and convalescent (t3m) time points. Monocytes and T cells expressed distinct transcriptomes, reflected by statistically significant differential expression of 558 T cell related genes. Monocytes expressed genes related to protein degradation and presented atypical activation of surface markers and cytoplasmic functions over time. Additionally, monocytes exhibited limited transcriptomic heterogeneity prior to surgery, and long-term patterns of gene expression associated with atherosclerosis showed three temporally distinct signatures. These data establish that post-cardiac surgery transcriptomes of monocytes differ even at three months compared to baselines, which may reflect latent ('smoldering') inflammation and persistent progression of tissue degenerative processes that should inform clinical care.

Multiple organ failure/dysfunction syndrome (MOF/MODS) is a major cause of mortality and morbidity among severe trauma patients. Current clinical practices entail monitoring physiological measurements and applying clinical score systems to diagnose its onset. Instead, we aimed to develop an early prediction model for MOF outcome evaluated soon after traumatic injury by performing machine learning analysis of genome-wide transcriptome data from blood samples drawn within 24 h of traumatic injury. We then compared its performance to baseline injury severity scores and detection of infections.

Buffy coat transcriptome and linked clinical datasets from blunt trauma patients from the Inflammation and the Host Response to Injury Study ("Glue Grant") multi-center cohort were used. According to the inclusion/exclusion criteria, 141 adult (age ≥ 16 years old) blunt trauma patients (excluding penetrating) with early buffy coat (≤ 24 h since trauma injury) samples were analyzed, with 58 MOF-cases and 83 non-cases. We applied the Least Absolute Shrinkage and Selection Operator (LASSO) and eXtreme Gradient Boosting (XGBoost) algorithms to select features and develop models for MOF early outcome prediction.

The LASSO model included 18 transcripts (AUROC [95% CI]: 0.938 [0.890-0.987] (training) and 0.833 [0.699-0.967] (test)), and the XGBoost model included 41 transcripts (0.999 [0.997-1.000] (training) and 0.907 [0.816-0.998] (test)). There were 16 overlapping transcripts comparing the two panels (0.935 [0.884-0.985] (training) and 0.836 [0.703-0.968] (test)). The biomarker models notably outperformed models based on injury severity scores and sex, which we found to be significantly associated with MOF (APACHEII + sex-0.649 [0.537-0.762] (training) and 0.493 [0.301-0.685] (test); ISS + sex-0.630 [0.516-0.744] (training) and 0.482 [0.293-0.670] (test); NISS + sex-0.651 [0.540-0.763] (training) and 0.525 [0.335-0.714] (test)).

The accurate assessment of MOF from blood samples immediately after trauma is expected to aid in improving clinical decision-making and may contribute to reduced morbidity, mortality and healthcare costs. Moreover, understanding the molecular mechanisms involving the transcripts identified as important for MOF prediction may eventually aid in developing novel interventions.

Sepsis is defined as a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection, characterized by a systemic inflammatory response to infection. The use of antibiotics, fluid resuscitation, and organ support therapy has limited prognostic benefit in patients with sepsis, and its incidence is not diminishing, which is attracting increased attention in medicine. Sepsis remains one of the most debilitating and expensive illnesses. One of the main reasons of septic mortality is now understood to be disruption of immune homeostasis. Immunotherapy is revolutionizing the treatment of illnesses in which dysregulated immune responses play a significant role. This "trained immunity", which is a potent defense against infection regardless of the type of bacteria, fungus, or virus, is attributed to the discovery that the innate immune cells possess immune memory via metabolic and epigenetic reprogramming. Here we reviewed the immunotherapy of innate immune cells in sepsis, the features of trained immunity, and the relationship between trained immunity and sepsis.

Severe burn injury elicits a profound stress response with the potential for high morbidity and mortality. If polytrauma is present, patient outcomes appear to be worse. Sex-based comparisons indicate females have worse outcomes than males. There are few effective drug therapies to treat burn shock and secondary injury progression. The lack of effective drugs appears to arise from the current treat-as-you-go approach rather than a more integrated systems approach. In this review, we present a brief history of burns research and discuss its pathophysiology from a systems' perspective. The severe burn injury phenotype appears to develop from a rapid and relentless barrage of damage-associated molecular patterns, pathogen-associated molecular patterns, and neural afferent signals, which leads to a state of hyperinflammation, immune dysfunction, coagulopathy, hypermetabolism, and intense pain. We propose that if the central nervous system control of cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored early, these secondary injury processes may be minimized. The therapeutic goal is to switch the injury phenotype to a healing phenotype by reducing fluid leak and maintaining tissue O2 perfusion. Currently, no systems-based therapies exist to treat severe burns. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine, and magnesium (ALM) to treat hemorrhagic shock, traumatic brain injury, and sepsis. Our early studies indicate that the ALM therapy holds some promise in supporting cardiovascular and pulmonary functions following severe burns. Future research will investigate the ability of ALM therapy to treat severe burns with polytrauma and sex disparities, and potential translation to humans.

Severe trauma is an intractable problem in healthcare. Patients have a widespread immune system response that is complex and vital to survival. Excessive inflammatory response is the main cause of poor prognosis and poor therapeutic effect of medications in trauma patients. Cytokines are signaling proteins that play critical roles in the body's response to injuries, which could amplify or suppress immune responses. Studies have demonstrated that cytokines are closely related to the severity of injuries and prognosis of trauma patients and help present cytokine-based diagnosis and treatment plans for trauma patients. In this review, we introduce the pathophysiological mechanisms of a traumatic inflammatory response and the role of cytokines in trauma patients. Furthermore, we discuss the potential of cytokine-based diagnosis and therapy for post-traumatic inflammatory response, although further clarification to elucidate the underlying mechanisms of cytokines following trauma is warranted.

Millions of microorganisms make up the complex microbial ecosystem found in the human gut. The immune system's interaction with the gut microbiota is essential for preventing inflammation and maintaining intestinal homeostasis. Numerous metabolic products that can cross-talk between immune cells and the gut epithelium are metabolized by the gut microbiota. Traumatic injury elicits a great and multifaceted immune response in the minutes after the initial offense, containing simultaneous pro- and anti-inflammatory responses. The development of innovative therapies that improve patient outcomes depends on the gut microbiota and immunological responses to trauma. The altered makeup of gut microbes, or gut dysbiosis, can also dysregulate immunological responses, resulting in inflammation. Major human diseases may become more common as a result of chronic dysbiosis and the translocation of bacteria and the products of their metabolism beyond the mucosal barrier. In this review, we briefly summarize the interactions between the gut microbiota and the immune system and human disease and their therapeutic probiotic formulations. We also discuss the immune response to traumatic injury.

The immune response of critically ill patients, such as those with sepsis, severe trauma, or major surgery, is heterogeneous and dynamic, but its characterization and impact on outcomes are poorly understood. Until now, the primary challenge in advancing our understanding of the disease has been to concurrently address both multiparametric and temporal aspects.

We used a clustering method to identify distinct groups of patients, based on various immune marker trajectories during the first week after admission to ICU. In 339 severely injured patients, we initially longitudinally clustered common biomarkers (both soluble and cellular parameters), whose variations are well-established during the immunosuppressive phase of sepsis. We then applied this multi-trajectory clustering using markers composed of whole blood immune-related mRNA.

We found that both sets of markers revealed two immunotypes, one of which was associated with worse outcomes, such as increased risk of hospital-acquired infection and mortality, and prolonged hospital stays. This immunotype showed signs of both hyperinflammation and immunosuppression, which persisted over time.

Our study suggest that the immune system of critically ill patients can be characterized by two distinct longitudinal immunotypes, one of which included patients with a persistently dysregulated and impaired immune response. This work confirms the relevance of such methodology to stratify patients and pave the way for further studies using markers indicative of potential immunomodulatory drug targets.

To determine whether scheduled low-dose, short-term ketorolac modulates cytokine concentrations in orthopaedic polytrauma patients.

Secondary analysis of a double-blinded, randomized controlled trial.

Single Level I trauma center from August 2018 to October 2022.

Orthopaedic polytrauma patients between 18 and 75 years with a New Injury Severity Score greater than 9 were enrolled. Participants were randomized to receive 15 mg of intravenous ketorolac every 6 hours for up to 5 inpatient days or 2 mL of intravenous saline similarly.

Daily concentrations of prostaglandin E2 and interleukin (IL)-1a, IL-1b, IL-6, and IL-10. Clinical outcomes included hospital and intensive care unit length of stay, pulmonary complications, and acute kidney injury.

Seventy orthopaedic polytrauma patients were enrolled, with 35 participants randomized to the ketorolac group and 35 to the placebo group. The overall IL-10 trend over time was significantly different in the ketorolac group ( P = 0.043). IL-6 was 65.8% higher at enrollment compared to day 3 ( P < 0.001) when aggregated over both groups. There was no significant treatment effect for prostaglandin E2, IL-1a, or IL-1b ( P > 0.05). There were no significant differences in clinical outcomes between groups ( P > 0.05).

Scheduled low-dose, short-term, intravenous ketorolac was associated with significantly different mean trends in IL-10 concentration in orthopaedic polytrauma patients with no significant differences in prostaglandin E2, IL-1a, IL-1b, or IL-6 levels between groups. The treatment did not have an impact on clinical outcomes of hospital or intensive care unit length of stay, pulmonary complications, or acute kidney injury.

Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

The complement system, an upstream recognition system of innate immunity, is activated upon SARS-CoV-2 infection. To gain a deeper understanding of the extent and duration of this activation, we investigated complement activation profiles during the acute phase of COVID-19, its persistence post-recovery and dynamic changes in relation to disease severity.

Serial blood samples were obtained from two cohorts of hospitalized COVID-19 patients (n = 457). Systemic complement activation products reflecting classical/lectin (C4d), alternative (C3bBbP), common (C3bc) and terminal pathway (TCC and C5a) were measured during hospitalization (admission, days 3-5 and days 7-10), at 3 months and after 1 year. Levels of activation and temporal profiles during hospitalization were related to disease severity defined as respiratory failure (PO2/FiO2 ratio <26.6 kPa) and/or admission to intensive care unit, 60-day total mortality and pulmonary pathology after 3 months.

During hospitalization, TCC, C4d, C3bc, C3bBbP and C5a were significantly elevated compared to healthy controls. Severely ill patients had significantly higher levels of TCC and C4d (p < 0.001), compared to patients with moderate COVID-19. Escalated levels of TCC and C4d during hospitalization were associated with a higher risk of 60-day mortality (p < 0.001), and C4d levels were additionally associated with chest CT changes at 3 months (p < 0.001). At 3 months and 1 year, we observed consistently elevated levels of most complement activation products compared to controls.

Hospitalized COVID-19 patients display prominent and long-lasting systemic complement activation. Optimal targeting of the system may be achieved through enhanced risk stratification and closer monitoring of in-hospital changes of complement activation products.

In this paper, we present a review of several selected talks presented at the CTTACC conference (Cellular Therapies in Trauma and Critical Care) held in Scottsdale, AZ in May 2023. This conference review highlights the potential for cellular therapies to "reset" the dysregulated immune response and restore physiologic functions to normal. Improvements in medical care systems and technology have increasingly saved lives after major traumatic events. However, many of these patients have complicated post-traumatic sequelae, ranging from short-term multi-organ failure to chronic critical illness.

Patients with chronic critical illness have been found to have dysregulated immune responses. These abnormal and harmful immune responses persist for years after the initial insult and can potentially be mitigated by treatment with cellular therapies.

The sessions emphasized the need for more research and clinical trials with cellular therapies for the treatment of a multitude of chronic illnesses: post-trauma, radiation injury, COVID-19, burns, traumatic brain injury (TBI) and other chronic infections.