COMPREHENSIVE THERAPEUTIC EFFICACY ANALYSIS OF INTRAVENOUS IMMUNOGLOBULIN IN TREATING SEPSIS-INDUCED COAGULOPATHY: A SINGLE-CENTER, RETROSPECTIVE OBSERVATIONAL STUDY

Sepsis induced coagulopathy is a common cause of death in patients with severe sepsis. These stem from an uncontrolled inflammatory response in the body which leads to cellular and molecular damage. Thus, septic patients complicated by coagulopathy exhibit immunosuppression. Fang et al. (pp. 4–12) retrospectively reviewed the outcome of septic patients with coagulopathy treated with intravenous immunoglobulin (IVIg) to help improve immune status and coagulation function in sepsis. The study reported early administration of IVIg in patients with severe septic coagulopathy improves the prognosis of septic coagulopathy and reduces the 28-day mortality rate.

PROACTIVE SCREENING ALGORITHM FOR EARLY-ONSET PNEUMONIA IN PATIENTS WITH OUT-OF-HOSPITAL CARDIAC ARREST: A BEFORE-AFTER IMPLEMENTATION STUDY

Early-onset pneumonia (EOP) is a serious complication after cardiac arrest which can be hampered at the early phase of out-of-hospital cardiac arrest (OHCA) management. An algorithm for proactive screening for EOP was designed to minimize the delay in diagnosis. Lemée et al. (pp. 13–19) conducted a single-center observational study comparing the outcomes of mechanically-ventilated adult patients with OHCA, before and implementation of the algorithm for proactive diagnosis of EOP. The algorithm was not associated with a significant change in the time to antibiotic initiation but was associated with an independent improvement in oxygenation parameters.

EFFECT OF GENDER ON 28-DAY SURVIVAL RATES AND TRANSFUSION VOLUME IN SEVERE TRAUMA PATIENTS: A MULTICENTER OBSERVATIONAL STUDY

In trauma, severely injured patients are more likely to be male, but the number of patients and the injury mechanism differ according to sex. There is limited consistent evidence on the relationship between sex, prognosis, transfusion volume, and age-specific analysis to determine the impact of sex hormones on the prognosis of trauma patients. Tsuchida et al. (pp. 20–25) conducted a multicenter, collaborative post-hoc analysis of adult trauma patients to clarify the relationship between sex with survival and transfusion volume. Results showed that survival at 28 days was significantly lower in males. However, this was not observed in patients aged <50 years. Factors other than sex hormones may be responsible for differences in posttraumatic outcomes by gender.

NOVEL ECHOCARDIOGRAM ANALYSIS OF CARDIAC DYSFUNCTION IS ASSOCIATED WITH MORTALITY IN PEDIATRIC SEPSIS

Cardiovascular dysfunction is attributed to sepsis related mortality. This dysfunction can be assessed using echocardiography. A semiautomated algorithm was developed to quantify cardiac chamber morphology motion, and strain from echocardiograms without relying on interpretation by cardiologists. Cater et al. (pp. 26–31) studied the use of the algorithm to determine the echocardiogram indices most strongly associated with mortality in pediatric sepsis. The retrospective cohort study of pediatric patients showed the feasibility of obtaining clinically relevant echocardiogram indices using the algorithm. Also, abnormal strain echocardiography was associated with clinically relevant outcomes and mortality. The novel algorithm could help categorize high-risk patients with pediatric sepsis.

EFFECT OF STRATIFIED DOSE OF NOREPINEPHRINE ON CELLULAR IMMUNE RESPONSE IN PATIENTS WITH SEPTIC SHOCK AND THE CONSTRUCTION OF A PROGNOSTIC RISK MODEL

Norepinephrine (NE) is one of the most used drugs in the ICU and is the preferred vasoactive drug for patients with septic shock. However, high dose of NE has an inhibitory effect on the cellular immune function in patients with septic shock, leading to a higher mortality rate. Wang et al. (pp. 32–43) analyzed the effect of a stratified dose of norepinephrine on the cellular immune response of patients with septic shock using a single-center, observational, and two-way cohort study. Age, norepinephrine weighted average dose, and IL-6 were risk factors affecting the prognosis of patients with septic shock. Nutrition, absolute value of T lymphocytes, and mHLA-DR were protective factors affecting the prognosis of patients.

CAUSAL ROLES OF SERUM URIC ACID LEVELS AND GOUT IN SEPSIS: A MENDELIAN RANDOMIZATION STUDY

Serum uric acid (UA), the end product of purine metabolism is commonly associated with gout. Attention has been drawn to the potential correlation between UA levels and septicemia. Studies have showed that UA has a role in inflammatory responses, oxidative stress and immune regulation which indicates a positive correlation between elevated UA levels and septicemia. Qin et al. (pp. 44–50) investigated the causal effect of UA levels, gout and sepsis using Mendelian Randomization. The study showed elevated UA levels was causally linked with sepsis. However, there was no contributory role of serum UA in sepsis and mortality.

DIMINISHED EXPRESSION OF GLS IN CD4+ T CELLS SERVES AS A PROGNOSTIC INDICATOR ASSOCIATED WITH CUPROPTOSIS IN SEPTIC PATIENTS

Cuproptosis is a recently identified form of regulated cell death which is dependent on intracellular copper. Excess copper selectively disrupts a group of metabolic lipoylated enzymes potentially leading to cuproptosis. These may serve as biomarkers of sepsis. Yang et al. (pp. 51–62) analyzed and identified therapeutic cuproptosis-related biomarkers using peripheral blood samples in septic patients. Through WGCNA, they identified three cuproptosis related genes namely, GLS, LIPT1, and DLD. Next an investigation into GLS expression in Jurkat cells was conducted and analyzed levels of O-GlcNAc in cellular systems. It was also confirmed thru chelation of copper with TTM that alteration of GLS could not be rescued in activated CD4+ T cells but restoration of iron-sulfur cluster proteins occurred after chelation of intracellular copper and prior to LPS induction.

EFFECTS OF LEVOSIMENDAN ON DIAPHRAGMATIC DYSFUNCTION IN PATIENTS WITH SEPSIS

Diaphragm dysfunction is one of the cofounding factors of failed weaning in patients with sepsis which is related to poor prognosis. No medication has currently been approved for treatment of respiratory muscle weakness. Wu et al. (pp. 63–68) investigated the use of levosimendan to augment contractility of the respiratory muscles and improve weaning outcomes in patients with sepsis-induced diaphragm dysfunction. Levosimendan enhanced diaphragmatic contractile function but patient weaning outcomes was not statistically significant.

VASOPRESSOR REDUCTION EFFECT OF POLYMYXIN B HEMOPERFUSION IN PATIENTS WITH PERITONITIS-INDUCED SEPTIC SHOCK: A PROPENSITY SCORE-MATCHED ANALYSIS

Polymyxin B is an antimicrobial with activity against gram-negative bacteria through denaturation of the bacterial cell wall and inactivation of endotoxins. Endotoxins play a major role in the pathogenesis of septic shock. Polymyxin B hemoperfusion (PMX-HP) is an extracorporeal blood purification technique to remove endotoxins. This study retrospectively assessed adult patients with peritonitis induced septic shock who underwent major abdominal surgery to control source of sepsis and were treated with PMX-HP. Cho et al. (pp. 69–73) reported PMX-HP reduced vasopressor requirement but does not reduce ICU mortality.

MELATONIN ATTENUATES RENAL ISCHEMIA-REPERFUSION INJURY BY REGULATING MITOCHONDRIAL DYNAMICS AND AUTOPHAGY THROUGH AMPK/DRP1

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury and renal allograft loss following renal transplantation. With the knowledge that melatonin mitigates IRI, Wang et al. (pp. 74–84) utilized HK-2 cells and rats to assess whether pretreatment with melatonin provides a protective effect prior to induction of hypoxia-reoxygenation or IRI, respectively. The authors found that in an AMPK-dependent manner, melatonin pretreatment shieled the kidneys from IRI through mitigation of excessive mitochondrial fission, moderation of autophagy levels, and preservation of appropriate mitochondrial fission.

BONE MARROW MESENCHYMAL STROMAL CELL-DERIVED EXOSOMAL NRF2 AMELIORATES CEREBRAL ISCHEMIA-REPERFUSION INJURY BY TRANSCRIPTIONALLY ACTIVATING LIN28A

As a potential consequence of a stroke or neurological surgical procedures, cerebral ischemia-reperfusion injury (CIRI) can result in significant impairments to brain function. Using a murine model of middle cerebral artery occlusion (MCAO), in addition to human glioblastoma cells, Liu et al. (pp. 85–94) demonstrated that bone marrow mesenchymal stromal cell (BMSC) derived exosomal nuclear factor erythroid 2-related factor (NRF2) can alleviate CIRI through its transcriptional activation of acyl-Coa synthetase long chain family member 4 (Lin28a). When overexpressed in response to NRF2 stimulation, Lin28a significantly improved nerve cell apoptosis, oxidative stress, and inflammatory responses, hallmarks of CIRI.

MDIVI-1 ALLEVIATES SEPSIS-INDUCED LIVER INJURY BY INHIBITING STING SIGNALING ACTIVATION

Amidst the many organs affected by sepsis, overactivation of Kupffer cells (KCs) in the liver leads to release of proinflammatory cytokines, causing significant hepatic damage. Following their previous work which identified activation of stimulator of interferon genes (STING) signaling within KCs and its subsequent inhibition in response to dynamin-related protein 1 (DRP1) knockdown, Zhang et al. (pp. 95–102) investigate the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) treatment, a selective inhibitor of DRP1, in ameliorating sepsis induced liver injury. Here, the authors show that inhibition of STING signaling activation in KCs not only mitigates liver injury but significantly decreases the mortality of septic mice, outcomes which are worsened when STING signaling is catalyzed with DMXAA.

OMX: A NOVEL OXYGEN DELIVERY BIOTHERAPEUTIC IMPROVES OUTCOMES IN AN OVINE MODEL OF CONTROLLED HEMORRHAGIC SHOCK

Despite whole blood or blood product transfusion being the first line treatment for hemorrhagic shock, its efficacy is limited in environments when robust supplies cannot be maintained. Due to these challenges, hemorrhagic shock remains a global leader of morbidity and mortality. Maltepe et al. (pp. 103–110) sought to determine the effect of OMX, a novel non-hemoglobin-based oxygen carrier, in treating hemorrhagic shock within a lamb model of acute controlled hemorrhage. Combined with improvements to metabolic and hemodynamic outcomes, OMX treated lambs had significantly greater survival, providing promise to OMX therapy in inadequate oxygen delivery disease states.

VENOARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION REDUCES MYOCARDIAL AND MITOCHONDRIAL DAMAGE IN ACUTE MYOCARDIAL INFARCTION

Extracorporeal membrane oxygenation (ECMO) oxygenates blood externally, and in the context of cardiogenic shock, it provides cardiopulmonary support, maintains hemodynamic stability, and alleviates cardiac load. The use of ECMO in myocardial infarction is controversial. Ni Et al. (pp. 111–118) investigated the efficacy of ECMO in treating myocardial infarction using a rat model. The ECMO showed a smaller myocardial infarct size, a larger percentage ejection fraction and had a protective effect on the mitochondria of rat cardiomyocytes. However, ECMO delayed the opening time of the coronary artery.

CIRCVMA21-RELATED PATHWAY ALLEVIATES LIPOPOLYSACCHARIDE-INDUCED HK-2 CELL INJURY

Frequently observed within sepsis’ detrimental effect on the body is the manifestation of acute kidney injury (AKI), resulting in a sharp decline in renal function. As previous reports have shown the potential of circular RNAs in mitigating AKI, Li et al. (pp. 119–126) investigate the molecular mechanisms beneath this therapeutic effect. Using lipopolysaccharide (LPS) to induce HK2 cell injury, the authors report that circular RNA, circVMA21, ameliorated LPS-induced cell inflammation, apoptosis, and oxidative stress through its inhibition of miR-337-3p and subsequent positive regulatory effect on ZEB2, a nuclear transcription factor.

SIRT3 MEDIATES THE CARDIOPROTECTIVE EFFECT OF THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST AND RESUSCITATION BY RESTORING AUTOPHAGIC FLUX VIA THE PI3K/AKT/MTOR PATHWAY

Although cardiopulmonary resuscitation (CPR) practices have undergone substantial improvements in recent times, cardiac arrest (CA) still contributes greatly to early death in patients, with postresuscitation cardiac dysfunction being a major contributor. Importantly, therapeutic hypothermia (TH) has been shown to provide cardioprotective effects following CA, prompting inquiries into the molecular processes beneath TH. Through both in vivo and in vitro explorations, Wang et al. (pp. 127–138) demonstrate that CA reduces Sirt3 expression, an outcome restored by TH, and which further leads to improved autophagic flux via the PI3K/Akt/mTOR pathway.

MURAMYL DIPEPTIDE CAUSES MITOCHONDRIAL DYSFUNCTION AND INTESTINAL INFLAMMATORY CYTOKINE RESPONSES IN RATS

The migration of intestinal bacteria and their products, such as muramyl dipeptide (MDP), can trigger significant inflammatory damage to the small intestine, leading to gastrointestinal infection and ultimately sepsis. Given this process is appreciated as a common cause of sepsis, Zhao et al. (pp. 139–145) investigate the effect of MDP on the intestinal mucosa and distant organs in a rodent model of sepsis. Here, the authors find that MDP translocation increases organ damage, the inflammatory response, and, through its regulation of the NOD2/AMPK/LC3 pathway, reduces mitochondrial autophagy, leading to mitochondrial dysfunction in the intestinal epithelium.

INFLUENCES OF HEAT STRESS ON GLUTAMATE TRANSMISSION-DEPENDENT EXPRESSION LEVELS OF IL-1β AND IL-18 IN BV-2 MICROGLIAL CELLS

Despite its profound clinical consequences, such as central nervous system dysfunction and at times, multi-organ dysfunction syndrome, heat stroke and its molecular mechanisms remain unelucidated. Here, Chen et al. (pp. 146–152) address this gap in the literature by exploring the relationship between heat stress (HS) and proinflammatory factors within microglial cells. This study found that HS significantly increases glutamate release which further positively regulates the expression levels of IL-1β and IL-18 in microglial cells.