Psychedelic 25H-NBOMe attenuates post-sepsis depression in rats.

Sepsis-associated encephalopathy, which manifests in severe cognitive and depressive symptoms, is directly linked to neuroinflammation. Our study investigates the efficacy of 25H-NBOMe, a phenethylamine, in alleviating these symptoms, potentially offering an innovative treatment for post-sepsis depression. Wistar rats, weighing between 250-300 g, were subjected to cecal ligation and puncture (CLP) surgery to induce sepsis. Depressive-like behaviors were assessed using the forced swim test (FST) on either day 7 or 14 post-surgery, to establish the presence of depressive symptoms. The impact of 25H-NBOMe treatment was then evaluated, focusing on the head-twitch response (HTR), performance in the FST, and GFAP expression in the prefrontal cortex. Treatment with 25H-NBOMe resulted in significant behavioral changes, demonstrated by decreased immobility and increased swimming times in the FST, along with a rise in the HTR. These outcomes indicate a reduction in depressive-like symptoms post-sepsis and the psychoactive effects of the compound. Furthermore, a notable decrease in GFAP expression in the study highlights the compound's impact on mitigating sepsis-induced astrogliosis. This study demonstrates the effectiveness of 25H-NBOMe, a psychedelic in the phenethylamine class, in treating post-sepsis depression and reducing astrogliosis. However, the psychedelic nature of 25H-NBOMe calls for further investigation into similar compounds with less psychoactive impact, crucial for advancing treatment options for neuropsychiatric symptoms following sepsis.

[Analysis of the current quality of life status and influencing factors of sepsis survivors in intensive care unit].

OBJECTIVE: To explore the current situation and influencing factors of quality of life of septic patients in intensive care unit (ICU) after discharge, and to provide theoretical basis for clinical early psychological intervention and continuity of care. METHODS: A prospective observational study was conducted. The septic patients who were hospitalized in the department of critical care medicine of the Affiliated Hospital of Jining Medical University and discharged with improvement from January 1 to December 31, 2022 were selected as the research objects. The demographic information, basic diseases, infection site, vital signs at ICU admission, severity scores of the condition within 24 hours after ICU admission, various biochemical indexes, treatment process, and prognostic indexes of all the patients were recorded. All patients were assessed by questionnaire at 3 months of discharge using the 36-item short-form health survey scale (SF-36 scale), the activities of daily living scale (ADL scale), and the Montreal cognitive assessment scale (MoCA scale). Multiple linear regression was used to analyze the factors influencing the quality of life of septic patients after discharge from the hospital. RESULTS: A total of 200 septic patients were discharged with improvement and followed up at 3 months of discharge, of which 150 completed the questionnaire. Of the 150 patients, 57 had sepsis and 93 had septic shock. The total SF-36 scale score of septic patients at 3 months of discharge was 81.4±23.0, and the scores of dimensions were, in descending order, role-emotional (83.4±23.0), mental health (82.9±23.6), bodily pain (82.8±23.3), vitality (81.6±23.2), physical function (81.4±23.5), general health (81.1±23.3), role-physical (79.5±27.0), and social function (78.8±25.2). There was no statistically significant difference in the total SF-36 scale score between the patients with sepsis and septic shock (82.6±22.0 vs. 80.7±23.6, P > 0.05). Incorporating the statistically significant indicators from linear univariate analysis into multiple linear regression analysis, and the results showed that the factors influencing the quality of life of septic patients at 3 months after discharge included ADL scale score at 3 months after discharge [ß= 0.741, 95% confidence interval (95%CI) was 0.606 to 0.791, P < 0.001], length of ICU stay (ß= -0.209, 95%CI was -0.733 to -0.208, P = 0.001), duration of mechanical ventilation (ß= 0.147, 95%CI was 0.122 to 0.978, P = 0.012), total dosage of norepinephrine (ß= -0.111, 95%CI was -0.044 to -0.002, P = 0.028), mean arterial pressure (MAP) at ICU admission (ß= -0.102, 95%CI was -0.203 to -0.007, P = 0.036) and body weight (ß= 0.097, 95%CI was 0.005 to 0.345, P = 0.044). CONCLUSIONS: The quality of life of patients with sepsis at 3 months after discharge is at a moderately high level. The influencing factors of the quality of life of patients with sepsis at 3 months after discharge include the ADL scale score at 3 months after discharge, the length of ICU stay, the duration of mechanical ventilation, the total dosage of norepinephrine, MAP at ICU admission and body weight, and healthcare professionals should enhance the treatment and care of the patients during their hospitalization based on the above influencing factors, and pay attention to early psychological intervention and continued care for such patients.

The role of neutrophil gelatinase-associated lipocalin and iron homeostasis in object recognition impairment in aged sepsis-survivor rats.

Older adult patients with sepsis frequently experience cognitive impairment. The roles of brain neutrophil gelatinase-associated lipocalin (NGAL) and iron in older sepsis patients remain unknown. We investigated the effects of lipopolysaccharide-induced sepsis on novel object recognition test, NGAL levels, an inflammatory mediator tumor necrosis factor-α (TNFα) levels, and iron ion levels in the hippocampus and cortex of young and aged rats. The effect of an iron chelator deferoxamine pretreatment on aged sepsis rats was also examined. Young sepsis-survivor rats did not show impaired novel object recognition, TNFα responses, or a Fe2+/Fe3+ imbalance. They showed hippocampal and cortical NGAL level elevations. Aged sepsis-survivor rats displayed a decreased object discrimination index, elevation of NGAL levels and Fe2+/Fe3+ ratio, and no TNFα responses. Pretreatment with deferoxamine prevented the reduction in the object recognition of aged sepsis-survivor rats. The elevation in hippocampal and cortical NGAL levels caused by lipopolysaccharide was not influenced by deferoxamine pretreatment. The lipopolysaccharide-induced Fe2+/Fe3+ ratio elevation was blocked by deferoxamine pretreatment. In conclusion, our findings suggest that iron homeostasis in the cortex and hippocampus contributes to the maintenance of object recognition ability in older sepsis survivors.

Electroacupuncture treatment ameliorated the long-term cognitive impairment via activating eNOS/NO pathway and related Aß downregulation in sepsis-survivor mice.

OBJECTIVE: Sepsis is a major challenge in intensive care unit worldwide and the septic survivors are left with long-term cognitive deficits. This work aims to explore the effects of electroacupuncture (EA) on long-term cognitive function and its underlying mechanism in sepsis-survivor mice. METHODS: Sepsis was induced by cecal ligation and puncture in C57BL/6 male mice. Seven days post-surgery, sepsis-survivor mice were treated with EA or nonacupoint EA for 17 days twice daily. Then, cognitive function was evaluated by Morris water maze task. The hippocampus tissue were collected from the mice at 30 days post-surgery. The level of nitric oxide and the expression of endothelial nitric oxide (eNOS), phospho-eNOS (p-eNOS), and amyloid ß-peptide (Aß) were measured. RESULTS: Compared with the sham-operated control, sepsis-survivors had significant cognitive deficits evidenced by the increased time of escape latency and reduced crossing number in Morris water maze task, as well as lower NO and p-eNOS level and higher Aß level. EA treatment at GV20 and ST36 acupoints but not at a nonacupoint improved the cognitive function, increased the NO and p-eNOS level, and decreased Aß generation; while eNOS inhibitor (l-NAME) undermined the efficacy of EA treatment. CONCLUSION: In conclusion, repeated EA treatment could ameliorate the long-term cognitive impairment via manipulating the expression of p-eNOS and related Aß in sepsis-survivor mice.

Long-term sequelae of critical illness in sepsis, trauma and burns: A systematic review and meta-analysis.

BACKGROUND: Sepsis, major trauma, and severe burn injury are life-threatening critical illnesses that remain significant contributors to worldwide morbidity and mortality. The three underlying etiologies share pathophysiological similarities: hyperinflammation, hypermetabolism, and acute immunomodulation. The aims of this study were to assess the current state of long-term outcome research and to identify key outcome parameters between the three forms of critical illness. METHODS: This systematic review and meta-analysis (MA) were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. PubMed was searched from January 1, 1975, to December 31, 2019. Studies were assessed for eligibility by independent reviewers. Inclusion criteria were studies reporting at least a 6-month follow-up of health-related quality of life and organ-specific sequelae within the three etiologies: severe burn injury, sepsis, and major trauma. RESULTS: In total, 125 articles could be included in the systematic review and 74 in the MA. The mean follow-up time was significantly longer in burn studies, compared with sepsis and trauma studies. The majority of patients were from the sepsis group, followed by burns, and major trauma studies. In the overall health-related quality of life, as assessed by Short Form 36 and European Quality-of-Life Index, the three different etiologies were comparable with one another. CONCLUSION: The effects of critical illness on survivors persist for years after hospitalization. Well-reported and reliable data on the long-term outcomes are imperative, as they can be used to determine the treatment choice of physicians and to guide the expectations of patients, improving the overall quality of care of three significant patient cohorts. LEVEL OF EVIDENCE: Systematic review and MA, level III.

Folic acid alleviates the blood brain barrier permeability and oxidative stress and prevents cognitive decline in sepsis-surviving rats.

Sepsis is a complication of an infection which imbalance the normal regulation of several organ systems, including the central nervous system (CNS). Evidence points towards inflammation and oxidative stress as major steps associated with brain dysfunction in sepsis. Thus, we investigated the folic acid (FA) effect as an important antioxidant compound on acute brain dysfunction in rats and long term cognitive impairment and survival. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) or sham (control) and treated orally with FA (10 mg/kg after CLP) or vehicle (veh). Animals were divided into sham + veh, sham + FA, CLP + veh and CLP + FA groups. Twenty-four hours after surgery, the hippocampus and prefrontal cortex were obtained and assayed for levels of blood brain barrier (BBB) permeability, nitrite/nitrate concentration, myeloperoxidase (MPO) activity, thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. Survival was performed during 10 days after surgery and memory was evaluated. FA reduced BBB permeability, MPO activity in hippocampus and pre frontal cortex in 24 h and lipid peroxidation in hippocampus and improves the survival rate after sepsis. Long term cognitive improvement was verified with FA in septic rats compared with CLP + veh. Our data demonstrates that FA reduces the memory impairment in 10 days after sepsis and mortality in part by decreasing BBB permeability and oxidative stress parameters in the brain.

Limits of the Glasgow Coma Scale When Assessing for Sepsis in Allogeneic Hematopoietic Cell Transplant Recipients.

BACKGROUND: The well-documented association between acute mental status changes and sepsis development and progression makes acute mental status an attractive factor for sepsis screening tools. However, the usefulness of acute mental status within these criteria is limited to the frequency and accuracy of its capture. The Glasgow Coma Scale (GCS) score-the acute mental status indicator in many clinical sepsis criteria-is infrequently captured among allogeneic hematopoietic cell transplant recipients with suspected infections, and its ability to serve as an indicator of acute mental status among this high-risk population is unknown. OBJECTIVE: We evaluated the GCS score as an indicator of acute mental status during the 24 hours after suspected infection onset among allogeneic hematopoietic cell transplant recipients. METHODS: Using data from the first 100 days posttransplant for patients transplanted at a single center between September 2010 and July 2017, we evaluated the GCS score as an indicator of documented acute mental status during the 24 hours after suspected infection onset. From all inpatients with suspected infections, we randomly selected a cohort based on previously published estimates of GCS score frequency among hematopoietic cell transplant recipients with suspected infections and performed chart review to ascertain documentation of clinical acute mental status within the 24 hours after suspected infection onset. RESULTS: A total of 773 patients had ≥1 suspected infections and experienced 1,655 suspected infections during follow-up-625 of which had an accompanying GCS score. Among the randomly selected cohort of 100 persons with suspected infection, 28 were accompanied with documented acute mental status, including 18 without a recorded GCS. In relation to documented acute mental status, the GCS had moderate to high sensitivity and high specificity. DISCUSSION: These data indicate that, among allogeneic hematopoietic cell transplant recipients with suspected infections, the GCS scores are infrequently collected and have a moderate sensitivity. If sepsis screening tools inclusive of acute mental status changes are to be used, nursing teams need to increase measurement of GCS scores among high sepsis risk patients or identify a standard alternative indicator.

Trajectories of depression in sepsis survivors: an observational cohort study.

BACKGROUND: Advances in critical care medicine have led to a growing number of critical illness survivors. A considerable part of them suffers from long-term sequelae, also known as post-intensive care syndrome. Among these, depressive symptoms are frequently observed. Depressive symptom trajectories and associated factors of critical illness survivors have rarely been investigated. Study objective was to explore and compare different trajectories of depressive symptoms in sepsis survivors over 1 year after discharge from ICU. METHODS: Data of a randomized controlled trial on long-term post-sepsis care were analyzed post hoc. Depressive symptoms were collected at 1, 6 and 12 months post-ICU discharge using the Major Depression Inventory (MDI), among others. Statistical analyses comprised descriptive analysis, univariate and multivariate, linear and logistic regression models and Growth Mixture Modeling. RESULTS: A total of 224 patients were included into this analysis. We identified three latent classes of depressive symptom trajectories: Over the course of 1 year, 152 patients recovered from mild symptoms, 27 patients showed severe persistent symptoms, and 45 patients recovered from severe symptoms. MDI sum scores significantly differed between the three classes of depressive symptom trajectories at 1 and 6 months after ICU discharge (p < 0.024 and p < 0.001, respectively). Compared with other classes, patients with the mild recovered trajectory showed lower levels of chronic pain (median sum score of 43.3 vs. 60.0/53.3 on the Graded Chronic Pain Scale, p < 0.010) and posttraumatic stress (4.6% with a sum score of ≥ 35 on the Posttraumatic Stress Scale 10 vs. 48.1%/33.3%, p < 0.003); and higher levels of health-related quality of life (HRQOL) using the Short Form-36 scale within 1 month after ICU discharge (p < 0.035). CONCLUSIONS: In the first year after discharge from ICU, sepsis survivors showed three different trajectories of depressive symptoms. Course and severity of depressive symptoms were associated with chronic pain, posttraumatic stress and reduced HRQOL at discharge from ICU. Regular screening of sepsis survivors on symptoms of depression, chronic pain and posttraumatic stress within 1 year after ICU may be considered. Trial registration ISRCTN, ISRCTN 61744782. Registered April 19, 2011-Retrospectively registered, http://www.isrctn.com/ISRCTN61744782 .

Depression and Long-Term Survival Among South Korean Sepsis Survivors: A Nationwide Cohort Study From 2011 to 2014.

OBJECTIVES: We investigated the prevalence of pre- and postsepsis depression and examined the association between diagnosis of pre- and postsepsis depression and 5-year all-cause mortality among survivors of sepsis. DESIGN: A population-based cohort study. SETTING: Data were obtained from the National Health Insurance Service database in South Korea. PATIENTS: Sepsis survivors were defined as those who were admitted with a main diagnosis of sepsis or septic shock and had survived for over 365 days. MEASUREMENTS AND MAIN RESULTS: Sepsis survivors who were diagnosed with depression before sepsis were defined as the presepsis depression group, whereas those who had no history of depression but were newly diagnosed with depression within 1 year of diagnosis of sepsis were defined as the postsepsis depression group. All other participants comprised the control group. A total of 45,826 sepsis survivors were included in the final analysis. Among the survivors, 1,105 (2.4%) were in the postsepsis depression group, whereas 9,626 (21.0%) were in the presepsis depression group. The 5-year all-cause mortality rate in the pre- and postsepsis depression group was 44.1% and 46.2%, whereas that in the control group was 30.4%. Multivariable Cox regression modeling revealed that the risk of 5-year all-cause mortality rate in the postsepsis depression group was 1.29-fold (hazard ratio = 1.29; 95% CI = 1.18-1.41; p < 0.001) higher than that of the control group, whereas the presepsis depression group was not significantly associated with 5-year all-cause mortality (p = 0.509). CONCLUSIONS: Among sepsis survivors in South Korea, 2.4%% were newly diagnosed with depression within 1 year after their sepsis diagnosis. In addition, postsepsis depression was independently associated with higher 5-year all-cause mortality among sepsis survivors. Our results suggest that patients with a history of sepsis and associated depression may be a high-risk group that interventions may be directed toward.

Trajectory of Cognitive Decline After Sepsis.

OBJECTIVES: Cognitive impairment is an important consequence of sepsis. We sought to determine long-term trajectories of cognitive function after sepsis. DESIGN: Prospective study of the Reasons for Geographic and Racial Differences in Stroke cohort. SETTING: United States. PATIENTS: Twenty-one thousand eight-hundred twenty-three participants greater than or equal to 45 years, mean (sd) age 64.3 (9.2) years at first cognitive assessment, 30.9% men, and 27.1% Black. MEASUREMENTS AND MAIN RESULTS: The main exposure was time-dependent sepsis hospitalization. The primary outcome was global cognitive function (Six-Item Screener range, 0-6). Secondary outcomes were incident cognitive impairment (Six-Item Screener score ≤ 4 [impaired] vs ≥5 [unimpaired]), new learning (Consortium to Establish a Registry for Alzheimer Disease Word List Learning range, 0-30), verbal memory (word list delayed recall range, 0-10), and executive function/semantic fluency (animal fluency test range, ≥ 30). Over a median follow-up of 10 years (interquartile range, 6-12 yr), 840 (3.8%) experienced sepsis (incidence 282 per 1,000 person-years). Sepsis was associated with faster long-term declines in Six-Item Screener (-0.02 points per year faster [95% CI, -0.01 to -0.03]; p < 0.001) and faster long-term rates of incident cognitive impairment (odds ratio 1.08 per year [95% CI, 1.02-1.15]; p = 0.008) compared with presepsis slopes. Although cognitive function acutely changed after sepsis (0.05 points [95% CI, 0.01-0.09]; p = 0.01), the odds of acute cognitive impairment (Six-Item Screener ≤ 4) immediately after sepsis was not significant (odds ratio, 0.81 [95% CI, 0.63-1.06]; p = 0.12). Sepsis hospitalization was not associated with acute changes or faster declines in word list learning, word list delayed recall, or animal fluency test. CONCLUSIONS: Sepsis is associated with accelerated long-term decline in global cognitive function.

What Animal Models Can Tell Us About Long-Term Psychiatric Symptoms in Sepsis Survivors: a Systematic Review.

Lower sepsis mortality rates imply that more patients are discharged from the hospital, but sepsis survivors often experience sequelae, such as functional disability, cognitive impairment, and psychiatric morbidity. Nevertheless, the mechanisms underlying these long-term disabilities are not fully understood. Considering the extensive use of animal models in the study of the pathogenesis of neuropsychiatric disorders, it seems adopting this approach to improve our knowledge of postseptic psychiatric symptoms is a logical approach. With the purpose of gathering and summarizing the main findings of studies using animal models of sepsis-induced psychiatric symptoms, we performed a systematic review of the literature on this topic. Thus, 140 references were reviewed, and most of the published studies suggested a time-dependent recovery from behavior alterations, despite the fact that some molecular alterations persist in the brain. This review reveals that animal models can be used to understand the mechanisms that underlie anxiety and depression in animals recovering from sepsis.

[Mental Distress and Resilience in Severe Somatic Diseases: An Analysis of Dyadic Relations]. / Psychische Belastung und Resilienz im Rahmen schwerer körperlicher Erkrankungen: eine Analyse dyadischer Zusammenhänge.

AIMS: In this article, we present 3 studies examining patients with current or previous severe physical illness and their partners with respect to dyadic concordance, gender and role differences in mental distress and resilience. METHODS: Study 1 included 55 patients and their partners on average 4.5 years after severe sepsis. Study 2 involved 49 patients with lung cancer, predominantly in advanced stage with metastases, and their partners. In study 3, 69 cancer patients with various tumor entities and tumor stages undergoing additional outpatient homeopathic treatment as well as their partners were examined. All studies used the Hospital Anxiety and Depression Scale (HADS) to measure mental distress and the short version of the Resilience Scale RS-13 to assess resilience as a personality trait. Results were meta-analytically pooled across the 3 studies. RESULTS: We found dyadic concordances between patient and partner in anxiety (r=0.29 [0.06; 0.48], I2=55%) and depression (r=0.44 [0.31; 0.55], I2=0%), but not in resilience. Gender differences emerged consistently across all three studies, both female patients and partners showed more severe anxiety symptoms than males (d=0.58 [0.26; 0.91], I2=0% for patients; d=0.53 [- 0.06; 1.12], I2=69% for partners). Results were heterogeneous for gender differences in depression and for role differences. Higher resilience scores were associated with lower mental distress both in patients and partners. There is some evidence that resilience has a protective effect for mental distress of the spouse. DISCUSSION AND CONCLUSION: Based on the results on dyadic concordance between patients and partners in mental distress somatic diseases should always be considered from a systemic perspective. Mental distress of both patients and partners requires special attention in psychosocial support, and partnership resources should be taken into account for coping with the disease.

S100A9 Upregulation Contributes to Learning and Memory Impairments by Promoting Microglia M1 Polarization in Sepsis Survivor Mice.

Sepsis-associated encephalopathy (SAE) is a clinical syndrome of brain dysfunction secondary to sepsis, which is characterized by long-term neurocognitive deficits such as memory, attention, and executive dysfunction. However, the mechanisms underlying SAE remain unclear. By using transcriptome sequencing approach, we showed that hippocampal S100A9 was significantly increased in sepsis induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge. Thus, we used S100A9 inhibitor Paquinimod to study the role of S100A9 in cognitive impairments in CLP-induced and LPS-induced mice models of SAE. Sepsis survivor mice underwent behavioral tests or the hippocampal tissues subjected to Western blotting, real-time quantitative PCR, and immunohistochemistry. Our results showed that CLP-induced and LPS-induced memory impairments were accompanied with increased expressions of hippocampal microglia Iba1 and CD86 (M1 markers), but reduced expression of Arg1 (M2 marker). Notably, S100A9 inhibition significantly improved the survival rate and learning and memory impairments in sepsis survivors, with a shift from M1 to M2 phenotype. Taken together, our study suggests that S100A9 upregulation might contribute to learning and memory impairments by promoting microglia M1 polarization in sepsis survivors, whereas S100A9 inhibition might provide a potential therapeutic target for SAE.

Emergency nurses' experiences of the implementation of early goal directed fluid resuscitation therapy in the management of sepsis: a qualitative study.

BACKGROUND: Severe sepsis can lead to organ failure and death if immediate treatment, such as intravenous fluids and antibiotics, are not commenced within the first hour. Time - critical initiation of intravenous fluids which in other words is early goal directed fluid resuscitation has not always been given its clinical priority. This qualitative study aimed at exploring the experiences of emergency nurses initiating early goal directed fluid resuscitation in patients with sepsis. METHODS: Using an exploratory approach, face - to - face semi - structured interviews were conducted with ten registered nurses working in emergency departments across New South Wales, Australia. Thematic analysis was used for data analysis. FINDINGS: Participants described various factors that inhibited the timely initiation of early goal directed fluid resuscitation, some clinical practice challenges, and strategies to improve nursing practice. Most participants, particularly those practicing as Clinical Initiatives Nurses suggested the incorporation of nurse initiated early goal directed fluid resuscitation for patients with sepsis as part of their scope of practice. CONCLUSION: Our findings identified several barriers that inhibit effective nurse - initiated early goal directed fluid resuscitation. It is anticipated that these findings will provide validation for the re-evaluation of the existing protocols and practice guidelines to increase the scope of practice of emergency nurses initiating early goal directed fluid resuscitation.

Effects of S100B neutralization on the long-term cognitive impairment and neuroinflammatory response in an animal model of sepsis.

The nervous system is one of the first systems to be affected during sepsis. Sepsis not only has a high risk of mortality, but could also lead to cerebral dysfunction and cognitive impairment in long-term survival patients. The receptor for advanced glycation end products (RAGE) can interact with several ligands, and its activation triggers a series of cell signaling events, resulting in the hyperinflammatory condition related to sepsis. Recent studies show that elevated levels of S100B (RAGE ligand) are associated with the pathophysiology of neurodegenerative disorders. They also participate in inflammatory brain diseases and may lead to an increased activation of microglia and astrocytes, leading to neuronal death. This study aimed to determine the effect of S100B inhibition on the neuroinflammatory response in sepsis. Sepsis was induced in Wistar rats by cecal ligation and perforation (CLP). There were three groups: Sham, CLP, and CLP +10 µg/kg of monoclonal antibody (Anti-S100B) administered intracerebroventricularly. The animals were killed 30 days after sepsis following behavioral evaluation by open field, novel object recognition, and splash test. The hippocampus, prefrontal cortex, and amydgala were used for the determination of S100B and RAGE proteins by western blotting and for the evaluation of cytokine levels and verification of the number of microglial cells by immunohistochemistry. On day 30, both the Sham and CLP + anti-S100B groups were capable of recovering the habitual memory in the open field task. Regarding novel object recognition, Sham and CLP + anti-S100B groups increased the recognition index during the test session in comparison to the training session. There was a significant increase in the time of grooming in CLP + anti-S100B in comparison to the CLP group. There was a modulation of cytokine levels and immunohistochemistry showed that the CLP + anti-S100B group had a decrease in the number of microglial cells only in the hippocampus. These results helped to understand the role of S100B protein in the pathophysiology of sepsis-associated encephalopathy and could be helpful to further experimental studies regarding this subject.

INT-777 prevents cognitive impairment by activating Takeda G protein-coupled receptor 5 (TGR5) and attenuating neuroinflammation via cAMP/ PKA/ CREB signaling axis in a rat model of sepsis.

BACKGROUND: Survivors of sepsis must often endure significant cognitive and behavioral impairments after discharge, but research on the relevant mechanisms and interventions remains lacking. TGR5, a member of the class A GPCR family, plays an important role in many physiological processes, and recent studies have shown that agonists of TGR5 show neuroprotective effects in a variety of neurological disorders. To date, no studies have assessed the effects of TGR5 on neuroinflammatory, cognitive, or behavioral changes in sepsis models. METHODS: A total of 267 eight-week-old male Sprague-Dawley rats were used in this study. Sepsis was induced via cecal ligation and puncture (CLP). All animals received volume resuscitation. The rats were given TGR5 CRISPR oligonucleotide intracerebroventricularly 48 h before CLP surgery. INT-777 was administered intranasally 1 h after CLP, and the cAMP inhibitor, SQ22536, was administered intracerebroventricularly 1 h after CLP. Survival rate, bodyweight change, and clinical scores were assessed, and neurobehavioral tests, western blot, and immunofluorescence staining were performed. The cognitive function of rats was measured using the Morris water maze during 15-20 days after CLP. RESULTS: The expression of TGR5 in the rat hippocampus was upregulated, and peaked at 3 days after CLP. The survival rate of rats after CLP was less than 50%, and the growth rate, in terms of weight, was significantly decreased. While INT-777 treatment did not improve these changes, the treatment did reduce the clinical scores of rats at 24 h after CLP. On day 15 and later, the surviving mice completed a series of behavioral tests. CLP rats showed spatial and memory deficits and anxiety-like behaviors, but INT-777 treatment significantly improved these effects. Mechanistically, immunofluorescence analysis showed that INT-777 treatment reduced the number of microglia in the hippocampus, neutrophilic infiltration, and the expression of inflammatory factors after CLP in rats. Moreover, INT-777 treatment significantly increased the expression of TGR5, cAMP, p-PKA, and p-CREB, but downregulated the expression of IL-1ß, IL-6, and TNF-α. CRISPR-mediated TGR5 knockdown and SQ22536 treatment abolished the neuroprotective effects of TGR5 activation after CLP. CONCLUSION: This study demonstrates that INT-777 treatment reduced neuroinflammation and microglial cell activation, but improved cognitive impairment in the experimental sepsis rats. TGR5 has translational potential as a therapeutic target to improve neurological outcomes in sepsis survivors.

pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors.

Although more patients survive sepsis and are increasingly discharged from the hospital, they often experience long-term cognitive and psychological impairment with significant socioeconomic impact. However, the pathophysiological mechanisms have not been fully elucidated. In the present study, we showed that LPS induced long-term neurobehavioral abnormities, as reflected by significantly decreased freezing time to context and sucrose preference. Using a high-throughput quantitative proteomic screen, we showed that phosphorylation of synaptic GTPase-activating protein 1 (pSynGAP1) was identified as the hub of synaptic plasticity and was significantly decreased following LPS exposure. This decreased pSynGAP was associated with significantly lower theta and gamma oscillations in the CA1 of the hippocampus. Notably, restoration of pSynGAP1 by roscovitine was able to reverse most of these abnormities. Taken together, our study suggested that pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might play a critical role in long-term neurobehavioral abnormities of sepsis survivors.

Older Sepsis Survivors Suffer Persistent Disability Burden and Poor Long-Term Survival.

OBJECTIVES: Sepsis has been called a "disease of the elderly," and as in-hospital mortality has decreased, more sepsis survivors are progressing into poorly characterized long-term outcomes. The purpose of this study was to describe the current epidemiology of sepsis in older adults compared with middle-aged and young adults. DESIGN: Prospective longitudinal study with young (≤45 years), middle-aged (46-64 years), and older (≥65 years) patient groups. SETTING: University tertiary medical center. PARTICIPANTS: A total of 328 adult surgical intensive care unit (ICU) sepsis patients. MEASUREMENTS: Patients were characterized by (1) baseline demographics and predisposition, (2) septic event, (3) hospital outcomes and discharge disposition, (4) 12-month mortality, and (5) Zubrod Performance Status, physical function (Short Physical Performance Battery and handgrip strength), and cognitive function (Hopkins Verbal Learning Test, Controlled Oral Word Association, and Mini-Mental Status Examination) at 3-, 6-, and 12-month follow-up. Loss to follow-up was due to death (in 68), consent withdrawal (in 32), and illness and scheduling difficulties: month 3 (in 51), month 6 (in 29), and month 12 (in 20). RESULTS: Compared with young and middle-aged patients, older patients had (1) significantly more comorbidities at presentation (eg, chronic renal disease 6% vs 12% vs 21%), intra-abdominal infections (14% vs 25% vs 37%), septic shock (12% vs 25% vs 36%), and organ dysfunctions; (2) higher 30-day mortality (6% vs 4% vs 17%) and fewer ICU-free days (median = 25 vs 23 vs 20); (3) more progression into chronic critical illness (22% vs 34% vs 42%) with higher poor disposition discharge to non-home destinations (19% vs 40% vs 62%); (4) worse 12-month mortality (11% vs 14% vs 33%); and (5) poorer Zubrod Performance Status and objectively measured physical and cognitive functions with only slight improvement over 12-month follow-up. CONCLUSION: Compared with younger patients, older sepsis survivors suffer both a higher persistent disability burden and 12-month mortality.

Dyadic post-traumatic stress after intensive care: Case report of a sepsis patient and his wife.

INTRODUCTION: Following intensive care treatment, patients and thier spouse often report traumatic memories that are frequently associated with post-traumatic stress symptoms. In this case report, we describe the case of a sepsis survivor and his wife who both suffered concurrently from intensive care associated post-traumatic stress symptoms as long-term sequelae. Both were treated with internet-based cognitive-behaviuoral writing therapy (iCBT) for post-traumatic stress disorder (PTSD) after intensive care. METHODS: Traumatic memories recalled during exposure in sensu as part of iCBT are described. Outcome data measured before, during and after psychotherapeutic treatment were analyzed. FINDINGS: Both, the patient and his wife showed characteristic symptoms of PTSD three years after discharge from the intensive care unit (ICU) comprising of intrusions, negative emotions, and hyperarousal. They reported unpleasant ICU memories from a patient's and relative's perspective, respectively. In both, the patient and his wife, a decline of symptoms with respect to all outcome measures during the course of iCBT from pre-treatment to three-month follow-up was observed. CONCLUSION: Experiences of critical illness and intensive care can lead to post-traumatic stress in patients and their partners. Hence, it may be useful to offer mental health screening and psychotherapeutic treatment options to both ICU patients and their partners.

Sickness Behavior Score Is Associated with Neuroinflammation and Late Behavioral Changes in Polymicrobial Sepsis Animal Model.

The use of reliable scores is a constant development in critical illness. According to Sepsis-3 consensus, the use of Sequential Organ Failure Assessment (SOFA) score of 2 or more is associated with a higher mortality of sepsis patients. In experimental research, due murine animal model limitations, the use of a score systems can be an alternative to assess sepsis severity. In this work, we suggest a sickness behavior score (SBS) that uses physiological variables to assess sepsis severity and mortality. Animals were evaluated daily by the presence of six indicators of sickness behavior: temperature alteration, preference of water/sucrose, liquid intake, food intake, body weight, and movimentation. Male adult Wistar rats were evaluated daily after sepsis induction by cecal ligation and puncture (CLP) or laparotomy only (sham) for determination of SBS. Oxidative stress, IL-6, and HPA axis markers (corticosterone and adrenal gland weight) were evaluated 24 h after CLP to determine the correlation with the acute SBS and neuroinflammation. Also, BDNF and four cognitive behavioral tests were correlated with the chronic SBS, i.e., sum of 8 days after surgery. In result, septic rats presented higher SBS than sham animals. Sepsis severity markers were associated with acute and chronic SBS. Also, SBS was negative correlated with the cognitive tests. In conclusion, SBS shows to be reliable score to predict sepsis severity and mortality. The use of score system provides the analysis of global sickness behavior, beyond evaluation of each parameter individually.