Macrophage activation markers are associated with infection and mortality in patients with acute liver failure.

BACKGROUND AND AIMS: Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration. METHODS: Patients ALF from the United States Acute Liver Failure Study Group (USALFSG, n = 224) and King's College Hospital (n = 40) together with healthy controls (HC, n = 50) were recruited. Serum from early (Days 1-3) and late (>Day 3) time points were analysed for MAMs by enzyme-linked immunosorbent assay correlated to markers of illness severity and 21-day spontaneous survival. Surface expression phenotyping was performed via Flow Cytometry on CD14+ monocytes. RESULTS: All MAMs serum concentrations were significantly higher in ALF compared to controls (p < .0001). sCD206 concentration was higher in early and late stages of the disease in patients with bacteraemia (p = .002) and infection in general (p = .006). In MELD-adjusted multivariate modelling, sCD206 and sCD163 were independently associated with mortality. CD14+ monocyte expression of CD206 (p < .001) was higher in patients with ALF compared with controls and correlated with SOFA score (p = .018). sCD206 was independently validated as a predictor of infection in an external cohort. CONCLUSIONS: sCD206 is increased in serum of ALF patients with infections and poor outcome and is upregulated on CD14+ monocytes. Later measurements of sCD163 and sCD206 during the evolution of ALF have potential as mechanistic predictors of mortality. sCD206 should be explored as a biomarker of sepsis and mortality in ALF.

Global trends in BMS research using publication as a surrogate marker: A 30 year review.

Obesity is a global pandemic with increasing prevalence and long-term negative health outcomes. Bariatric metabolic surgery (BMS) is the most effective treatment option for achieving long-term weight loss. A systematic search was performed from 1990 to 2020 of BMS procedures using standardised groups. Data were collected on operation type reported, country and continent of publication. North America and Europe were the leading contributors to global publications in BMS, producing 41.3 % (n = 4931) and 37.1 % (n = 4436) of publications respectively, with increasing publications from Asia. Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) were the most studied procedure types with number of publications continuing to increase over time. A plateau and downward trend was seen for Laparoscopic Adjustable Gastric Band (LAGB) publication from 2015 to 2019. An increase in emerging/experimental techniques over the past decade is observed.

Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure.

BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening disease characterised by high-grade inflammation and immunoparesis, which is associated with a high incidence of death from sepsis. Herein, we aimed to describe the metabolic dysregulation in ALF and determine whether systemic immune responses are modulated via the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidylcholinic acid (LPA) pathway. METHODS: Ninety-six individuals with ALF, 104 with cirrhosis, 31 with sepsis and 71 healthy controls (HCs) were recruited. Pathways of interest were identified by multivariate statistical analysis of proton nuclear magnetic resonance spectroscopy and untargeted ultraperformance liquid chromatography-mass spectrometry-based lipidomics. A targeted metabolomics panel was used for validation. Peripheral blood mononuclear cells were cultured with LPA 16:0, 18:0, 18:1, and their immune checkpoint surface expression was assessed by flow cytometry. Transcript-level expression of the LPA receptor (LPAR) in monocytes was investigated and the effect of LPAR antagonism was also examined in vitro. RESULTS: LPC 16:0 was highly discriminant between ALF and HC. There was an increase in ATX and LPA in individuals with ALF compared to HCs and those with sepsis. LPCs 16:0, 18:0 and 18:1 were reduced in individuals with ALF and were associated with a poor prognosis. Treatment of monocytes with LPA 16:0 increased their PD-L1 expression and reduced CD155, CD163, MerTK levels, without affecting immune checkpoints on T and NK/CD56+T cells. LPAR1 and 3 antagonism in culture reversed the effect of LPA on monocyte expression of MerTK and CD163. MerTK and CD163, but not LPAR genes, were differentially expressed and upregulated in monocytes from individuals with ALF compared to controls. CONCLUSION: Reduced LPC levels are biomarkers of poor prognosis in individuals with ALF. The LPC-ATX-LPA axis appears to modulate innate immune response in ALF via LPAR1 and LPAR3. Further investigations are required to identify novel therapeutic agents targeting these receptors. IMPACT AND IMPLICATIONS: We identified a metabolic signature of acute liver failure (ALF) and investigated the immunometabolic role of the lysophosphatidylcholine-autotaxin-lysophosphatidylcholinic acid pathway, with the aim of finding a mechanistic explanation for monocyte behaviour and identifying possible therapeutic targets (to modulate the systemic immune response in ALF). At present, no selective immune-based therapies exist. We were able to modulate the phenotype of monocytes in vitro and aim to extend these findings to murine models of ALF as a next step. Future therapies may be based on metabolic modulation; thus, the role of specific lipids in this pathway require elucidation and the relative merits of autotaxin inhibition, lysophosphatidylcholinic acid receptor blockade or lipid-based therapies need to be determined. Our findings begin to bridge this knowledge gap and the methods used herein could be useful in identifying therapeutic targets as part of an experimental medicine approach.

Immunometabolic analysis shows a distinct cyto-metabotype in Covid-19 compared to sepsis from other causes.

Background: In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19. Aims: Define the immunometabolic signature of Covid-19. Methods: 65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis. Results: Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-É£ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls. Conclusions: In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-É£ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-É£ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.

Systematic review and meta-analysis of the diagnostic accuracy of procalcitonin for post-operative sepsis/infection in liver transplantation.

BACKGROUND: Post-operative infection is a major cause of morbidity and mortality in Liver Transplantation (LT). Early diagnosis and antimicrobial treatment improves outcomes and ruling out sepsis aids immunosuppression decisions. Procalcitonin (PCT) has recently become part of such decision making in COVID-19 pneumonia but its role in LT is not established. We assessed the diagnostic accuracy of PCT as a diagnostic biomarker for infection or sepsis following LT. METHODS: A systematic search was conducted for studies reporting diagnostic performance of PCT for infection/sepsis following LT. Studies were assessed for reporting of diagnostic accuracy, relevance and quality. RESULTS: Eight studies with 363 participants reported data on the diagnostic accuracy of PCT, with pooled sensitivity, specificity, diagnostic odds ratio and summary receiver operator curve of 70% (95% CI 62-78), 77% (95% CI 73-83), 15.82 (95% CI 5.82-43.12) and 0.871 respectively. There was variability in the timing of sampling (post-operative day 1-8) and range of cut-off values (0.48 to 42.8 ng/mL). Heterogeneity was reduced when only studies with adult LT recipients were considered. CONCLUSIONS: PCT performs moderately well as a diagnostic test for postoperative infection/sepsis following LT. This marker is more suited for use in adult LT populations.

Streptococcus anginosus is associated with postoperative intraabdominal collections in appendicitis.

AIM OF STUDY: Streptococcus anginosus group (SA) (formerly Streptococcus milleri) are pathogens recognised to have a high risk of postoperative collection in appendicitis, although little data exist specifically in children. We performed a retrospective review of all microbiological data from appendicectomies to assess whether there was an association in children. METHODS: A retrospective case note review of patients admitted to a paediatric tertiary centre coded for appendicitis from January 2015 to October 2016 was completed. Initial length of stay (LOS), cumulative hospital days, histology, microbiology, and radiology reports were recorded. The postoperative antibiotic regimen was based on surgeon's choice and not standardised. MAIN RESULTS: 231 children were identified, and 18 were excluded. In the remainder, 169 (78.9%) had positive microbiology cultures, and of these 45 were positive for SA (26.6%). There was no significant variation in monthly incidence (P=0.58). Patients with SA+ve cultures were associated with complicated appendicitis on histology (P=0.01), longer LOS and cumulative hospital days (P=0.001), and increased likelihood of developing postoperative collections (P=0.001). The relative risk of developing a postoperative collection with SA+ve cultures was 2.40. There was no difference in time to presentation, histology, or intervention between SA and non-SA patients who developed collections. All SA cultures were sensitive to penicillin and erythromycin. CONCLUSION: SA cultured from intraoperative serial swabs is associated with an increased risk of developing postoperative collection (2.40). Using this information with standardisation of antimicrobial management may reduce the rate of postoperative complications in paediatric appendicitis. LEVEL OF EVIDENCE: Level II prognosis study.

An audit of traumatic brain injury (TBI) in a busy developing-world trauma service exposes a significant deficit in resources available to manage severe TBI.

BACKGROUND: Traumatic brain injury (TBI) affects large numbers of patients, both adults and children, and significant resources are needed to manage it. OBJECTIVE: To determine the burden of TBI and the adequacy of available resources to manage in the Pietermaritzburg Metropolitan Trauma Service (PMTS). METHODS: All patients with a TBI were identified from the hybrid electronic medical registry at Grey's and Edendale hospitals in Pietermaritzburg (PMB), KwaZulu-Natal, South Africa. Patients were classified according to severity of head injury and age. We defined mild TBI as Glasgow coma scale (GCS) 13 - 15, moderate as GCS 9 - 12, and severe as GCS ≤8, in accordance with international standards. We divided the cohort according to ages 0 - 5 years, 6 - 10 years, >10 - 17 years and adults (>17 years). RESULTS: From January 2012 to December 2014, 3 301 patients were treated for TBI in PMB. The mean age was 27.4 (standard deviation 14.4) years. There were 2 632 males and 564 females. There were 2 540 mild, 326 moderate, and 329 severe TBI admissions during the period under review. A total of 139 (4.2%) patients died. A total of 242 (7.3%) patients were admitted to the intensive care unit (ICU), of whom 137 (57.0%) had a GCS of ≤9. Only 27.0% of patients with a GCS of ≤9 were admitted to the ICU. CONCLUSION: There is a significant burden of TBI managed by the PMTS. Critical care resources available to manage patients with TBI are inadequate.

Civilian cerebral gunshot wounds: a South African experience.

BACKGROUND: Cerebral gunshot wounds represent one of the most lethal forms of traumatic brain injury, but there is a paucity of literature on the topic, especially from the developing world. We reviewed our experience and describe the spectrum and outcome of civilian cerebral gunshot wounds in a major metropolitan trauma centre in South Africa. METHODS: This was a retrospective study of all patients with isolated cerebral gunshot wounds managed by the Pietermaritzburg Metropolitan Trauma Service over a 5-year period from 2010 to 2014. RESULTS: One hundred and two patients were included, 92% (94/102) were male and the mean age was 29 years. Fifty-four per cent (55/102) of all patients were from urban areas. The mean time from injury to arrival was 6 h (standard deviation: 5) for urban patients and 15 h (standard deviation: 5.2) for rural patients (P < 0.001). Ninety-four per cent (94/102) of all injuries were related to interpersonal violence and involved low velocity firearms. Twenty per cent of all patients (20/102) had a Glasgow Coma Scale 3-8, 20% (20/102) 9-12 and 61% (61/102) 12-15. All 102 patients underwent computed tomography scans. Thirty per cent (31/102) required neurosurgical interventions. The overall mortality rate was 22% (22/102). There was a significant difference in mortality between urban and rural patients (9% versus 36%, P < 0.001). CONCLUSIONS: Cerebral gunshot wounds are associated with significant mortality and protracted delay to definitive care is common in our setting. Those who survive the delayed transfer to definitive care generally do well and have reasonably good clinical outcomes.

Implementation of a combined Cardiopulmonary Resuscitation and Treatment Escalation Plan document in a District General Hospital.

Documentation of appropriate escalation of treatment was identified as a problem for junior doctors and Critical Care Outreach Nurses at Musgrove Park Hospital. An audit of resuscitation and escalation documentation of all wards found that of the patients who were not for Cardiopulmonary resuscitation (and therefore not for full escalation of care), 78.4% had no documentation of the appropriate level of escalation of treatment should they deteriorate. The majority of junior doctors had experienced cases where they felt that inappropriate treatment had been given, where no escalation plan was documented. Using several Plan, Do, Study, Act (PDSA) cycles, drawing tools used in other trusts and departments, and the views of clinicians, we developed a treatment escalation plan (TEP) tool, to be included in the resuscitation form. This included consideration of referral to critical care, ward based non-invasive ventilation, and appropriate use of intravenous or oral antibiotics. This then prompted the responsible clinician to consider and document appropriate escalation of treatment. The CPR-TEP form was trialed using a quasi-experiment design allowing the aim to be tested using two groups - intervention and control. All patients in the intervention group were not for CPR and therefore had their TEP-CPR form filled in fully (n=68). The control group consisted of patients who were not for CPR but who did not have a TEP form filled in (n=36). The appropriateness of OOH (out of hours) treatment in those patients who experienced clinical deterioration was judged by questionnaire-based feedback from the in-hours team the following morning. Levels of inappropriate treatment between the two groups were compared to test the aim. At the end of the study period, questionnaire feedback indicated that 11.1% of patients in the group with the new CPR-TEP document had received inappropriate OOH care compared to 44.4% of patients in the group without the document. Using the TEP alongside resuscitation documentation prompts the responsible clinician to consistently consider and document the appropriate escalation of care for their patient, improving communication with the out of hours team and appropriate escalation of care in the event of patient deterioration.