Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Specifically, the regulation and the impact of the latter have become better understood in which the highly catabolic status during sepsis and its similarity with starvation responses appear to be essential in the poor prognosis in sepsis. It seems logical that new interventions based on the recognition of new therapeutic targets in the key metabolic pathways should be developed and may have a good chance to penetrate to the bedside. In this review, we concentrate on the pathological changes in metabolism, observed during sepsis, and the presumed underlying mechanisms, with a focus on the level of the organism and the interplay between different organ systems.

https://www.embopress.org/doi/pdf/10.15252/emmm.201708712

Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?

Specific and Complex Reprogramming of Cellular Metabolism in Myeloid Cells during Innate Immune Responses

Sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection”. Contrary to the older definitions, the current one not only focuses on inflammation, but points to systemic disturbances in homeostasis, including metabolism. Sepsis leads to sepsis-induced dysfunction and mitochondrial damage, which is suggested as a major cause of cell metabolism disorders in these patients. The changes affect the metabolism of all macronutrients. The metabolism of all macronutrients is altered. A characteristic change in carbohydrate metabolism is the intensification of glycolysis, which in combination with the failure of entering pyruvate to the tricarboxylic acid cycle increases the formation of lactate. Sepsis also affects lipid metabolism—lipolysis in adipose tissue is upregulated, which leads to an increase in the level of fatty acids and triglycerides in the blood. At the same time, their use is disturbed, which may result in the accumulation of lipids and their toxic metabolites. Changes in the metabolism of ketone bodies and amino acids have also been described. Metabolic disorders in sepsis are an important area of research, both for their potential role as a target for future therapies (metabolic resuscitation) and for optimizing the current treatment, such as clinical nutrition.

/pdf/metabolic-alterations-in-sepsis-3e1jhn4u47.pdf

Metabolic Alterations in Sepsis

Recent trends in analytical methods for the determination of amino acids in biological samples.

In recent years, it has become appreciated that immune cells have different metabolic profiles depending on their activation status. During sepsis, circulating leukocytes go through a hyperinflammatory state, which can be accompanied or followed by defective antimicrobial defenses (also described as immune tolerance or paralysis). In this review, the modulation of different cellular metabolic pathways during sepsis in monocytes and macrophages will be discussed. Glycolysis is studied extensively in sepsis and is up-regulated in hyperinflammatory cells, whereas in immune tolerance, it is often down-regulated. Few data are available on other metabolic pathways in immune cells from patients with sepsis. The pentose phosphate pathway is up-regulated during acute hyperinflammatory responses, whereas fatty acid β-oxidation is increased later during sepsis and is associated with an anti-inflammatory (M2) phenotype of macrophages. Within the amino acid metabolism we will discuss the most studied metabolites. Collectively, these data argue that exploration of the immunometabolic pathways in sepsis is an important area of research, and the targeting of metabolic pathways may represent a promising novel strategy as a therapy of sepsis.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.4MR0216-066R

Cellular metabolism of myeloid cells in sepsis

Objectives The goal of this work was to explore the dynamic concentration profiles of 42 amino acids and the significance of these profiles in relation to sepsis, with the aim of providing guidance for clinical therapies. Methods Thirty-five critically ill patients with sepsis were included. These patients were further divided into sepsis (12 cases) and severe sepsis (23 cases) groups or survivor (20 cases) and non-survivor (15 cases) groups. Serum samples from the patients were collected on days 1, 3, 5, 7, 10, and 14 following intensive care unit (ICU) admission, and the serum concentrations of 42 amino acids were measured. Results The metabolic spectrum of the amino acids changed dramatically in patients with sepsis. As the disease progressed further or with poor prognosis, the levels of the different amino acids gradually increased, decreased, or fluctuated over time. The concentrations of sulfur-containing amino acids (SAAs), especially taurine, decreased significantly as the severity of sepsis worsened or with poor prognosis of the patient. The serum concentrations of SAAs, especially taurine, exhibited weak negative correlations with the Sequential Organ Failure Assessment (SOFA) (r=-0.319) and Acute Physiology and Chronic Health Evaluation (APACHE) II (r=-0.325) scores. The areas under the receiver operating characteristic curves of cystine, taurine, and SAA levels and the SOFA and APACHE II scores, which denoted disease prognosis, were 0.623, 0.674, 0.678, 0.86, and 0.857, respectively. Conclusions Critically ill patients with disorders of amino acid metabolism, especially of SAAs such as cystine and taurine, may provide an indicator of the need for the nutritional support of sepsis in the clinic. Trial registration ClinicalTrial.gov identifier NCT01818830.

/pdf/dynamic-changes-in-amino-acid-concentration-profiles-in-25dfsfpsu3.pdf

Dynamic changes in amino acid concentration profiles in patients with sepsis.

Objective
To explore the influence of environment factors on the migratory birds population with chronic obstructive pulmonary disease (MDCOPD).


Methods
A total of 82 stable MDCOPD patients from Beijing area, who went to Hainan Branch of PLA General Hospital and the People's Hospital of Sanya for treatment between September 2012 and May 2014, were recruited in this study.At Sanya, from October to April of the following year (wintertime), all the patients were evaluated by COPD assessment test (CAT) and modified medical research council (mMRC) questionnaire, and follow-up was performed every 2 months.From May to September (summertime), when the MDCOPD patients came back to Beijing area, the patients were evaluated by CAT and mMRC questionnaire again, and still follow-up was performed every 2 months.The scores of before and after living environment changed were compared.Acute exacerbations or hospitalizations were recorded if any occurred in the patients during the follow up period, and the patients were reevaluated by the two questionnaires 1 month later after they became stable.At the same time, the daily air quality index (AQI) from the national urban air quality publishing platform and the temperature and relative humidity from the local weather network were recorded.


Results
The score of CAT in Sanya was significantly lower than that in Beijing ((20.0±8.0) vs (26.4±7.1) scores, P<0.001); the score of mMRC in Sanya was also significantly lower than Beijing ((1.9±0.8) vs (2.9±0.9) scores, P=0.001). Based on the latest guidelines, the classification of COPD patients changed from D (in Beijing) to C (in Sanya) according to mMRC scores, while the CAT scores from the two cities did not cause the change of classification.The difference of temperature between wintertime of Sanya and summertime of Beijing was not significant ((23.1±4.2) vs (24.3±2.3) ℃, P=0.674); the wintertime's AQI in Sanya was significantly lower than the summertime's AQI in Beijing ((49.4±8.9) vs (113.1±14.2) μg/m3,P<0.001); the relative humidity of wintertime in Sanya was significantly higher than that of summertime in Beijing ((90.6±4.9)% vs ((58.0±10.0)%, P=0.001).


Conclusion
When the MDCOPDs live in the area where has a better air quality and higher relative humidity, their quality of life and activity tolerance can be improved obviously.


Key words: 
Pulmonary disease, chronic obstructive; Environmental pollution; Migration; Score

Influence of environmental factors on the migratory birds population with chronic obstructive pulmonary disease

Lymphocyte apoptosis appears to play an important role in immunodysfunction in sepsis. We investigated the role of miR-223 in cell proliferation and apoptosis to identify potential target downstream proteins in sepsis. We recruited 143 patients with sepsis and 44 healthy controls from the Chinese PLA General Hospital. Flow cytometry was used to sort monocytes, lymphocytes, and neutrophils from fresh peripheral blood. A miR-223 mimic and inhibitor were used for transient transfection of Jurkat T cells. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to assess expression of the miRNAs in cells. Western blot analysis was performed to measure protein expression. We evaluated the cell cycle and apoptosis by using flow cytometry (FCM) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Expression of miR-223 was significantly higher in the survivor group than in the nonsurvivor group. Multiple linear regression analysis revealed that SOFA scores correlated negatively with miR-223 and monocyte counts, with β coefficients (95% CI) of - 0.048 (- 0.077, - 0.019) and - 47.707 (- 83.871, - 11.543), respectively. miR-223 expression also correlated negatively with the percentage of apoptosis in lymphocytes. The rate of apoptosis in the miR-223 mimic group was significantly lower than that of the negative control, with an adverse outcome observed in the miR-223 inhibitor group. We also found that miR-223 enhanced the proliferation of Jurkat T cells and that inhibiting miR-223 had an inhibitory effect on the G1/S transition. We conclude that miR-223 can serve as a protective factor in sepsis by reducing apoptosis and enhancing cell proliferation in lymphocytes by interacting with FOXO1. Potential downstream molecules are HSP60, HSP70, and HTRA.

/pdf/the-protective-role-of-mir-223-in-sepsis-induced-mortality-52lhp4qx3k.pdf

The protective role of miR-223 in sepsis-induced mortality.

Objectives To assess the cost-effectiveness of Paxlovid in reducing severe COVID-19 and its associated morality, and to investigate the affordable price of Paxlovid in China. Materials and methods Using a Markov model, two interventions by Paxlovid prescription (with and without prescription) were compared in terms of COVID-19-related clinical outcomes and economic loss. COVID-related costs were collected from the societal perspective. Effectiveness data were obtained from literature. The primary outcomes were total social cost, disability adjusted life-years (DALYs) and net monetary benefit (NMB). Scenario analyses were performed to investigate the affordable price of Paxlovid in China. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analysis (PSA) were performed to verify the model robustness. Results Compared with the non-Paxlovid cohort, the NMBs of the Paxlovid cohort were only higher in the subgroup of patients aged over 80 years old, regardless of their vaccination status. Our scenario analysis found that, the price ceiling of Paxlovid/box for it to be cost-effective was RMB 8,993 (8,970–9,009) in those aged over 80 years old who were not vaccinated, which is the highest; and was RMB 35 (27–45) in those aged 40–59 years old who were vaccinated, which is the lowest. Sensitivity analyses found that the incremental NMB for the vaccinated people aged over 80 years was most sensitive to the efficacy of Paxlovid and the cost-effectiveness probability of Paxlovid increased with its decreasing price. Conclusion Under the current marketing price of Paxlovid/box (RMB 1,890), using Paxlovid was only cost-effective in people aged over 80 years old regardless of their vaccination status.

/pdf/cost-effectiveness-of-paxlovid-in-reducing-severe-covid-19-24x1wo5m.pdf

Cost-effectiveness of Paxlovid in reducing severe COVID-19 and mortality in China

This meta-analysis was performed to determine the accuracy of procalcitonin (PCT) in predicting mortality in pneumonia patients with different pathogenic features and disease severities. A systematic search of English-language articles was performed using PubMed, Embase, Web of Knowledge and the Cochrane Library to identify studies. The diagnostic value of PCT in predicting prognosis was determined using a bivariate meta-analysis model. The Q-test and I(2) index were used to test heterogeneity. A total of 21 studies comprising 6007 patients were included. An elevated PCT level was a risk factor for death from community-acquired pneumonia (CAP) (risk ratio (RR) 4.38, 95% confidence interval (CI) 2.98-6.43), particularly in patients with a low CURB-65 score. The commonly used cut-off, 0.5 ng/mL, had low sensitivity (SEN) and was not able to identify patients at high risk of dying. Furthermore, the PCT assay with functional SEN <0.1 ng/mL was necessary to predict mortality in CAP in the clinic. For critically ill patients, an elevated PCT level was associated with an increased risk of mortality (RR 4.18, 95% CI: 3.19-5.48). The prognostic performance was nearly equal between patients with ventilator-associated pneumonia (VAP) and patients with CAP.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/resp.12704

Prognostic value of procalcitonin in pneumonia: A systematic review and meta-analysis.

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