OBJECTIVES:To quantify immunological dysfunction in surgical patients with presence/absence of sepsis using a droplet digital polymerase chain reaction (ddPCR) transcriptomic analysis. The study also ...aims to evaluate this approach for improving identification of sepsis in these patients.
BACKGROUND:Immune dysregulation is a central event in sepsis. Quantification of the expression of immunological genes participating in the pathogenesis of sepsis could represent a new avenue to improve its diagnosis.
METHODS:Expression of 6 neutrophil protease genes (MMP8, OLFM4, LCN2/NGAL, LTF, PRTN3, MPO) and also of 5 genes involved in the immunological synapse (HLA-DRA, CD40LG, CD3E, CD28, ICOS) was quantified in blood from 101 surgical patients with sepsis, 53 uninfected surgical patients, and 16 blood donors by using ddPCR. Areas under receiver operating characteristic curves (AUROC) and multivariate regression analysis were employed to test individual genes and gene ratios to identify sepsis, in comparison with procalcitonin.
RESULTS:Sepsis-induced overexpression of neutrophil protease genes and depressed expression of immunological synapse genes. MMP8/HLA-DRA, LCN2/HLA-DRA outperformed procalcitonin in differentiating between patients with sepsis and surgical controls in the AUROC analysisLCN2/HLA-DRA0.90 (0.85–0.96), MMP8/HLA-DRA0.89 (0.84–0.95), procalcitonin0.80 (0.73–0.88) (AUROC, confidence interval 95%), and also in the multivariate analysisLCN2/HLA-DRA8.57 (2.25–32.62); MMP8/HLA-DRA8.03 (2.10–30.76), procalcitonin4.20 (1.15–15.43) odds ratio (confidence interval 95%). Gene expression levels of HLA-DRA were an independent marker of hospital mortality.
CONCLUSIONS:Quantifying the transcriptomic ratios MMP8/HLA-DRA, LCN2/HLA-DRA by ddPCR is a promising approach to improve sepsis diagnosis in surgical patients.
The aims of this study were to investigate changes in energy balance-associated metabolites associated with radiotherapy in patients with breast cancer, and to relate these changes to the clinical ...and pathological response-to-treatment. We studied 151 women with breast cancer who received radiotherapy following surgical excision of the tumor. Blood was obtained before and after the irradiation procedure. The control group was composed of 44 healthy women with a similar age distribution to that of the patients. We analyzed the concentrations of metabolites involved in glycolysis, citric acid cycle and amino acid metabolism using targeted quantitative metabolomics. Post-surgery, pre-radiotherapy, patients had major alterations in the serum concentrations of products of glycolysis, citric acid cycle and amino acid metabolism. The strongest alterations were decreases in serine, leucine and isoleucine concentrations. Alterations in metabolite levels were partially, or totally, reversed after irradiation; the concentrations of serine, leucine and isoleucine approached equivalence to those of the control group. Estrogen receptor-positive patients were those with lower concentrations, while triple negative patients had higher concentrations of these amino acids. The normalization of the amino acids serine, leucine and isoleucine concentrations could be clinically relevant because the normalization of these energy-balance metabolites would suggest that residual micro-metastatic disease had been effectively diminished by the radiotherapy, and may be an indicator of its efficacy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Higher expression of olfactomedin‐4 (OLFM4), a gene regulated by nuclear factor‐kappa B (NF‐κB), has been related to a higher risk of organ failure and death in patients with septic shock. ...We aimed to evaluate the association between OLFM4 single nucleotide polymorphisms (SNPs) and septic shock‐related death in 175 patients who underwent major surgery, as well as its performance in predicting mortality.
Materials and methods
We carried out a retrospective study. A total of seven OLFM4 SNPs were genotyped by Agena Bioscience's MassARRAY platform. Statistical analysis was performed by Kaplan‐Meier and Cox regression tests. The diagnostic performance for predicting septic shock‐related death was evaluated by the area under the receiver‐operating characteristic (AUROC) curve.
Results
Patients with rs17552047 A allele and rs1891944 TT genotype had higher survival than patients with rs17552047 G allele (P‐value = .024) and patients with rs1891944 CC/CT genotype (P‐value = .038). However, only rs17552047 was associated with a lower risk of death under an additive inheritance model (adjusted hazard ratio aHR = 0.44, 95% CI = 0.27‐0.71). The multivariate model with the most significant clinical variables (lactate, chronic kidney disease, peritonitis, heart disease and elective surgery) showed an AUROC of 0.776 for predicting septic shock‐related death. When we added the OLFM4 rs17552047 SNP to the previous model, the AUROC was 0.811 and was close to reaching significant differences with the previous model (P‐value = .065).
Conclusion
OLFM4 rs17552047 A allele predicts septic shock survival in patients who underwent major surgery. Furthermore, rs17552047, together with clinical variables, could be useful to predict the outcome of septic shock.
IL‐1B rs16944 polymorphism is related to septic shock and death Jiménez‐Sousa, María Ángeles; Medrano, Luz M.; Liu, Pilar ...
European journal of clinical investigation,
January 2017, 2017-Jan, 2017-01-00, 20170101, Letnik:
47, Številka:
1
Journal Article
Recenzirano
Background
IL‐1β is a primary mediator of systemic inflammatory response syndrome (SIRS) and it may lead to shock septic. Our aim was to analyse whether IL‐1B rs16944 polymorphism is associated with ...the onset of septic shock and death after major surgery.
Materials and methods
We performed a case–control study on 467 patients who underwent major cardiac or abdominal surgery. Of them, 205 patients developed septic shock (cases, SS group) and 262 patients developed SIRS (controls, SIRS group). The primary outcome variables were the development of septic shock and death within 90 days after diagnosis of septic shock. The IL‐1B rs16944 polymorphism was genotyped by Sequenom's MassARRAY platform. The association analysis was performed under a recessive genetic model (AA vs. GG/GC).
Results
The frequency of septic shock was higher in patients with IL‐1B rs16944 AA genotype than in patients with IL‐1B rs16944 GG/AG genotype when all patients were taken into account (63·6% vs. 41·8%; P = 0·006), cardiac surgery (52·2% vs. 33·3%; P = 0·072) and abdominal surgery (76·2% vs. 50·2%; P = 0·023). However, the IL‐1B rs16944 AA genotype was only associated with higher likelihood of septic shock in the analysis of all population adjusted odds ratio (aOR) = 2·26 (95%CI = 1·03; 4·97; P = 0·042, but not when it was stratified by cardiac surgery (P = 0·175) or abdominal surgery (P = 0·467). Similarly, IL‐1B rs16944 AA genotype was also associated with higher likelihood of septic shock‐related death in all population aOR = 2·67 (95%CI = 1·07; 4·97); P = 0·035.
Conclusions
IL‐1B rs16944 AA genotype seems to be related to the onset of septic shock and death in patients who underwent major surgery.
Oxidative stress may be a key player in COVID-19 pathogenesis due to its significant role in response to infections. A defective redox balance has been related to viral pathogenesis developing a ...massive induction of cell death provoked by oxidative stress. The aim of this study is to perform a complete oxidative stress profile evaluation regarding antioxidant enzymes, total antioxidant capacity and oxidative cell damage in order to characterize its role in diagnosis and severity of this disease.
Blood samples were obtained from 108 COVID-19 patients and 28 controls and metabolites representative of oxidative stress were assessed. The association between lipid peroxidation and 28-day intubation/death risk was evaluated by multivariable regression analysis. Probability of intubation/death to day-28 was analyzed by using Kaplan-Meier curves and tested with the log-rank test.
Antioxidant enzymes (Superoxide dismutase (SOD) and Catalase) and oxidative cell damage (Carbonyl and Lipid peroxidation (LPO)) levels were significantly higher in COVID-19 patients while total antioxidant capacity (ABTS and FRAP) levels were lower in these patients. The comparison of oxidative stress molecules’ levels across COVID-19 severity revealed that only LPO was statistically different between mild and intubated/death COVID-19 patients. COX multivariate regression analysis identified LPO levels over the OOP (LPO>1948.17 μM) as an independent risk factor for 28-day intubation/death in COVID-19 patients OR: 2.57; 95% CI: 1.10–5.99; p = 0.029. Furthermore, Kaplan-Meier curve analysis revealed that COVID-19 patients showing LPO levels above 1948.17 μM were intubated or died 8.4 days earlier on average (mean survival time 15.4 vs 23.8 days) when assessing 28-day intubation/death risk (p < 0.001).
These findings deepen our knowledge of oxidative stress status in SARS-CoV-2 infection, supporting its important role in COVID-19. In fact, higher lipid peroxidation levels are independently associated to a higher risk of intubation or death at 28 days in COVID-19 patients.
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•Antioxidant enzymes and oxidative cell damage levels were significantly higher while total antioxidant capacity was lower in COVID-19 patients.•Only lipid peroxidation was statistically different across COVID-19 severity.•Lipid peroxidation levels over 1948.17 μM are an independent risk factor for 28-day intubation/death in COVID-19 patients.•COVID-19 patients showing lipid peroxidation levels above 1948.17 μM were intubated or died 8.4 days earlier on average.
Summary Objectives Immunological dysregulation is now recognised as a major pathogenic event in sepsis. Stimulation of immune response and immuno-modulation are emerging approaches for the treatment ...of this disease. Defining the underlying immunological alterations in sepsis is important for the design of future therapies with immuno-modulatory drugs. Methods Clinical studies evaluating the immunological response in adult patients with Sepsis and published in PubMed were reviewed to identify features of immunological dysfunction. For this study we used key words related with innate and adaptive immunity. Results Ten major features of immunological dysfunction (FID) were identified involving quantitative and qualitative alterations of antigen presentation(FID1), T and B lymphocytes (FID2), natural killer cells (FID3), relative increase in T regulatory cells (FID4), increased expression of PD-1 and PD-ligand1(FID5), low levels of immunoglobulins(FID6), low circulating counts of neutrophils and/or increased immature forms in non survivors(FID7), hyper-cytokinemia (FID8), complement consumption (FID9), defective bacterial killing by neutrophil extracellular traps(FID10). Conclusions This review article identified ten major features associated with immunosuppression and immunological dysregulation in sepsis. Assessment of these features could help in utilizing precision medicine for the treatment of sepsis with immuno-modulatory drugs.
Sepsis has represented a substantial health care and economic burden worldwide during the previous several decades. Our aim was to analyze the epidemiological trends of hospital admissions, deaths, ...hospital resource expenditures, and associated costs related to sepsis during the twenty-first century in Spain.
We performed a retrospective study of all sepsis-related hospitalizations in Spanish public hospitals from 2000 to 2013. Data were obtained from records in the Minimum Basic Data Set. The outcome variables were sepsis, death, length of hospital stay (LOHS), and sepsis-associated costs. The study period was divided into three calendar periods (2000-2004, 2005-2009, and 2010-2013).
Overall, 2,646,445 patients with sepsis were included, 485,685 of whom had died (18.4%). The incidence of sepsis (events per 1000 population) increased from 3.30 (2000-2004) to 4.28 (2005-2009) to 4.45 (2010-2013) (p < 0.001). The mortality rates from sepsis (deaths per 10,000 population) increased from 6.34 (2000-2004) to 7.88 (2005-2009) to 7.89 (2010-2013) (p < 0.001). The case fatality rate (CFR) or proportion of patients with sepsis who died decreased from 19.1% (2000-2004) to 18.4% (2005-2009) to 17.9% (2010-2013) (p < 0.001). The LOHS (days) decreased from 15.9 (2000-2004) to 15.7 (2005-2009) to 14.5 (2010-2013) (p < 0.001). Total and per patient hospital costs increased from 2000 to 2011, and then decreased by the impact of the economic crisis.
Sepsis has caused an increasing burden in terms of hospital admission, deaths, and costs in the Spanish public health system during the twenty-first century, but the incidence and mortality seemed to stabilize in 2010-2013. Moreover, there was a significant decrease in LOHS in 2010-2013 and a decline in hospital costs after 2011.
Respiratory viruses are part of the normal microbiota of the respiratory tract, which sometimes cause infection with/without respiratory insufficiency and the need for hospital or ICU admission. The ...aim of this study is to determine the prevalence of respiratory viruses in nontransplanted postoperative septic patients as well as lymphocyte count influence in their presence and its relationship to mortality. 223 nontransplanted postsurgical septic patients were recruited on the Intensive Care Unit (ICU) at Hospital Clínico Universitario de Valladolid prior to the SARS-COV-2 pandemic. Patients were split into 2 groups according to the presence/absence of respiratory viruses. Multivariate logistic regression analysis was used to identify independent factors related to positive respiratory virus PCR test. Respiratory viruses were isolated in 28.7% of patients. 28-day mortality was not significantly different between virus-positive and virus-negative groups. Logistic regression analysis revealed that lymphocyte count ≤ 928/µl is independently associated with a positive PCR result OR 3.76, 95% CI (1.71-8.26), P = .001 adjusted by platelet count over 128,500/µL OR 4.27, 95% CI (1.92-9.50) P < .001 and the presence of hypertension OR 2.69, 95% CI (1.13-6.36) P = .025 as confounding variables. Respiratory viruses' detection by using PCR in respiratory samples of nontransplanted postoperative septic patients is frequent. These preliminary results revealed that the presence of lymphopenia on sepsis diagnosis is independently associated to a positive virus result, which is not related to a higher 28-day mortality.
COVID19 pandemic has forced physicians from different specialties to assist cases overload. Our aim is to assess gastroenterologist's assistance in COVID-19 by assessing mortality, ICU admission, and ...length of stay, and seek for risk factors for in-hospital mortality and longer hospital stay.
A total of 41 COVID-19 patients assisted by gastroenterologist (GI cohort) and 137 assisted by pulmonologist, internal medicine practitioners, and infectious disease specialists (COVID expert cohort) during October-November 2020 were prospectively collected. Clinical, demographic, imaging, and laboratory markers were collected and compared between both cohorts. Bivariate analysis and logistic regression were performed to search for risk factors of mortality and longer hospital stays.
A total of 27 patients died (15.1%), 11 were admitted to ICU (6.1%). There were no differences between cohorts in mortality (14.6% vs 15.4%;p = 0.90), ICU admission (12.1% vs 4%;p = 0.13), and length of stay (6.67 ± 4 vs 7.15 ± 4.5 days; p = 0.58). PaO2/FiO2 on admission (OR 0.991;CI95% 0.984-0.998) and age > 70 (OR 17.54;CI95% 3.93-78.22) were independently related to mortality. Age > 70, history of malignancy, diabetes, and cardiovascular disease were related to longer hospital stays (p < 0.001, p = 0.03, p = 0.04, p = 0.02 respectively)
COVID-19 assistance was similar between gastroenterologist and COVID experts when assessing mortality, ICU admission, and length of stay. Age>70 and decreased PaO2/FiO2 on admission were independent risk factors of mortality. Age and several comorbidities were related to longer hospital stay.
Sundown syndrome (SS) is the onset or worsening of behavioral symptoms in the evening in patients with dementia.
To identify the differential clinical profile of patients with dementia who present ...SS.
A cross-sectional, case-control observational study was conducted by retrospectively reviewing the medical records of patients with dementia in a specialized Memory Unit. We compared the characteristics of patients with and without SS, including sociodemographic variables, etiology, and severity of the dementia, behavioral symptoms, sleep disorders (considering insomnia and hypersomnia), other diseases and treatments employed. We identified the factors related to SS and conducted a logistic regression analysis to establish a predictive nomogram.
Of the 216 study patients with dementia, 41 (19%) had SS. There was a predominance of women (2.4:1), advanced age (p = 0.0001), dependence (p < 0.0001), institutionalization (p < 0.0001), caregiver burden (p < 0.0001), anxiety (p < 0.0001), delirium (p < 0.0001), hallucinations (p < 0.0001), wandering (p < 0.0001), Lewy body dementia (p = 0.05), higher Global Deterioration Scale score (GDS; p < 0.0001), and sleep disorders (p < 0.0001). The multivariate analysis revealed that age (p = 0.048), GDS score (p = 0.01), and the presence of insomnia or hypersomnia (p < 0.0001) independently defined the presence of SS. We established a predictive nomogram for developing SS in patients with dementia, with a predictive capacity of 80.1%.
In our study, age, a higher score on the GDS, and the presence of insomnia or hypersomnia are differential clinical characteristics of patients with SS. We defined a nomogram that helps predicting the occurrence of SS in patients with dementia.
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