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ObjectiveDetermine if deep learning detects sepsis earlier and more accurately than other models. To evaluate model performance using implementation-oriented metrics that simulate clinical practice.Materials and MethodsWe trained internally and temporally validated a deep learning model (multi-output Gaussian process and recurrent neural network [MGP–RNN]) to detect sepsis using encounters from adult hospitalized patients at a large tertiary academic center. Sepsis was defined as the presence of 2 or more systemic inflammatory response syndrome (SIRS) criteria, a blood culture order, and at least one element of end-organ failure. The training dataset included demographics, comorbidities, vital signs, medication administrations, and labs from October 1, 2014 to December 1, 2015, while the temporal validation dataset was from March 1, 2018 to August 31, 2018. Comparisons were made to 3 machine learning methods, random forest (RF), Cox regression (CR), and penalized logistic regression (PLR), and 3 clinical scores used to detect sepsis, SIRS, quick Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS). Traditional discrimination statistics such as the C-statistic as well as metrics aligned with operational implementation were assessed.ResultsThe training set and internal validation included 42 979 encounters, while the temporal validation set included 39 786 encounters. The C-statistic for predicting sepsis within 4 h of onset was 0.88 for the MGP–RNN compared to 0.836 for RF, 0.849 for CR, 0.822 for PLR, 0.756 for SIRS, 0.619 for NEWS, and 0.481 for qSOFA. MGP–RNN detected sepsis a median of 5 h in advance. Temporal validation assessment continued to show the MGP–RNN outperform all 7 clinical risk score and machine learning comparisons.ConclusionsWe developed and validated a novel deep learning model to detect sepsis. Using our data elements and feature set, our modeling approach outperformed other machine learning methods and clinical scores.

Aims To investigate the causes of death and the associated clinical factors in patients with atrial fibrillation (AF) in the contemporary clinical practice. Methods and results The Fushimi AF Registry is a community-based prospective survey of AF patients since March 2011 in Fushimi-ku, Kyoto. We investigated causes of death and the clinical indicators of cardiovascular (CV) and non-CV death in 4045 patients with available follow-up data by the end of November 2016. The mean age was 73.6 ± 10.9 years and the mean CHA 2 DS 2 -VASc score was 3.38 ± 1.69. Oral anticoagulants were prescribed in 55% of patients. During a median follow-up of 1105 days, there were 705 all-cause deaths (5.5%/year); 180 CV (26% of total deaths), 381 non-CV (54%), and 144 undetermined causes (20%). The most common causes of CV and non-CV death were heart failure (14.5%), malignancy (23.1%), and infection/sepsis (17.3%), while mortality due to stroke was only 6.5%. Mortality due to infection/sepsis and undetermined causes increased with aging. On multivariate analysis, the strongest indicator of CV death was pre-existing heart failure [hazard ratio (HR) 2.42, 95% confidence interval (CI) 1.66-3.54; P < 0.001] and that of non-CV death was anaemia (HR 2.84, 95% CI 2.22-3.65; P < 0.001). Conclusion In a Japanese community-based AF cohort, CV death was not mainly related to stroke but to heart failure. Non-CV death, mainly malignancy and infection, comprised more than a half of all deaths, which increased substantially in accordance with aging. Clinical factors that were associated with CV and non-CV death were distinct.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells characterized by their immunosuppressive functions. MDSCs expand during chronic and acute inflammatory conditions, the best described being cancer. Recent studies uncovered an important role of MDSCs in the pathogenesis of infectious diseases along with sepsis. Here we discuss the mechanisms underlying the expansion and immunosuppressive functions of MDSCs, and the results of preclinical and clinical studies linking MDSCs to sepsis pathogenesis. Strikingly, all clinical studies to date suggest that high proportions of blood MDSCs are associated with clinical worsening, the incidence of nosocomial infections and/or mortality. Hence, MDSCs are attractive biomarkers and therapeutic targets for sepsis, especially because these cells are barely detectable in healthy subjects. Blocking MDSC-mediated immunosuppression and trafficking or depleting MDSCs might all improve sepsis outcome. While some key aspects of MDSCs biology need in depth investigations, exploring these avenues may participate to pave the way towards the implementation of personalized medicine and precision immunotherapy for patients suffering from sepsis.

This special issue wants to contribute to a better understanding of cardiac involvement in sepsis. Sepsis is a complex syndrome that has recently been defined as “life-threatening organ dysfunction due to a dysregulated host response to infection” [1, 2]. It should be considered a major public health problem since it affects millions of people worldwide each year, and it accounts for most deaths in critically ill patients. The presence of myocardial dysfunction in sepsis is associated with higher mortality. A great attention has been dedicated to improving our knowledge and understanding of the intricate mechanisms underlying sepsis. However, data from the literature suggest the need to implement strategies to reliably measure sepsis morbidity and mortality. In fact, methods based on analyses of insurance claim data using sepsis-specific codes or separate codes for infection and organ dysfunction are unreliable in informing or measuring the effects of policy changes [3, 4], and the postmortem diagnosis of sepsis is often elusive since postmortem investigations lack certain pathognomonic macroscopic and histopathological findings [5, 6]. From a morphological and diagnostic point of view, the term “septic disease” has been created to describe the cardiac involvement in the syndrome. However, this definition, rather than describing a morphological finding, was instead referred to the clinical setting. Although in recent years the concept of septic cardiomyopathy has evolved and it involves pathological alterations of myocardial cells in response to the multiplicity of acting mechanism of damage, the importance of structural changes during sepsis is often overlooked. In patients with sepsis, death is usually the result of a progressive multiorgan dysfunction, overlooking the primary infection through the hyperinflammation. The cardiac involvement as fundamental part of septic multiorgan dysfunction syndrome has been discussed for a long time. C. Pomara et al. explored the state of current knowledge on the molecular and biohumoral mechanisms of sepsis and correlate them with our ability at postmortem diagnosis. The authors highlight that a complete methodological approach, integrating clinical data by means of autopsy and histological and laboratory findings aiming to identify and demonstrate the host response to infectious insult, is mandatory. Such an approach would be likely to produce an accurate objective surveillance of deaths due to sepsis and improve our knowledge of the clinical-pathological correlation in sepsis, thus contributing to the evaluation of the effectiveness of therapies. Sepsis is characterized by symptoms and manifestations of organ dysfunction that may lead to fatal outcome. Myocardial dysfunction in sepsis is mediated by a complex interplay among several factors that still remains incompletely understood [7]. Circulatory compromise and microcirculatory alterations may, in part, explain cardiac impairment in sepsis. However, in recent years increasing attention has been paid to the study of other possible pathways of myocardial dysfunction in sepsis. The effects of the host's immune-inflammatory response with particular focus on depressant molecules, complement molecules, cellular adhesion molecules, and altered intracellular energetic, dysregulated intracellular calcium fluxes have been called upon in the pathophysiology of myocardial depression in sepsis. Oxidative-nitrosative stress may contribute to cardiac dysfunction in sepsis, and mitochondria are one of the major sites for generation of reactive oxygen species and reactive nitrosative species as a detrimental side product of oxidative energy metabolism [8]. M. Neri et al. reviewed the evidence for a role of oxidative-nitrosative stress unbalance and mitochondria dysfunction in myocardial depression in sepsis. NADPH oxidase-derived reactive oxygen species, the role of mitochondria, and finally the involvement of nitric oxide and peroxynitrite as critical factors in mediating myocardial dysfunction in sepsis are discussed. Measurement of biomarkers is a potential approach to early prediction of the risk of mortality in patients with sepsis. Over the years, a great amount of molecules has been proposed as potential biological markers [9]. However, only 20% of these biomarkers have been assessed specifically in appropriate studies for use in the diagnosis of sepsis [10]. To date an ideal clinical and postmortem marker of sepsis does not exist. Proadrenomedullin and copeptin are peptides cosynthesized together with adrenomedullin and vasopressin in endothelial cells and pituitary gland, respectively. These peptides are increased during sepsis. They have vasoactive, immune modulating, and metabolic properties. It was recently reported that adrenomedullin plays a central role in initiating the hyperdynamic response during the early stages of sepsis and was a useful predictor for development of severe sepsis and septic shock [11, 12]. W. Hu et al. discuss the prognostic value of adrenomedullin and atrial and brain natriuretic peptides in uroseptic patients induced by ureteroscopy. In their research article the authors suggest that the prognostic value of adrenomedullin is superior to atrial and brain natriuretic peptides and that all these molecules are robust independent predictors of in-hospital death in uroseptic patients. They conclude that adrenomedullin and atrial and brain natriuretic peptides may participate in initiating the hyperdynamic response during the early stages of sepsis in uroseptic patients and that these biomarkers could be considered strong predictors of adverse outcome in patients with urosepsis. Finally, two articles of the special issue discuss the potential link existing between inflammatory status and cardiometabolic disorders. It has been well established that inflammation is also able to affect lipoprotein metabolism. However, the precise mechanisms pathophysiologically linking metabolic dysfunction and inflammation are still under investigation. The biological basis for these associations includes both systemic and local tissue effects. Metabolic Syndrome (MetS) is a constellation of diseases that include obesity, diabetes, hypertension, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. These metabolic derangements trigger a persistent inflammatory cascade, whit recruitment of immune cells to the site of injury, and subsequent expression of cytokines and chemokines that amplify the inflammatory response [13]. A common link between inflammation and MetS has been suggested. In cardiometabolic disorders a high serum lipopolysaccharides activity has been demonstrated, thus suggesting a potential role of bacterial infections and immune response in their etiology [14]. One article discussed the serum adiponectin levels and the homeostasis model assessment-insulin resistance (HOMA-IR) that are reportedly associated with MetS. Y.-S. Ding et al. concluded that the adiponectin to HOMA-IR ratio (A/H) may be a better diagnostic marker for MetS than either HOMA-IR or adiponectin alone, and it may serve as an important biomarker to determine an increased risk for MetS in healthy middle-aged population. Y. Zhang et al. investigated the relationship between inflammatory markers and the atherogenic lipoprotein subfractions, and they hypothesized presence of heterogeneity in the relationship of systemic inflammatory markers with atherogenic lipoprotein subfractions, which would aid our understanding of their interplay in the pathogenesis of atherosclerotic disease. This special issue is dedicated to the cardiovascular involvement in sepsis. The high mortality associated with sepsis makes a thorough knowledge of its underlying mechanisms and its pathophysiological connections with the cardiometabolic disorders important.

ObjectiveStatins are among the most prescribed drugs worldwide and their recently discovered anti-inflammatory effect seems to have an important role in inhibiting proinflammatory cytokine production, chemokines expression and counteracting the harmful effects of sepsis on the coagulation system. We decided to perform a meta-analysis of all randomized controlled trials ever published on statin therapy in septic patients to evaluate their effect on survival and length of hospital stay.Data sources and study selectionArticles were assessed by four trained investigators, with divergences resolved by consensus. BioMedCentral, PubMed, Embase and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocation to treatment and comparison of statins versus any comparator in septic patients.Data extraction and synthesisData from 650 patients in 5 randomized controlled studies were analyzed. No difference in mortality between patients receiving statins versus control (44/322 [14%] in the statins group vs 50/328 [15%] in the control arm, RR = 0.90 [95% CI 0.65 to 1.26], p = 0.6) was observed. No differences in hospital stay (p = 0.7) were found.ConclusionsPublished data show that statin therapy has no effect on mortality in the overall population of adult septic patients. Scientific evidence on statins role in septic patients is still limited and larger randomized trials should be performed on this topic.

OBJETIVO: Descrever as características clínicas, os dados laboratoriais e o desfecho clínico de pacientes sépticos e não sépticos admitidos em UTI de um hospital privado na cidade de Salvador, Bahia, e identificar variáveis clínicas relacionadas ao pior prognóstico dos pacientes sépticos. MÉTODOS: Foi realizado um estudo longitudinal que incluiu todos os pacientes admitidos na UTI geral do Hospital Português, Salvador (BA), entre junho de 2008 e março de 2009. Na admissão na UTI, dois grupos de pacientes foram identificados: sépticos e não sépticos. Foram coletados dados epidemiológicos, clínicos e laboratoriais, e o escore Acute Physiology and Chronic Health Evaluation II (APACHE II) foi calculado. RESULTADOS: Dos 144 pacientes do estudo, 29 (20,1%) eram sépticos. Entre os pacientes sépticos, 55,2% eram do sexo masculino, a média de idade foi de 73,1 ± 14,6 anos, e a média do escore do APACHE II foi de 23,8 ± 9,1. No grupo não séptico, 36,3% eram do sexo masculino, a média de idade foi de 68,7 ± 17,7 anos, e a média do escore do APACHE II foi de 18,4 ± 9,5. Houve associações estatisticamente significantes entre o diagnóstico de sepse e as seguintes variáveis: escore do APACHE II, mortalidade na UTI, mortalidade hospitalar, FC, pressão arterial média, valor de hematócrito, contagem de leucócitos e uso de antibioticoterapia. O uso de medidas de suporte e valores reduzidos de hematócrito se relacionaram com um pior prognóstico entre os pacientes sépticos. CONCLUSÕES: Os pacientes diagnosticados com sepse apresentaram piores desfechos clínicos, provavelmente por causa de sua maior gravidade. O nível de hematócrito foi a única variável capaz de predizer o risco de morte entre pacientes sépticos. OBJECTIVE: To describe the clinical characteristics, laboratory data, and clinical outcomes of patients with and without sepsis admitted to the ICU of a private hospital in the city of Salvador, Brazil, and to identify clinical variables related to a worse prognosis in those with sepsis. METHODS: This was a longitudinal study including all patients admitted to the general ICU of the Hospital Português, in the city of Salvador, Brazil, between June of 2008 and March of 2009. At ICU admission, two groups of patients were identified: with sepsis and without sepsis. Epidemiological, clinical and laboratory data were collected, and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score was calculated. RESULTS: Of the 144 patients in the study, 29 (20.1%) had sepsis. Among the patients with sepsis, males accounted for 55.2%, the mean age was 73.1 ± 14.6 years, and the mean APACHE II score was 23.8 ± 9.1, compared with 36.3%, 68.7 ± 17.7 years, and 18.4 ± 9.5, respectively, among those without sepsis. There were significant associations between a diagnosis of sepsis and the following variables: APACHE II score; in-hospital mortality; ICU mortality; HR; mean arterial pressure; hematocrit level; white blood cell count; and antibiotic use. The use of life support measures and lower hematocrit levels were associated with a worse prognosis in the patients with sepsis. CONCLUSIONS: The patients diagnosed with sepsis presented worse clinical outcomes, probably due to their greater severity. Hematocrit level was the only variable that was a predictor of mortality risk in the patients with sepsis.

p. 85-92 Submitted by Edileide Reis (leyde-landy@hotmail.com) on 2014-04-15T11:59:44Z No. of bitstreams: 1 Octavio Henrique Coelho Messeder.pdf: 164014 bytes, checksum: 66d7d7afeb4c5ac58eb808370ca971f5 (MD5) Approved for entry into archive by Flávia Ferreira (flaviaccf@yahoo.com.br) on 2014-11-04T15:18:55Z (GMT) No. of bitstreams: 1 Octavio Henrique Coelho Messeder.pdf: 164014 bytes, checksum: 66d7d7afeb4c5ac58eb808370ca971f5 (MD5) Made available in DSpace on 2014-11-04T15:18:55Z (GMT). No. of bitstreams: 1 Octavio Henrique Coelho Messeder.pdf: 164014 bytes, checksum: 66d7d7afeb4c5ac58eb808370ca971f5 (MD5) Previous issue date: 2011 OBJETIVO: Descrever as características clínicas, os dados laboratoriais e o desfecho clínico de pacientes sépticos e não sépticos admitidos em UTI de um hospital privado na cidade de Salvador, Bahia, e identificar variáveis clínicas relacionadas ao pior prognóstico dos pacientes sépticos. MÉTODOS: Foi realizado um estudo longitudinal que incluiu todos os pacientes admitidos na UTI geral do Hospital Português, Salvador (BA), entre junho de 2008 e março de 2009. Na admissão na UTI, dois grupos de pacientes foram identificados: sépticos e não sépticos. Foram coletados dados epidemiológicos, clínicos e laboratoriais, e o escore Acute Physiology and Chronic Health Evaluation II (APACHE II) foi calculado. RESULTADOS: Dos 144 pacientes do estudo, 29 (20,1%) eram sépticos. Entre os pacientes sépticos, 55,2% eram do sexo masculino, a média de idade foi de 73,1 ± 14,6 anos, e a média do escore do APACHE II foi de 23,8 ± 9,1. No grupo não séptico, 36,3% eram do sexo masculino, a média de idade foi de 68,7 ± 17,7 anos, e a média do escore do APACHE II foi de 18,4 ± 9,5. Houve associações estatisticamente significantes entre o diagnóstico de sepse e as seguintes variáveis: escore do APACHE II, mortalidade na UTI, mortalidade hospitalar, FC, pressão arterial média, valor de hematócrito, contagem de leucócitos e uso de antibioticoterapia. O uso de medidas de suporte e valores reduzidos de hematócrito se relacionaram com um pior prognóstico entre os pacientes sépticos. CONCLUSÕES: Os pacientes diagnosticados com sepse apresentaram piores desfechos clínicos, provavelmente por causa de sua maior gravidade. O nível de hematócrito foi a única variável capaz de predizer o risco de morte entre pacientes sépticos.

Item does not contain fulltext OBJECTIVES: To determine the causes and predictors of mortality in systemic sclerosis (SSc). METHODS: Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan-Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. RESULTS: Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud's phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points). CONCLUSION: Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc. 01 oktober 2010

INTRODUCTION: Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis. METHODS: This was a multicenter, observational, and prospective study carried out in six Spanish Intensive Care Units. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis and 50 age- and sex-matched healthy controls in the study. Serum levels of MMP-9, MMP-10, TIMP-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 were measured in patients with severe sepsis at the time of diagnosis and in healthy controls. RESULTS: Sepsis patients had higher levels of MMP-10 and TIMP-1, higher MMP-10/TIMP-1 ratios, and lower MMP-9/TIMP-1 ratios than did healthy controls (P < 0.001). An association was found between MMP-9, MMP-10, TIMP-1, and MMP-9/TIMP-1 ratios and parameters of sepsis severity, assessed by the SOFA score, the APACHE-II score, lactic acid, platelet count, and markers of coagulopathy. Nonsurviving sepsis patients had lower levels of MMP-9 (P = 0.037), higher levels of TIMP-1 (P < 0.001), lower MMP-9/TIMP-1 ratio (P = 0.003), higher levels of IL-10 (P < 0.001), and lower TNF-alpha/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-alpha and IL-10 levels. The risk of death in sepsis patients with TIMP-1 values greater than 531 ng/ml was 80% higher than that in patients with lower values (RR = 1.80; 95% CI = 1.13 to 2.87;P = 0.01; sensitivity = 0.73; specificity = 0.45). CONCLUSIONS: The novel findings of our study on patients with severe sepsis (to our knowledge, the largest series reporting data about MMP levels in sepsis) are that reduced MMP-9/TIMP-1 ratios and increased MMP-10 levels may be of great pathophysiologic significance in terms of severity and mortality, and that TIMP-1 levels may represent a biomarker to predict the clinical outcome of patients with sepsis.