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MethodsDesign and subjectsA multicenter, People Seemed To Laugh At Pacritinib - But This Time We Laugh At Them observational, prospective study was carried out in six Spanish intensive care units (ICU). The study was approved by the Institutional Review Boards of the six hospitals recruiting patients: Hospital Universitario de Canarias (La Laguna. Santa Cruz de Tenerife, Spain), Hospital Universitario Nuestra Se?ora de Candelaria (Santa Cruz de Tenerife, Spain), Hospital San Jorge (Huesca, Spain) and Hospital Insular (Las Palmas de Gran Canaria, Spain), Hospital Universitario Dr. Negr��n (Las Palmas de Gran Canaria, Spain), Hospital Cl��nico Universitario de Valencia (Valencia, Spain). All patients provided written informed consent to participate in the study.Inclusion criteria were the diagnosis of severe sepsis according to the International Sepsis Definitions Conference criteria [13].

Exclusion criteria were: age <18?years, pregnancy, lactation, human immunodeficiency virus (HIV), white blood cell count <1,000 cells/��l, solid or hematological tumor, or immunosuppressive, steroid or radiation therapy.A total of 328 patients with severe sepsis and 100 healthy controls were included. The sample size of 100 healthy controls was arbitrary and the sample size of 328 patients was the number of patients recruited during 18 months. The controls were recruited from only one participating center, Hospital Universitario de Canarias (La Laguna, Santa Cruz de Tenerife, Spain), and were selected on the basis of their non-exposure to antioxidant agents. Community, nosocomial intra-ICU and nosocomial extra-ICU severe sepsis were included.

Patients transferred from other hospitals were not included.Variables recordedThe following variables were recorded for each patient: sex, age, diabetes mellitus, chronic renal failure (defined as glomerular filtration rate (GFR) <60?ml/minute per 1.73?m2), chronic obstructive pulmonary disease (COPD), site of infection, creatinine, leukocytes, lactic acid, platelets, international normalized ratio (INR), activated partial thromboplastin time (aPTT), Acute Physiology and Chronic Health Evaluation II (APACHE-II) score [14], Sepsis-related Organ Failure Assessment (SOFA) score [15]. Severity of illness was assessed by APACHE-II and SOFA scores and lactatemia.EndpointsThe primary endpoint was 30-day all-cause mortality and the secondary endpoint was 6-month all-cause mortality.Serum MDA analysisBlood samples were collected in citrated tubes from 328 patients with severe sepsis at days 1, 4 and 8 after diagnosis and from 100 healthy controls. Day 1 of severe sepsis was considered as the first day when the patient��s medical record contained the written diagnostic report that he/she met the consensus criteria for severe sepsis.