Diagnosis of postoperative adverse event and prognosis

Abstract

To provide a method for evaluating the possibility of occurrence of an adverse event in the health of a postoperative patient.SOLUTION: The present invention relates to a method for evaluating the possibility of occurrence of an adverse event in the health of a postoperative patient, the method including providing at least one sample of a patient who has had a surgery, is having a surgery, or is going to have a surgery. The sample is separated from the patient before a surgery, in perioperative period, or after a surgery. The level of the MR-proADM biomarker in the at least one sample is determined. The adverse event is a cardiovascular event and an infection disease and is alternatively a brain blood vessel event and an infection disease. The adverse event occurs within 30 days from a surgery and the level of the at least one biomarker is correlated to the possibility of the adverse event.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for diagnosis, prognosis, risk assessment, and / or risk stratification of adverse events in postoperative patient health, comprising providing at least one sample of a patient who has undergone, is undergoing, or is going to undergo surgery, the at least one sample being separated from the patient preoperatively, perioperatively, or postoperatively, and determining the level of at least one biomarker selected from the group consisting of proADM, PCT, and proET-1, or a fragment thereof, in the at least one sample, and the level of the at least one biomarker or a fragment thereof correlates with the likelihood of the adverse event. In some embodiments, the method is used to predict or diagnose the likelihood or low of postoperative infection or blood infection. In some embodiments, the method is used to predict or diagnose the likelihood or low of postoperative cardiovascular or cerebrovascular adverse events, preferably major adverse cardiovascular or cerebrovascular events (MACCE), major myocardial injury after non-cardiac surgery (MINS), or perioperative myocardial injury (PMI). In some embodiments, the methods additionally include treatment guidance, stratification, and / or control associated with said post-operative adverse events, particularly infections or cardiovascular or cerebrovascular adverse events. [Background technology]

[0002] Globally, over 300 million adults aged 45 years or older undergo major non-cardiac surgery every year (Weiser et al. 2015). Of these, millions die from complications within 30 days (Botto et al. 2014), and a significant proportion of patients suffer major cardiac complications within the first year after surgery (Ekelof et al. 2016). The main cause of postoperative mortality is cardiac complications due to ischemic injury of the myocardium, which causes cell damage and uncontrolled cell death (Botto et al. 2014, Sessler et al. 2018, Landesberg et al. 2009). In addition to the number of deaths, postoperative cardiac injury prolongs recovery and hospitalization by causing a significant number of postoperative complications, resulting in patient suffering and increased healthcare costs (Devereaux et al. 2015).

[0003] Postoperative Major Cardiovascular and Cerebrovascular Events (MACCE) MACCE, a major cardiovascular or cerebrovascular event, is the most common cause of serious perioperative morbidity and mortality, with incidence ranging from 1 to 7%, depending on the population studied (Sabate et al. 2011).

[0004] Ten percent of patients who develop MACCE die during hospitalization. Several independent preoperative and intraoperative risk factors for MACCE have been suggested, including coronary artery disease, chronic congestive heart failure, intraoperative hypotension, and blood transfusion. However, no risk stratification system with high sensitivity and specificity is available.

[0005] Postoperative myocardial infarction (MI) Myocardial infarction may be defined by myocardial necrosis caused by prolonged ischemia and is a common cause of death and disability (Thygesen et al. 2012). Two different mechanisms may cause myocardial infarction, both of which are seen after non-cardiac surgery. Type I MI is caused by acute coronary syndromes. Myocardial blood flow is reduced due to rupture, ulceration, erosion, or detachment of unstable atherosclerotic plaques in one or more coronary vessels, followed by intraluminal thrombosis (Landesberg et al. 2009, Devereaux et al. 2009). Type II MI is caused by a long-term imbalance between myocardial oxygen supply and demand and may result as a consequence of conditions such as cardiac arrhythmias, anemia, respiratory failure, hypotension, hypertension, or through the direct toxic effects of high levels of endogenous or exogenous circulating cortisol and catecholamines (Ekelof et al. 2016, Landesberg et al. (2009), Thygesen et al. 2012).

[0006] The diagnostic criteria for MI consist of an elevation of the cardiac biomarker troponin threefold above the upper level of the reference range in a background of suspected myocardial ischemia accompanied by either ischemic symptoms or ischemic electrocardiogram (ECG) findings (Thygesen et al. 2012 ).

[0007] Ischemic symptoms of MI include various combinations of nonspecific symptoms such as chest, upper extremity, or mandibular pain, dyspnea, etc. In most cases, symptoms last more than 20 minutes and are diffuse, not focal, positional, or influenced by motion.

[0008] However, patients with MI are often asymptomatic. This is the case in the case of postoperative MI, where myocardial injury often occurs within 48 hours after noncardiac surgery (Thygesen et al. 2012). A possible explanation for the lack of symptoms during this period is that patients are usually taking pain medications that mask the symptoms. This may partly explain why 65% ​​of perioperative myocardial infarctions (PMI) are asymptomatic and associated with poor outcomes (Devereaux et al. 2015, Devereaux et al. 2017). 12% of patients with PMI die within 30 days, with the majority of deaths occurring within 48 hours (Hanson et al. 2013).

[0009] Myocardial Injury After Noncardiac Surgery (MINS) MINS is a myocardial injury associated with adverse outcomes due to ischemia that occurs in 8% of surgical patients (Botto et al. 2014). 10% of patients with MINS die within 30 days, and MINS patients have a higher 1-year and >1-year mortality rate, as well as a higher incidence of nonfatal cardiac arrest, congestive heart failure, and stroke (Botto et al. 2014, Mauermann et al. 2016). Furthermore, local myocardial injury can stun the myocardium, leading to diastolic dysfunction and reduced cardiac output, which in turn can result in reduced peripheral blood supply, impaired tissue healing, and increased risk of wound infection (Noordzij et al. 2015).

[0010] The current diagnostic criterion for MINS is a postoperative troponin elevation determined to be due to myocardial ischemia (without evidence of nonischemic etiology), with or without ischemic symptoms. MINS preferably does not include perioperative myocardial injury resulting from etiologies other than ischemia, e.g., sepsis or pulmonary embolism. The criteria for MINS cover a broader range of myocardial injury than MI, from reversible myocardial injury to necrosis. This broader concept includes several signs of myocardial injury, making MINS a more appropriate term for surgical patients and reducing the risk of underestimating the extent of myocardial damage seen after noncardiac surgery (Mauermann et al. 2016).

[0011] 93.6% of MINS cases occur within 3 days after surgery. MINS patients have mild troponin elevations and often lack ischemic features (Noordzij et al. 2015). 84% of patients with MINS do not experience ischemic symptoms and only 34.9% show signs of ischemia on the ECG (Botto et al. 2014).

[0012] These findings indicate that reliable diagnosis of perioperative myocardial injury is in most cases only possible with serial postoperative troponin measurements. It has been reported that otherwise 93.1% of MINS and 68% of PMI may go undetected (Devereaux et al. 2017).

[0013] Furthermore, due to the delayed expression of troponin in the case of cardiac complications, there are periods without troponin, which hinders rapid initiation of treatment and increases the likelihood of serious complications and mortality.

[0014] The mechanism of MINS remains unclear, but it has been suggested to be similar to that behind PMI (Mauermann et al. 2016). Although several trials have been conducted to combat MINS, methods to safely and efficiently prevent myocardial injury are still unknown (Sessler et al. 2018). As an example, the POISE study, a large randomized trial administering beta-blockers perioperatively and postoperatively, was able to reduce the occurrence of major cardiovascular events by 30%, but at the same time increased the incidence of severe hypotension, stroke, and death (Devereaux et al. 2008). As it is difficult to detect or predict MINS based on clinical symptoms, clear diagnostic and prognostic measures based on molecular approaches are needed.

[0015] Perioperative myocardial injury (PMI) Perioperative myocardial injury (PMI) is a serious cause of mortality after non-cardiac surgery. As the majority of PMIs are asymptomatic, in the absence of systematic screening, PMI is routinely overlooked. Notably, PMI is a common complication after non-cardiac surgery and is associated with substantial short-term and long-term mortality, despite early detection during routine clinical screening. Mortality appears to be comparable in patients with PMI who do not meet any of the other additional criteria required for spontaneous acute myocardial infarction and in those who do (Puelacher et al. 2015). Given the difficulties in detecting PMI and in predicting whether a patient is at risk for PMI, additional measures are required to address these challenges and allow for suitable, preferably early or anticipatory, therapeutic or preventive measures.

[0016] Postoperative infection The development of infection after surgery is one of the major postoperative complications, causing pain, poor wound healing, the need for further treatment including antibiotics, prolonged hospital stay, and increased healthcare costs. Postoperative infections can lead to serious problems including surgical failure, sepsis, organ failure, and in some cases ultimately death.

[0017] A postoperative infection may be defined as any infection that occurs within 30 days of surgery and may be related to the surgery itself or to the postoperative course. The incidence of postoperative infections can vary widely and depends on the type of procedure performed and the patient's unique risk factors for developing an infection.

[0018] Post-operative infections may involve, for example, the wound itself, or deeper infections within a body cavity, or systemic infections, but may also include more distal infections such as pulmonary infections (e.g., pneumonia) or catheter-associated urinary tract infections.

[0019] Postoperative wound infections, also known as surgical site infections (SSIs), complicate the recovery process for many patients. As defined by the Centers for Disease Control and Prevention (CDC), these infections typically occur within 30 days of surgery in the area or part of the body where surgery was performed.

[0020] SSIs may be classified as superficial / incisional if they are limited to the skin and subcutaneous tissue, as deep incisional if they involve fascia and muscle, or as visceral space if they involve a body cavity (e.g., the abdominal cavity after gastrointestinal surgery) (Horan et al. 2008).

[0021] Deep tissue and organ space SSIs are less frequent than superficial SSIs, but are associated with increased morbidity / mortality, readmission rates, longer length of stay, and overall hospital-related costs when compared with superficial SSIs.While the majority of SSIs are uncomplicated, others may be severe and more challenging, often requiring extensive surgical debridement, multiple reoperations, and can be life-threatening.

[0022] Postoperative infections may result from several factors in addition to infection at the surgical site. Postoperative pneumonia and airway infections, for example, are generally considered to be signs of physiological and immunological disorders that occur after major surgery. Postoperative pulmonary infections are associated with coughing, phlegm, shortness of breath, chest pain, body temperature above 38°C, and pulse rates above 100 beats per minute. Up to half of people have asymptomatic chest symptoms after surgery, and up to a quarter may develop symptomatic disease.

[0023] The incidence of postoperative pulmonary complications in major surgery ranges from less than 1% to 23%. Several studies have shown that pulmonary complications are more common than cardiac complications, and postoperative respiratory failure is a common postoperative complication (Miskovic at al. 2017).

[0024] Diagnosis of surgical site infections can be difficult because signs and symptoms are often non-specific and may lack sensitivity in some clinical scenarios.

[0025] However, early diagnosis of postoperative infection is crucial to initiating appropriate treatment, such as antibiotic therapy.

[0026] Particularly serious postoperative infections are associated with blood infections or sepsis. Despite significant improvements in diagnostic and preventive measures, the incidence of sepsis continues to grow rapidly in hospitalized patients (Martin et al. 2003), with mortality ranging from 10% to 54%, depending on the level of disease severity, the definition of organ dysfunction used, and country-specific incidence (Kaukonen et al. 2014, Vincent et al. 2006).

[0027] For any postoperative disease, but especially for sepsis, early and accurate assessment of both the infection burden and disease severity in the context of the overall pathophysiological host response is crucial to make rapid and reliable decisions regarding diagnostic tests and treatment strategies.

[0028] In light of the prior art, there is a need to provide diagnostic and prognostic methods that may allow early diagnosis or risk assessment of post-operative adverse events, such as post-operative cardiovascular or cerebrovascular events or post-operative infections. Summary of the Invention

[0029] In light of the difficulties in the prior art, the technical problem underlying the present invention is to provide improved or alternative means for the diagnosis, prognosis, risk assessment, and / or risk stratification of adverse events in post-operative patient health, especially within the first few days after surgery.

[0030] The present invention therefore aims to provide methods, kits and further means for the diagnosis, prognosis, risk assessment and / or risk stratification of adverse events, including in particular post-operative infections or cardiovascular or cerebrovascular events.

[0031] One object of the present invention is to use a biomarker or a combination of biomarkers to distinguish whether a patient will suffer or is at risk of suffering an adverse event after surgery, either pre-operatively, peri-operatively, or post-operatively.

[0032] The solutions to the technical problem of the present invention are provided in the independent claims. Preferred embodiments of the invention are provided in the dependent claims. The present invention relates to a method for the diagnosis, prognosis, risk assessment, and / or risk stratification of adverse events in post-operative patient health, the method comprising: - Providing at least one sample from a patient who has undergone or will undergo surgery, wherein the at least one sample is isolated from the patient pre-operatively, intra-operatively, or post-operatively; - determining the level of at least one biomarker selected from the group consisting of proADM, PCT, and proET-1, or a fragment thereof, in said at least one sample, - the level of the at least one biomarker or a fragment thereof correlates with the likelihood of an adverse event.

[0033] The present invention particularly relates to a method for the diagnosis, prognosis, risk assessment and / or risk stratification of adverse events in post-operative patient health, the method comprising: - Providing at least one sample from a patient who has undergone surgery, is undergoing surgery, or is scheduled to undergo surgery, wherein the at least one sample is isolated from the patient pre-operatively, intra-operatively, or post-operatively; - determining the level of at least one biomarker in said at least one sample, - the level of said at least one biomarker or a fragment thereof correlates with the likelihood of said adverse event, wherein at least one biomarker is proADM or a fragment thereof and the adverse event is an infection.

[0034] The present invention particularly relates to a method for the diagnosis, prognosis, risk assessment and / or risk stratification of adverse events in post-operative patient health, the method comprising: - Providing at least one sample from a patient who has undergone surgery, is undergoing surgery, or is scheduled to undergo surgery, wherein the at least one sample is isolated from the patient pre-operatively, intra-operatively, or post-operatively; - determining the level of at least one biomarker in said at least one sample, - the level of said at least one biomarker or a fragment thereof correlates with the likelihood of said adverse event, wherein the at least one biomarker is PCT or a fragment thereof, and the adverse event is a cardiovascular or cerebrovascular event.

[0035] The present invention particularly relates to a method for the diagnosis, prognosis, risk assessment and / or risk stratification of adverse events in post-operative patient health, the method comprising: - Providing at least one sample from a patient who has undergone surgery, is undergoing surgery, or is scheduled to undergo surgery, wherein the at least one sample is isolated from the patient pre-operatively, intra-operatively, or post-operatively; - determining the level of at least one biomarker in said at least one sample, - the level of said at least one biomarker or a fragment thereof correlates with the likelihood of said adverse event, wherein at least one biomarker is proET-1 or a fragment thereof, and the adverse event is preferably an infection and / or a cardiovascular or cerebrovascular event.

[0036] The patient of the method of the present invention has undergone surgery, is undergoing surgery, or is scheduled to undergo surgery at the time of sample collection. The likelihood of occurrence of adverse events in the patient's health after surgery can be evaluated by the levels of the biomarkers proADM, PCT, and / or proET-1 before, during, or after surgery.

[0037] This method can be very useful for prompt treatment guidance of postoperative patients. By determining the levels of the biomarkers proADM, PCT, and / or proET-1, the possibility of adverse events such as infections or cardiovascular or cerebrovascular events can be determined independently of obvious clinical symptoms.

[0038] The likelihood of adverse events occurring after surgery can be assessed by comparing the levels of proADM, proET-1, and / or PCT, or fragments thereof, in the sample with a reference level (such as a threshold or cut-off value and / or a population average), the reference level corresponding to the levels of proADM, proET-1, and / or PCT, or fragments thereof, in patients who do not suffer from a subsequent adverse event after surgery and in patients who suffer from a subsequent adverse event after surgery. Optionally, the reference level may correspond to the levels of proADM, proET-1, and / or PCT, or fragments, in healthy subjects.

[0039] Therefore, the method of the present invention can help diagnose or predict the possibility of adverse events in the health of postoperative patients.This means that the method of the present invention can distinguish high-risk patients who are more likely to suffer from complications or will have more severe conditions in the future from low-risk patients, so that patients are not expected to have or will suffer from postoperative adverse events, such as infections or cardiovascular or cerebrovascular events, which may require certain therapeutic measures.

[0040] For postoperative patients, the surgical context often masks early clinical symptoms of an adverse event. Typically, during the first few days after surgery, and sometimes for extended periods, patients routinely receive numerous medications, including analgesics such as analgesic medications and nonsteroidal anti-inflammatory drugs (NSAIDs), that cushion the patient's or clinical individual's perception of possible early clinical symptoms of an adverse event.

[0041] For example, chest pain, shortness of breath, nausea, or weakness constitute the clinical symptoms of myocardial infarction. Stroke is typically accompanied by residual motor sensory or cognitive dysfunction. However, under the influence of residual anesthesia or additional analgesic medications, such symptoms may not be recognized at all or may be misdiagnosed. Similarly, early signs of infection such as headache, localized pain at the site of infection, weakness, or general deterioration of health may be masked by medication or misinterpreted as a predetermined consequence of surgery.

[0042] As shown in more detail by the data below, determining the levels of the biomarkers proADM, PCT, and / or proET-1 can be a valuable guide to treatment and monitoring, as it allows the prognosis or diagnosis of adverse events independent of clinical symptoms.

[0043] For example, early diagnosis of an infection using the methods described herein allows for the prompt initiation of appropriate antibiotic treatment.Similarly, diagnosis of a cardiovascular event may allow for the prompt initiation of coronary artery bypass grafting, administration of appropriate medications, or coronary angioplasty.

[0044] It was a surprising finding that the biomarkers proADM, PCT, and proET-1 showed similar potential as markers for predicting or diagnosing adverse events in postoperative patient health.

[0045] Adrenomedullin (ADM), a peptide containing 52 amino acids, was first isolated from human phenochromocytome (Kitamura K et al. 1993). ADM has been shown to have antihypertensive, immunomodulatory, metabolic, and vascular effects. It is a potent vasodilator and is widely produced in tissues, helping to maintain blood supply to individual organs. ADM stabilizes the microcirculation and protects against endothelial permeability and the resulting organ failure, and has shown considerable promise, especially in the fields of sepsis (Andaluz-Ojeda et al. 2015), lower respiratory tract infections (Hartmann et al. 2012, Albrich et al. 2011a, Albrich et al. 2011b, Albrich et al. 2013), lung transplantation (Riera et al. 2015), and thoracic surgery (Schoe et al. 2015).

[0046] Endothelin-1 is a family member of 21 amino acid peptides that are believed to play an important pathophysiological role in cardiovascular dysfunction (Haaf et al. 2014, Papssoutiriou et al. 2006). ET-1 is a potent vasoconstrictor and is primarily synthesized by endothelial cells. It plays a role in angiogenesis and the development of atherosclerosis by exerting mitogenic effects on smooth muscle cells and causing endothelial dysfunction and inflammation (Haaf et al. 2014, Zhang et al. 2017). Plasma levels of pro-ET-1 have been shown to be elevated in several cardiovascular pathologies, such as acute myocardial infarction, congestive heart failure, sepsis-induced myocardial dysfunction, pulmonary hypertension, coronary artery disease, hypertension, aging, diabetes, as well as ischemic heart disease and myocardial infarction (Haaf et al. 2014, Zhang et al. 2017, Setiano et al. 2016, Lundberg 2016).

[0047] PCT is a prehormone of calcitonin, normally secreted by C cells of the thyroid gland in response to hypercalcemia. Under these normal conditions, only small serum PCT concentrations are detectable (Whicher et al. 2001). In cases of bacterial infection, inflammation or sepsis, procalcitonin levels are elevated, and PCT is a well-known and routinely used biomarker to diagnose these diseases.

[0048] Although ADM, proET-1, and PCT are currently employed in different clinical scenarios, the biological functions of these biomarkers exhibit common features. In particular, both ADM and PCT have been shown to interact with the calcitonin receptor complex in endothelial cells, specifically the calcitonin gene-related peptide receptor (CGRP receptor) (Sexton et al. 2008, Nikitenko et al. 2006, Smith et al. 2002). Furthermore, plasma levels of proET-1 have also been shown to correlate with CGRP, indicating a common signaling pathway, for example in the regulation of blood pressure (Parlapiano et al. 1999, Wang et al. 2004).

[0049] Calcitonin gene-related peptide (CGRP) is an endogenous vasoactive peptide encoded by the calcitonin gene in neuronal cells, which is distributed throughout the cardiovascular system and has been shown to act as a potent vasodilator. CGRP and its receptors have been proposed to be involved in the pathophysiology of migraine, in particular (Ho Tony W. et al. GRP and its receptors provide new insights into migraine pathophysiology Nature Reviews Neurology vol. 6, pp. 573-582 (2010)). However, plasma levels of CGRP have also been shown to be elevated in sepsis (Joyce et al. 1990), and a more general role for CGRP receptors in the control of pain and inflammation has been proposed (Benemei et al. 2009).

[0050] Without intending to be bound by theory, the surprising finding of the common potential of proADM, PCT, and proET-1 in the diagnosis and prognosis of postoperative adverse events, as shown in the data, may be related to their common interaction with calcitonin gene-related peptide (CGRP) and their receptors, as well as other receptors of the calcitonin complex receptor family.

[0051] The method may also be valuable as a predictor of risk of adverse events and in guiding postoperative patient monitoring. If the levels of the biomarkers proADM, PCT, and / or proET-1 indicate a high likelihood of postoperative adverse events, medical personnel may adjust the frequency and / or intensity of monitoring. Depending on the prognosis of the adverse event, specialized diagnostic tools may be used and routine testing procedures may be performed at more frequent intervals.

[0052] In this regard, the methods are particularly valuable for risk assessment or stratification, allowing for the grouping or classification of patients into different groups, such as risk groups requiring more frequent monitoring or additional diagnostics, or treatment groups that receive certain different therapeutic treatment regimens depending on the classification.

[0053] Therefore, the possibility of early diagnosis or prognosis using the biomarkers described herein not only allows for rapid treatment guidance to improve patient outcomes but also helps in adopting more resource-efficient strategies.

[0054] In one embodiment, the adverse event is a cardiovascular or cerebrovascular event.

[0055] In one embodiment, the adverse event is myocardial infarction (MI).

[0056] In one embodiment, the adverse event is myocardial injury after non-cardiac surgery (MINS).

[0057] In one embodiment, the adverse event is perioperative myocardial injury (PMI).

[0058] In one embodiment, the adverse event is a major adverse cardiovascular or cerebrovascular event (MACCE).

[0059] In one embodiment, the adverse event is stroke and / or transient ischemic attack.

[0060] In one embodiment, the adverse event is an infection.

[0061] In one embodiment, the adverse event is a fungal, bacterial, or viral infection.

[0062] In one embodiment, the adverse event is a localized infection, such as, for example, a respiratory infection, a urinary tract infection, a skin infection, or an abdominal infection.

[0063] In one embodiment, the adverse event is a systemic blood infection, sepsis, severe sepsis, and / or septic shock.

[0064] In one embodiment, the adverse events are a cardiovascular or cerebrovascular event and an infection, which preferably occur in a close temporal relationship to each other, preferably simultaneously.

[0065] In one embodiment, the adverse events are myocardial injury after non-cardiac surgery (MINS) and infection.

[0066] In one embodiment, the adverse events are perioperative myocardial injury (PMI) and infection.

[0067] In one embodiment, the adverse events are major adverse cardiovascular or cerebrovascular events (MACCE) and infections.

[0068] In one embodiment, the adverse events are cardiovascular or cerebrovascular events and blood infections.

[0069] In one embodiment, the adverse events are myocardial injury after non-cardiac surgery (MINS) and blood infections.

[0070] In one embodiment, the adverse events are major adverse cardiovascular or cerebrovascular events (MACCE) and blood infections.

[0071] In one embodiment, the adverse events are perioperative myocardial injury (PMI) and blood infection.

[0072] It is quite unexpected that, based on the measurement of the biomarkers described herein, accurate and reliable conclusions can be drawn about whether a patient will suffer from cardiovascular or cerebrovascular events such as MINS or MACCE, as well as infections such as blood infections after surgery. This prognostic ability of proADM, PCT, and / or proET-1 in the specific context described herein is novel and surprising, allowing for improved detection, prediction, and management of adverse events surrounding surgery. The combined assessment of these possible adverse events is also of particular clinical relevance. Optimal treatment guidelines may be highly dependent on such assessment, since measures or medications to treat infections may be detrimental to cardiovascular or cerebrovascular events and vice versa. By providing a diagnosis or prognosis of both adverse events, clinicians may choose the best possible treatment approach.

[0073] For example, when predicting or diagnosing MACCE, PMI, or MINS, subsequent clinical procedures such as bypass surgery or angioplasty increase the risk of exacerbating a possible infection. Early preemptive anti-infective therapy, such as antibiotic therapy, can be critical to overall positive patient outcomes.

[0074] In one embodiment, the surgery is a non-cardiac surgery, and at the time the sample is isolated from the patient, the patient has undergone, is undergoing, or is scheduled to undergo a non-cardiac surgery. Preferably, the non-cardiac surgery is a major non-cardiac surgery, which includes more extensive surgery, and typically must be performed under general anesthesia and requires at least one night of hospitalization.

[0075] In one embodiment, the surgery is abdominal or gastrointestinal surgery and at the time the sample is isolated from the patient, the patient has undergone, is undergoing, or is scheduled to undergo abdominal or gastrointestinal surgery.

[0076] The term hospitalization preferably refers to the maintenance of control and / or evaluation of a patient's condition within a hospital, whether in the emergency room, a ward, an intensive care unit, or elsewhere in a hospital or clinic.

[0077] In one embodiment, the surgery is abdominal surgery and at the time the sample is isolated from the patient, the patient has undergone, is undergoing, or is scheduled to undergo abdominal surgery.

[0078] In one embodiment, the patient is 50 years of age or older, or 55, 60, 65, 70, or 75 years of age or older, making the methods described herein particularly valuable to patients in these age groups as they are at particularly high risk of developing adverse events following surgery.

[0079] In a preferred embodiment of the method of the present invention, the sample is isolated from the patient about 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days before or after surgery.

[0080] In other embodiments, samples are isolated at time points between 30 minutes and 12 hours, 12 to 36 hours, 3 to 5 days, 7 to 14 days, 8 to 12 days, or 9 to 11 days before or after surgery.

[0081] Ranges between any given above values ​​can be used to define the time points at which samples are obtained.

[0082] In one embodiment, the sample is isolated pre-operatively, within 7 days, preferably within 3 days, 1 day, 12 hours, or less, prior to surgery.

[0083] In one embodiment, the sample is isolated pre-operatively, at least 3 hours, preferably at least 6 hours, before surgery.

[0084] In one embodiment, the sample is isolated pre-operatively, within 7 days, preferably within 3 days, more preferably within 1 day, at least 3 hours, preferably at least 6 hours prior to surgery.

[0085] The above embodiment allows prediction of postoperative adverse events before surgery begins. If the risk of adverse events is particularly high, surgery may be postponed or even canceled. Furthermore, preoperative risk assessment of postoperative adverse events allows the administration of prophylactic drugs, such as antibiotics in case of infections, or anticoagulants in case of cardiovascular or cerebrovascular events.

[0086] In one embodiment, the sample is isolated from the patient post-operatively, at least 12 hours, 24 hours, 48 ​​hours, 72 hours, or more, and / or within 72 hours, 48 ​​hours, 24 hours, 12 hours, or less, after surgery.

[0087] In one embodiment, the sample is isolated post-operatively, within 12 hours, preferably within 6 hours, after surgery. The embodiment preferably relates to isolation of the sample while the patient is monitored in a post-anesthesia care unit (PACU).

[0088] In one embodiment, the sample is isolated on post-surgery day 1 (POD1), in which case the sample is preferably isolated 12 to 36 hours after surgery, preferably 18 to 30 hours after surgery.

[0089] In one embodiment, the sample is isolated on post-surgery day 2 (POD2), in which case the sample is preferably isolated 36 to 60 hours after surgery, preferably 42 to 54 hours after surgery.

[0090] In one embodiment, the sample is isolated on post-surgery day 3 (POD3), in which case the sample is preferably isolated 60 to 84 hours after surgery, preferably 66 to 78 hours after surgery.

[0091] In some embodiments, the invention describes the use of biomarker levels from samples at one, two, or three time points, e.g., preoperatively, in the postanesthesia care unit (PACU), or 1, 2, or 3 days after surgery (POD1-POD3), to assess the likelihood of a postoperative adverse event. As shown by the data below, the different time courses of biomarker levels in patients with and without adverse events allow for particularly reliable prognosis or diagnosis when samples are taken at two or more time points and percentages or absolute differences for the different sample points are analyzed.

[0092] In one embodiment, a first sample is isolated pre- and / or peri-operatively and a second sample is isolated post-operatively.

[0093] In one embodiment, the first sample is isolated pre-operatively and the second sample is isolated peri-operatively and / or post-operatively.

[0094] In one embodiment, the first sample is isolated within 3 days, preferably within 1 day or less, prior to surgery, and the second sample is isolated within 12 hours, preferably within 6 hours or less, after surgery.

[0095] In one embodiment, the first sample is isolated within 3 days, preferably within 1 day or less, prior to surgery, and the second sample is isolated within 1, 2, 3 or more days after surgery.

[0096] In one embodiment, the first sample is isolated within 12 hours, preferably within 6 hours, after surgery, and the second sample is isolated within 1, 2, 3 or more days after surgery.

[0097] In one embodiment, the first sample is isolated 1 day after surgery and the second sample is isolated 2, 3 or more days after surgery.

[0098] In one embodiment, the first sample is isolated two days after surgery and the second sample is isolated three or more days after surgery.

[0099] In one embodiment, a first sample is isolated from a patient at a first time point and a second sample is isolated from a patient at a second time point, preferably with at least 6, 12, 24, 36, 48, or more hours elapsed between the first and second time points. However, it is preferred that less than 72 hours, no more than 48 hours elapse, such that the preferred period between sample isolations can be, for example, 6 to 72 hours, 6 to 48 hours, 12 to 72 hours, 12 to 48 hours, or any other combination of the preferred maximum and minimum periods described above.

[0100] In the context of the present invention, a lower level of the marker in the second sample determined compared to the first sample may indicate that the level of the respective marker in the patient over the observation time is decreased. Conversely, an increase in the level in the second sample compared to the first sample may indicate that the level of the marker over the observation time is increased.

[0101] In one embodiment, a method for diagnosis, prognosis, risk assessment, and / or risk stratification of an adverse event in post-operative patient health comprises isolating first and second samples at first and second time points, and the likelihood of the adverse event is correlated with an absolute difference in the levels of biomarkers, a ratio of the levels of biomarkers, and / or a rate of change in the levels of biomarkers relative to the first and second time points.

[0102] The rate of change in the level of a biomarker relative to a first and second time point preferably refers to the absolute difference in the level of the biomarker relative to the time difference between said first and second time points.

[0103] With respect to the first and second time points, any combination of the time points disclosed herein for isolating samples may be preferred without being intended to be limiting, and thus the first and second time points may refer to within 3 days, within 1 day, or less before surgery, within 6 hours, within 12 hours, or less after surgery, and 1 day, 2 days, or 3 days after surgery, with it being understood that preferably at least 6 hours, 12 hours, 24 hours, or more have elapsed between the first and second time points.

[0104] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and an increase or plateauing in levels of proADM, PCT, and / or proET-1, or fragments thereof, indicates an increased likelihood of a post-operative adverse event.

[0105] In a preferred embodiment of the invention, the sample is selected from the group consisting of a blood sample, such as a whole blood sample, a serum or plasma sample, a saliva sample, and a urine sample.

[0106] In one embodiment, determining the level of proADM or a fragment thereof comprises determining the level of MR-proADM in the sample. As shown in the examples below, MR-proADM, preferably determined using an established immunoassay product from BRAHMS (Hennigsdorf, Germany), indicates a reliable and effective prognosis by the methods described herein. Alternative ADM molecules, such as mature adrenomedullin or PAMP, including precursors or fragments, can also be used.

[0107] In one embodiment, determining the level of PCT or a fragment thereof comprises determining the level of PCT1-116, PCT2-116, or PCT3-116 in the sample. As shown in the examples below, PCT1-116, PCT2-116, or PCT3-116 are preferably determined using established immunoassay products from BRAHMS (Hennigsdorf, Germany) and show reliable and effective prognosis by the methods described herein. Alternative PCT molecules, such as calcitonin or katacalcin, including precursors or fragments, may also be used.

[0108] In one embodiment, determining the level of proET-1 or a fragment thereof comprises determining the level of CT-proET-1 in the sample. As shown in the examples below, CT-proET-1, preferably determined using an established immunoassay product from BRAHMS (Hennigsdorf, Germany), indicates a reliable and effective prognosis by the methods described herein. Alternative proET-1 molecules, including precursors or fragments, may also be used.

[0109] In one embodiment, the method further comprises treatment guidance, stratification, and / or control.The method allows the application of a certain therapy, therapeutic activity, or medical intervention to treat or prevent the adverse event based on the determined level of one or more biomarkers.The treatment guidance, stratification, and / or control depends on the adverse event, especially with respect to its type and / or diagnosed / predicted severity.

[0110] In one embodiment, the level of at least one biomarker correlates with the likelihood of infection, which indicates initiation of treatment with an anti-infective agent, preferably an antibacterial or antibiotic agent.

[0111] In some embodiments, the method comprises a molecular analysis of a sample from the patient to detect the infection. The sample used for the molecular analysis to detect the infection is preferably a blood sample, a blood culture sample, a tissue sample. In a preferred embodiment, the molecular analysis is a method aimed at detecting one or more biomolecules derived from a pathogen that may cause the infection. The one or more biomolecules may be nucleic acids, proteins, sugars, carbohydrates, lipids, and / or combinations thereof, such as glycosylated proteins, and preferably nucleic acids. The biomolecules are preferably specific for one or more pathogens. According to a preferred embodiment, such biomolecules are detected by one or more methods for the analysis of biomolecules, selected from the group including nucleic acid amplification methods such as PCR, qPCR, RT-PCR, qRT-PCR, or isothermal amplification, mass spectrometry, detection of enzyme activity, and detection methods based on immunoassays. Further methods of molecular analysis are known to those skilled in the art and are included in the method of the present invention.

[0112] Using additional molecular analysis of the sample, a person skilled in the art may also select an appropriate anti-infective agent to treat the infection. Advantageously, the level of the determined biomarker may help guide the intensity of the treatment. Generally speaking, a higher level of the biomarker indicates a more severe infection state, and thus may guide a more intensive, e.g., more frequent or higher dose, treatment.

[0113] In one embodiment, the level of at least one biomarker correlates with the likelihood of an adverse cardiovascular or cerebrovascular event indicating further diagnostic evaluation selected from CT scan, MRI scan, angiogram, arteriogram, X-ray, echocardiogram, ECG, and EEG.

[0114] After evaluating the possibility of cardiovascular or cerebrovascular adverse events, additional tests may be performed, for example, to obtain more information about the patient's condition. For example, if myocardial infarction or myocardial injury is predicted or diagnosed, the patient may be sent for an electrocardiogram (preferably a 12-lead ECG). More extensive imaging tests include coronary angiography or coronary catheterization.

[0115] If a stroke is predicted or diagnosed, the patient may be sent for a neurological examination (such as National Institutes of Health Stroke Scale (NIHSS), CT scan, MRI scan, Doppler ultrasound, or arteriogram).

[0116] In this regard, the potential of biomarkers for early diagnosis or prediction is particularly valuable, since the deterioration of the patient's overall health depends on rapid counter-therapy.

[0117] In some embodiments, the method may include the use of additional diagnostic methods to identify the underlying pathology. Any diagnostic method known in the art may be used, and a person skilled in the art will be able to select the appropriate diagnostic method for cardiovascular or cerebrovascular events. In some embodiments, the methods described herein include other diagnostic methods, such as physical measurements of cardiac or motor function known in the art, in addition to or as an alternative to the measurement of other biomarkers. Additional diagnostic measures may also include the determination of other biomarkers indicative of cardiac disease, such as cardiac troponin (cTn).

[0118] In one embodiment, the level of at least one biomarker correlates with the likelihood of an adverse cardiovascular or cerebrovascular event, indicating initiation or readiness for anticoagulant therapy, oxygen therapy, lytic therapy, percutaneous coronary intervention, percutaneous transluminal angioplasty, coronary artery bypass grafting, and / or stent implantation.

[0119] In some embodiments, medical treatment includes administration of statins, beta-blockers, alpha-2-adrenergic agonists, or other anti-ischemic agents such as calcium channel blockers or nitrates, and may be used as a preventative treatment strategy before an adverse event such as myocardial infarction or injury occurs.

[0120] In one embodiment, the level of at least one biomarker correlates with the likelihood of a post-operative adverse event indicating that the patient will require frequent monitoring and / or critical care.

[0121] Preferably, critical care refers to therapeutic measures that aim to stabilize or alleviate the health condition of patients who are at risk of developing or are in a life-threatening condition.For example, in the case of serious infections, such as blood infections, examples of critical care treatments include, but are not limited to, infusion therapy, intravenous antibiotics, and in some embodiments, essentially any treatment other than oral antibiotics.For cardiovascular or cerebrovascular events, critical care may, for example, involve oxygen therapy, dissolution therapy, or emergency or coronary artery bypass grafting, and / or stent implantation.

[0122] Frequent monitoring preferably refers to frequent assessment of the patient's health status with respect to adverse events, and may include monitoring of general parameters of health status, such as blood pressure, respiratory rate, oxygen partial pressure, body temperature, etc., or more specific additional parameters or diagnostic measures as described above with respect to adverse events. Frequent monitoring may preferably refer to monitoring at intermittent time intervals of up to 6 hours, preferably 3 hours, 2 hours, or 1 hour.

[0123] In some embodiments, for example in an ICU, the monitoring is continuous.

[0124] In some embodiments, a level of at least one biomarker above a threshold indicates a high likelihood of an adverse event.

[0125] In some embodiments, a level of at least one biomarker above a threshold indicates a low likelihood of an adverse event.

[0126] According to the present invention, the term "indicative" in the context of "indicating a high probability of an adverse event" and "indicating a low probability of an adverse event" is intended as a measure of risk and / or likelihood. Preferably, an "indication" of the presence or absence of an adverse event or the presence or absence of a risk of developing said adverse event is intended as a possibility for risk assessment or diagnosis, and is typically not interpreted in a restrictive manner to clearly refer to the absolute presence or absence of said event.

[0127] Thus, the term "indicative of an adverse event" may be understood as indicating a high likelihood of occurrence of an adverse event, respectively.

[0128] With the above in mind, the use of the thresholds disclosed herein allows a reliable diagnosis of adverse events or an estimation of their risk, allowing appropriate action by medical professionals.

[0129] In embodiments of the invention, deviations from the following disclosed possible thresholds, e.g., ±20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, as well as exact thresholds, are also disclosed and claimed.

[0130] The threshold values ​​disclosed herein preferably refer to the measurement of proADM, PCT, proET-1 or fragments thereof protein levels in a plasma sample obtained from a patient by means of the Thermo Scientific BRAHMS KRYPTOR assay or an assay suitable for an automated system. Thus, the values ​​disclosed herein may vary to some extent depending on the detection / measurement method used, and the specific values ​​disclosed herein are also intended to read corresponding values ​​determined by other methods.

[0131] All threshold values ​​disclosed herein for levels of markers or biomarkers such as ADM, PCT, or proET-1 are to be understood as being "above" or below a particular threshold. For example, an embodiment relating to a level of proADM or a fragment thereof greater than 1.2 nmol / L is to be understood as relating to a level of proADM or a fragment thereof equal to or greater than 1.2 nmol / L.

[0132] Embodiments relating to determining the level of proADM or a fragment thereof to diagnose or predict cardiovascular or cerebrovascular events ADM / MACCE: In one embodiment, determining the level of at least one additional biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE.

[0133] In one embodiment, the sample is isolated before surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 nmol / L and 0.8 nmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8 nmol / L.

[0134] In one embodiment, the sample is isolated postoperatively within 12 hours, preferably within 6 hours, of surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.1 nmol / L and 1.4 nmol / L ±20% or more indicates a high probability of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4 nmol / L.

[0135] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.4 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8 nmol / L.

[0136] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.8 nmol / L ±20% or more indicates a high probability of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.5 5, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68 , 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0137] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.9 nmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6 , 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1. 76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9nmol / L.

[0138] In one embodiment, the sample is isolated after surgery and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.1 nmol / L and 1.5 nmol / L ±20% or more indicates a high probability of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0139] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.4 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8 nmol / L.

[0140] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of proADM or a fragment thereof, and an increased level of proADM or a fragment thereof indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE.

[0141] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein an increase in the level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 0.01 nmol / L and 0.5 nmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value for the increase in proADM or a fragment thereof between the first and second time points. For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5nmol / L.

[0142] ADM / MINS: In one embodiment, determining the level of at least one additional biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS.

[0143] In one embodiment, the sample is isolated preoperatively, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 nmol / L and 0.8 nmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8 nmol / L.

[0144] In one embodiment, the sample is isolated postoperatively within 12 hours, preferably within 6 hours, of surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.1 nmol / L and 1.4 nmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4 nmol / L.

[0145] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.5 5, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68 , 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0146] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.5 5, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68 , 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0147] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.5 5, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68 , 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0148] In one embodiment, the sample is isolated after surgery and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.1 nmol / L and 1.5 nmol / L ±20% or more indicates a high probability of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0149] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.5 5, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68 , 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0150] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of proADM or a fragment thereof, and an increase or plateauing in the level of proADM or a fragment thereof indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS.

[0151] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein an increase in the level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 0.01 nmol / L and 0.5 nmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered as a suitable threshold value for the increase in proADM or a fragment thereof between the first and second time points. For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5nmol / L.

[0152] Embodiments relating to determining the level of PCT or a fragment thereof to diagnose or predict cardiovascular or cerebrovascular events PCT / MACCE: In one embodiment, determining the level of the at least one additional biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE.

[0153] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 0.4 μg / L ±20% or more indicates a high probability of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4 μg / L.

[0154] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 1.2 μg / L ±20% or more indicates a high probability of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.8 ...2, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.8, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.8, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.8, 0.85, .9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1 .06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2μg / L.

[0155] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.8 μg / L and 1.8 μg / L ±20% or more indicates a high probability of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1. .05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3 ,1.31,1.32,1.33,1.34,1.35,1.36,1.37,1.38,1.39,1.4,1.41,1.42,1.43,1.44,1.45,1.46,1.47,1.48,1.49,1.5,1.51,1.52,1.53,1.54,1.55,1 .56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68 , 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8 μg / L.

[0156] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 1 μg / L and 2 μg / L ±20% or more indicates a high probability of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1. 5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75 , 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1. 88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2μg / L.

[0157] In one embodiment, the sample is isolated postoperatively, one or more days after surgery, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.9 μg / L and 1.5 μg / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered a suitable threshold value. For example, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2 , 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1 .36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5μg / L.

[0158] In one embodiment, the sample is isolated postoperatively, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 1 μg / L and 2 μg / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1. 5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75 , 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1. 88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2μg / L.

[0159] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment thereof, and an increase or plateauing in the level of PCT or a fragment thereof indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE.

[0160] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein an increase in the level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 0.5 μg / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered a suitable threshold value for the increase in PCT or a fragment thereof between the first and second time points. For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5 μg / L.

[0161] PCT / MINS: In one embodiment, determining the level of the at least one additional biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS.

[0162] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker includes determining the level of PCT or a fragment thereof, and a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.25 μg / L and 0.4 μg / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4 μg / L.

[0163] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 1.1 μg / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered a suitable threshold value. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1 μg / L.

[0164] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.8 μg / L and 1.3 μg / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.0 5, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.1 8, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3μg / L.

[0165] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.8 μg / L and 1.4 μg / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1 , 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1 .26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4μg / L.

[0166] In one embodiment, the sample is isolated postoperatively, one or more days after surgery, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 1 μg / L and 1.3 μg / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered a suitable threshold value. For example, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3 μg / L.

[0167] In one embodiment, the sample is isolated postoperatively, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 1 μg / L and 1.3 μg / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered a suitable threshold value. For example, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3 μg / L.

[0168] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment thereof, and an increase or plateauing in the level of PCT or a fragment thereof indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS.

[0169] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours, or more elapsed between the first and second time points, and determining the level of at least one biomarker includes determining the level of PCT or a fragment thereof, wherein an increase in the level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 0.6 μg / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered a suitable threshold value for the increase in PCT or a fragment thereof between the first and second time points. For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0. 35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0. 48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6μg / L.

[0170] Embodiments relating to determining the level of proET-1 or a fragment thereof for diagnosing or predicting a cardiovascular or cerebrovascular event proET-1 / MACCE: In one embodiment, determining the level of at least one additional biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE.

[0171] In one embodiment, the sample is isolated before surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 60 pmol / L and 85 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 pmol / L.

[0172] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 100 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 pmol / L.

[0173] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 105 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0174] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 105 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0175] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 105 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0176] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 85 pmol / L and 105 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MACCE. Any value within this range may be considered as a suitable threshold value. For example, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0177] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, and an increase or plateauing in the level of proET-1 or a fragment thereof indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE.

[0178] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein an increase in the level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 1 pmol / L and 10 pmol / L ±20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MACCE. Any value within this range may be considered as a suitable threshold value for the increase in proET-1 or a fragment thereof between the first and second time points. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 pmol / L.

[0179] proET-1 / MINS: In one embodiment, determining the level of at least one additional biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold indicates an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS.

[0180] In one embodiment, the sample is isolated before surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 60 pmol / L and 85 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 pmol / L.

[0181] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 75 pmol / L and 105 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0182] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 75 pmol / L and 105 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0183] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 75 pmol / L and 105 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0184] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 75 pmol / L and 105 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0185] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 75 pmol / L and 105 pmol / L ±20% or more indicates a high probability of cardiovascular or cerebrovascular adverse events, preferably MINS. Any value within this range may be considered as a suitable threshold value. For example, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0186] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably within 12 hours of surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably 1 or 2 days after surgery, preferably with at least 12 hours, 24 hours, or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein an increase in the level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 3 pmol / L and 20 pmol / L ± 20% or more indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS. Any value within this range may be considered as a suitable threshold value for the increase in proET-1 or a fragment thereof between the first and second time points. For example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 pmol / L.

[0187] Embodiments relating to determining the level of proET-1, PCT, or proADM, or fragments thereof, to diagnose or predict a cardiovascular or cerebrovascular event that is a PMI. In one embodiment, determining the level of at least one biomarker comprises determining the level of proET-1, PCT, and / or proADM, or fragments thereof, and a level of proET-1, PCT, and / or proADM, or fragments thereof, above a threshold indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably perioperative myocardial injury (PMI). Samples may be taken preoperatively or intraoperatively in some embodiments.

[0188] Embodiments relating to determining the level of proADM or a fragment thereof to diagnose or predict an infection ADM / any infection: In one embodiment, determining the level of at least one biomarker includes determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold indicates a high likelihood of infection.

[0189] In one embodiment, the sample is isolated preoperatively, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 nmol / L and 0.8 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8 nmol / L.

[0190] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.0 nmol / L and 1.2 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered as a suitable threshold value. For example, 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2 nmol / L.

[0191] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.5 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0192] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.5 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0193] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining a level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.1 nmol / L and 1.5 nmol / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value. For example, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0194] In one embodiment, the sample is isolated after surgery and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.1 nmol / L and 1.5 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0195] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.5 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0196] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker includes determining a level of proADM or a fragment thereof, and an increase or plateauing in the level of proADM or a fragment thereof indicates a high likelihood of infection.

[0197] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12, 24, 36, 48 or more hours having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein an increase in the level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 0.01 nmol / L and 0.4 nmol / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value for the increase in proADM or a fragment between the first and second time points. For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4 nmol / L.

[0198] ADM / Blood-borne diseases: In one embodiment, determining the level of at least one biomarker includes determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold indicates a high likelihood of a blood-borne infection.

[0199] In one embodiment, the sample is isolated preoperatively and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 nmol / L and 0.9 nmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.84, 0.85, 0.86, 0.87, 0.88.0.89, 0.9 nmol / L.

[0200] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.0 nmol / L and 1.3 nmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3 nmol / L.

[0201] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker includes determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.2 nmol / L and 1.8 nmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 , 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1. 66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0202] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker includes determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.2 nmol / L and 1.8 nmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 , 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1. 66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0203] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker includes determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.2 nmol / L and 1.8 nmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 , 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1. 66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0204] In one embodiment, the sample is isolated after surgery and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.1 nmol / L and 1.5 nmol / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0205] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94 .55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.6 8, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0206] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of proADM or a fragment thereof, and an increase or plateauing in the level of proADM or a fragment thereof indicates a high likelihood of a blood infection.

[0207] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12, 24, 36, 48 or more hours having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein an increase in the level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 0.01 nmol / L and 0.4 nmol / L ±20% or more indicates a high likelihood of blood infection. Any value within this range may be considered a suitable threshold value for the increase in proADM or a fragment between the first and second time points. For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4 nmol / L.

[0208] PCT / any infection: In one embodiment, determining the level of the at least one biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold indicates an increased likelihood of infection.

[0209] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker includes determining the level of PCT or a fragment thereof, where a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.2 μg / L and 0.3 μg / L ±20% or more indicates a high probability of infection. Any value within this range may be considered as a suitable threshold value. For example, 0.1, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3 μg / L.

[0210] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 0.9 μg / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9 μg / L.

[0211] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker includes determining the level of PCT or a fragment thereof, where a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 1.3 μg / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1. , 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1 .16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3μg / L.

[0212] In one embodiment, the sample is isolated post-operatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 1.3 μg / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0 .95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.1 3, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3μg / L.

[0213] In one embodiment, the sample is isolated postoperatively, one or more days after surgery, and determining the level of at least one biomarker includes determining a level of PCT or a fragment thereof, where a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 1.1 μg / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.9 ... .85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0 .98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1 μg / L.

[0214] In one embodiment, the sample is isolated postoperatively, 2, 3, or more days after surgery, and determining the level of at least one biomarker includes determining the level of PCT or a fragment thereof, where a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 1.3 μg / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1. , 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1 .16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3μg / L.

[0215] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably where at least 12, 24, 36, 48 or more hours have elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment thereof, and an increased level of PCT or a fragment thereof indicates an increased likelihood of infection.

[0216] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12, 24, 36, 48 or more hours having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein an increase in the level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 0.6 μg / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value for the increase in PCT or a fragment between the first and second time points. For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0. 35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0. 48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6μg / L.

[0217] PCT / Blood-borne diseases: In one embodiment, determining the level of the at least one biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold indicates an increased likelihood of a blood-borne infection.

[0218] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker includes determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 0.3 μg / L ±20% or more indicates a high probability of blood infection. Any value within this range may be considered as a suitable threshold value. For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3 μg / L.

[0219] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker includes determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 1.8 μg / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89 ,0.9,0.91,0.92,0.93,0.94,0.95,0.96,0.97,0.98,0.99,1,1.01,1.02,1.03,1.04,1.05,1.06,1.07,1.08,1.09,1.1,1.11,1.12,1.13,1.14,1.15,1.16,1.17,1.18,1.19,1.2,1 .21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1 .66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8μg / L.

[0220] In one embodiment, the sample is isolated post-operatively, 2 days after surgery, and determining the level of the at least one biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 2.3 μg / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1 .1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9 , 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2. 11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3μg / L.

[0221] In one embodiment, the sample is isolated post-operatively, 3 days after surgery, and determining the level of the at least one biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 2.3 μg / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1. 1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1. 5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1. 9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2. 11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3μg / L.

[0222] In one embodiment, the sample is isolated postoperatively, one or more days after surgery, and determining the level of at least one biomarker includes determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 1.8 μg / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89 ,0.9,0.91,0.92,0.93,0.94,0.95,0.96,0.97,0.98,0.99,1,1.01,1.02,1.03,1.04,1.05,1.06,1.07,1.08,1.09,1.1,1.11,1.12,1.13,1.14,1.15,1.16,1.17,1.18,1.19,1.2,1 .21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1 .66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8μg / L.

[0223] In one embodiment, the sample is isolated postoperatively, 2, 3 or more days after surgery, and determining the level of the at least one biomarker comprises determining a level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 1 μg / L and 2.3 μg / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32 ,1.33,1.34,1.35,1.36,1.37,1.38,1.39,1.4,1.41,1.42,1.43,1.44,1.45,1.46,1.47,1.48,1.49,1.5,1.5,1.5,1.51,1.52,1.53,1.54,1.55,1.56,1.57,1.58,1.59,1.6,1.61,1.62,1.63,1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3μg / L.

[0224] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12, 24, 36, 48 or more hours having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment thereof, and an increased level of PCT or a fragment thereof indicates a high likelihood of a blood infection.

[0225] In one embodiment, the first sample is isolated from the patient at a first time point, preferably postoperatively, one or more days after surgery, and the second sample is isolated from the patient at a subsequent second time point, preferably at least 12, 24, 36, 48 or more hours having elapsed between the first and second time points, and determining the level of at least one biomarker includes determining the level of PCT or a fragment thereof, wherein an increase in the level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 1 μg / L ±20% or more indicates a high likelihood of blood infection. Any value within this range may be considered a suitable threshold value for the increase in PCT or a fragment thereof between the first and second time points. For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0 .55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0 .78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1μg / L.

[0226] proET-1 / any infection: In one embodiment, determining the level of at least one biomarker includes determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold indicates a high likelihood of infection.

[0227] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 85 pmol / L and 95 pmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 pmol / L.

[0228] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 95 pmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 pmol / L.

[0229] In one embodiment, the sample is isolated postoperatively, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 95 pmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 pmol / L.

[0230] proET-1 / blood infections: In one embodiment, determining the level of at least one biomarker includes determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold indicates a high likelihood of a blood-borne infection.

[0231] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 85 pmol / L and 105 pmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0232] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 110 pmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 pmol / L.

[0233] In one embodiment, the sample is isolated postoperatively, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 110 pmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 pmol / L.

[0234] ADM / Infectious Diseases and MACCE / MINS: In one embodiment, determining the level of at least one biomarker includes determining the level of proADM or a fragment thereof, and a level of proADM or a fragment thereof above a threshold indicates an increased likelihood of infection, preferably a blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS.

[0235] In one embodiment, the sample is isolated before surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 nmol / L and 0.9 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9 nmol / L.

[0236] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.0 nmol / L and 1.6 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1. 46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6nmol / L.

[0237] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 2.2 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1. 75,1.76,1.77,1.78,1.79,1.8,1.81,1.82,1.83,1.84,1.85,1.86,1.87,1.88,1.89,1.9,1.91,1.92,1.93,1.94,1.95,1.96,1.97,1. 98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2nmol / L.

[0238] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 2.3 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54 ,1.55,1.56,1.57,1.58,1.59,1.6,1.61,1.62,1.63,1.64,1.65,1.66,1.67,1.68,1.69,1.7,1.71,1.72,1.73,1.74,1.75,1.76,1.77,1.78,1.79,1. 8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2. 06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2 .19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3nmol / L.

[0239] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 2.3 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54 ,1.55,1.56,1.57,1.58,1.59,1.6,1.61,1.62,1.63,1.64,1.65,1.66,1.67,1.68,1.69,1.7,1.71,1.72,1.73,1.74,1.75,1.76,1.77,1.78,1.79,1. 8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2. 06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2 .19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3nmol / L.

[0240] In one embodiment, the sample is isolated after surgery and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 2 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1. 65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.8 3, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2nmol / L.

[0241] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 2.3 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54 ,1.55,1.56,1.57,1.58,1.59,1.6,1.61,1.62,1.63,1.64,1.65,1.66,1.67,1.68,1.69,1.7,1.71,1.72,1.73,1.74,1.75,1.76,1.77,1.78,1.79,1. 8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2. 06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2 .19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3nmol / L.

[0242] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, and an increased level of proADM or a fragment thereof indicates an increased likelihood of infection, preferably a blood infection, and a cardiovascular or cerebrovascular adverse event, preferably MACCE and / or MINS.

[0243] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, and an increase in the level of proADM or a fragment thereof above a threshold value selected from a range of values ​​between 0.01 nmol / L and 1 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value for the increase in proADM or a fragment thereof between the first and second time points. For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0. 29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0 .8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1nmol / L.

[0244] PCT / Infectious Diseases and MACCE / MINS: In one embodiment, determining the level of the at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold indicates an increased likelihood of infection, preferably a blood infection, and a cardiovascular or cerebrovascular adverse event, preferably MACCE and / or MINS.

[0245] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 0.4 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4 μg / L.

[0246] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 1.8 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.8 9, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1. 2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.291.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1 .51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1. 66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8μg / L.

[0247] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 3 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0. 98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.291.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1. 38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.7 7, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.4, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.5, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2.58, 2. 59, 2.6, 2.61, 2.62, 2.63, 2.64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.7, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.8, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.9, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99, 3μg / L.

[0248] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 3 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0. 98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.291.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1. 38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.7 7, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.4, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.5, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2.58, 2. 59, 2.6, 2.61, 2.62, 2.63, 2.64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.7, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.8, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.9, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99, 3μg / L.

[0249] In one embodiment, the sample is isolated after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 3 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1. 09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.291.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1. 49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1 .89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.4, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.5, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2.58, 2.59, 2.6, 2.61, 2.62, 2.63, 2.64, 2. 65, 2.66, 2.67, 2.68, 2.69, 2.7, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.8, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.9, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99, 3μg / L.

[0250] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 1 μg / L and 3 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value.For example, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.291.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1 .75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2 , 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25 ,2.26,2.27,2.28,2.29,2.3,2.31,2.32,2.33,2.34,2.35,2.36,2.37,2.38,2.39,2.4,2.41,2.42,2.43,2.44,2.45,2.46,2.47,2.48,2.49,2.5, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2.58, 2.59, 2.6, 2.61, 2.62, 2.63, 2.64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.7, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.8, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.8 8, 2.89, 2.9, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99, 3 μg / L.

[0251] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably where at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more have elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment thereof, and an increase or plateauing in the level of PCT or a fragment thereof indicates an increased likelihood of infection, preferably a blood infection, and a cardiovascular or cerebrovascular adverse event, preferably MACCE and / or MINS.

[0252] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment thereof, and an increase in the level of PCT or a fragment thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 2 μg / L ± 20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value for the increase in PCT or a fragment thereof between the first and second time points.For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0. 94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1 3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65 , 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.8 3, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2μg / L.

[0253] proET-1 / infection and MACCE / MINS: In one embodiment, determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, and a level of proET-1 or a fragment thereof above a threshold indicates an increased likelihood of infection, preferably a blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS.

[0254] In one embodiment, the sample is isolated before surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, and a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 60 pmol / L and 85 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 pmol / L.

[0255] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 110 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 pmol / L.

[0256] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 120 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 pmol / L.

[0257] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 120 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 pmol / L.

[0258] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 120 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 pmol / L.

[0259] In one embodiment, the sample is isolated after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 110 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 pmol / L.

[0260] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 120 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 pmol / L.

[0261] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, and an increase or plateauing in the level of proET-1 or a fragment thereof indicates an increased likelihood of infection, preferably a blood infection, and a cardiovascular or cerebrovascular adverse event, preferably MACCE / MINS.

[0262] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein an increase in the level of proET-1 or a fragment thereof above a threshold value selected from a range of values ​​between 1 pmol / L and 40 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value for the increase in proET-1 or a fragment thereof between the first and second time points. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 pmol / L.

[0263] Embodiments relating to determining the levels of proET-1, PCT or proADM, or fragments thereof, for diagnosing or predicting cardiovascular or cerebrovascular events, which are PMI, and infectious diseases, such as blood infections: In one embodiment, determining the level of at least one biomarker comprises determining the level of proET-1, PCT, and / or proADM, or fragments thereof, and a level of proET-1, PCT, and / or proADM, or fragments thereof above a threshold indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably perioperative myocardial injury (PMI), and the presence of an infection, preferably a blood infection. Samples may be taken preoperatively or intraoperatively in some embodiments.

[0264] In a further aspect, the present invention relates to a kit for carrying out the method of the present invention, the kit comprising: - a detection reagent for determining the level of at least one biomarker selected from the group consisting of proADM, PCT, and proET-1, or fragments thereof; - reference data regarding the likelihood of postoperative adverse events, in particular reference data regarding threshold or cut-off values, which reference data is preferably stored on a computer readable medium and / or used in the form of a computer executable code configured to compare the determined level of at least one biomarker selected from proADM, PCT and proET-1, or a fragment thereof, with the threshold or cut-off value.

[0265] The invention will be further described by reference to the following drawings, which illustrate non-limiting possible preferred embodiments presented to further illustrate the invention. [Brief description of the drawings]

[0266] [Figure 1] Plasma levels of MR-proADM at all sampling points in patients with and without MACCE expressed as the mean with standard error of the mean (SEM). [Diagram 2] Plasma levels of PCT at all sampling points in patients with and without MACCE expressed as the mean with standard error of the mean (SEM). [Diagram 3] Plasma levels of CT-proET-1 at all sampling points in patients with and without MACCE expressed as the mean with standard error of the mean (SEM). [Figure 4] Plasma levels of creatinine at all sampling points in patients with and without MACCE expressed as medians with interquartile range (IQR). [Diagram 5] Plasma levels of MR-proADM at all sampling points in patients with and without MINS expressed as the mean with standard error of the mean (SEM). [Figure 6] Plasma levels of PCT at all sampling points in patients with and without MINS expressed as the mean with standard error of the mean (SEM). [Figure 7] Plasma levels of CT-proET-1 at all sampling points in patients with and without MINS expressed as the mean with standard error of the mean (SEM). [Figure 8] Plasma levels of MR-proADM at all sampling points in patients with and without any infection expressed as the mean with the standard error of the mean (SEM). [Figure 9] Plasma levels of PCT at all sampling points in patients with and without any infection expressed as the mean with standard error of the mean (SEM). [Figure 10] Plasma levels of CT-proET-1 at all sampling points in patients with and without any infection expressed as the mean with standard error of the mean (SEM). [Figure 11] Plasma levels of MR-proADM at all sampling points in patients with and without blood infections expressed as the mean with standard error of the mean (SEM). [Figure 12] Plasma levels of PCT at all sampling points in patients with and without blood-borne infections expressed as the mean with standard error of the mean (SEM). [Figure 13] Plasma levels of CT-proET-1 at all sampling points in patients with and without blood-borne infections expressed as the mean with standard error of the mean (SEM). [Figure 14] Plasma levels of MR-proADM at all sampling points in patients with infection and MACCE compared with patients who suffered only one or none of the adverse events, expressed as the mean with the standard error of the mean (SEM). [Figure 15]Plasma levels of PCT at all sampling points in patients with infection and MACCE compared with patients who suffered only one or none of the adverse events, expressed as the mean with the standard error of the mean (SEM). [Figure 16] Plasma levels of CT-proET-1 at all sampling points in patients with infection and MACCE compared with patients who suffered only one or none of the adverse events, expressed as the mean with the standard error of the mean (SEM). [Figure 17] Plasma levels of MR-proADM at all sampling points in patients with MACCE and no infection compared with patients with MACCE and any infection, expressed as the mean with standard error of the mean (SEM). [Figure 18] Plasma levels of PCT at all sampling points in patients with MACCE and no infection compared with patients with MACCE and any infection, expressed as the mean with standard error of the mean (SEM). [Figure 19] Plasma levels of CT-proET-1 at all sampling points in patients with MACCE and no infection compared with patients with MACCE and any infection, expressed as the mean with standard error of the mean (SEM). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0267] The present invention relates to a method for the diagnosis, prognosis, risk assessment and / or risk stratification of adverse events in post-operative patient health. As is evident from the data presented herein, the likelihood of the presence or absence of an adverse event in post-operative patient health is indicated by the levels of proADM, PCT, proET-1 or fragments thereof, which provide information for treatment guidance, stratification and / or control.

[0268] The present invention has the advantage over conventional methods in that the methods and kits of the present invention are rapid, objective, easy to use, reliable and accurate for diagnosing, prognosing, monitoring and guiding treatment of post-operative patients.

[0269] The methods and kits of the present invention relate to markers that are easily measurable in a conventional manner in a clinic, since the levels of proADM, PCT and / or proET-1 can be determined in a conventionally obtained blood sample, or in a further biological fluid or sample obtained from the subject.

[0270] As used herein, a "patient" or "subject" may be a vertebrate. In the context of the present invention, the term "subject" includes both humans and animals, particularly mammals, and other organisms.

[0271] "Post-operative patient" refers to a patient or subject who has undergone surgery.

[0272] As used herein, the term "surgery" refers to the treatment of disease, injury, and deformity by manual or operative methods. Common surgical procedures include, but are not limited to, abdominal surgery, ear surgery, bench surgery, cardiac surgery, cineplastic surgery, conservative surgery, cosmetic surgery, cytoreductive surgery, dental surgery, maxillofacial surgery, general surgery, major surgery, minor surgery, Mohs surgery, open heart surgery, organ transplantation, orthopedic surgery, cosmetic surgery, psychosurgery, radical surgery, reconstructive surgery, sonic surgery, stereotactic surgery, structural surgery, thoracic surgery, and veterinary surgery. The method of the present invention is suitable for patients who are going to undergo any type of surgery that deals with any part of the body, including but not limited to the above, as well as any type of general surgery, major surgery, or minor surgery.

[0273] Minor surgery is any invasive surgical procedure in which only skin or mucosal and connective tissue is removed, for example, cutting a blood vessel for catheter placement, implanting a pump into subcutaneous tissue.

[0274] Major surgery is any invasive surgical procedure involving more extensive resection, such as entering a body cavity, removing an organ, or altering normal anatomical structures. Preferably, major surgery must be performed under general anesthesia and requires at least one night of hospitalization.

[0275] "Non-cardiac surgery" refers to surgery that is not cardiac surgery.

[0276] "Cardiac surgery" refers to any surgical procedure performed on the heart or surrounding tissue (e.g., cardiac tissue, neural tissue, vascular tissue, and / or the like). Cardiac surgery includes open-heart surgery, heart valve surgery including pericardial open-heart surgery (e.g., in the pericardium, selected via thoracoscopy, thoracotomy, mediastinotomy, sternotomy, incised and opened by a diaphragmatic xyphoid pathway scheme), bypass surgery (e.g., coronary artery bypass surgery), or aneurysm repair.

[0277] "Major non-cardiac surgery" preferably encompasses major abdominal surgery, gastrointestinal, respiratory surgery, thoracic surgery, endocrine surgery, lymphatic surgery, bone or joint surgery, surgery in the genital area, and / or breast surgery.

[0278] "Abdominal surgery" preferably encompasses any surgical procedure that involves opening the patient's abdomen.

[0279] "Gastrointestinal surgery" or "abdominal surgery" includes, for example and preferably, appendectomy, Caesarean section, exploratory laparotomy, glossectomy, esophagectomy, gastrectomy, proctocolectomy, colectomy, hepatectomy, cholecystectomy, pancreatectomy, gastrostomy, gastroduodenostomy, gastroenterostomy, ileostomy, jejunostomy, colostomy, cholecystostomy, hepatic portojejunostomy, myotomy, or sphincterotomy.

[0280] As used herein, the term "preoperative" is used synonymously with "presurgical" and refers to the period before surgery. Preferably, the "preoperative" period begins with the scheduling of surgery, may include the period of preparing the subject for surgery, and ends with the initiation of the procedures or techniques that constitute the surgery.

[0281] As used herein, the term "perioperative" refers to the period during a surgical procedure, i.e., while the procedures or techniques that constitute the procedure are being performed.

[0282] As used herein, the term "postsurgical" is used synonymously with "postoperative" and refers to the period following a surgical procedure, beginning after completion of the procedures or techniques that constitute the procedure and in the days or weeks following the procedure.

[0283] When biomarkers are determined preoperatively as described herein, preoperative preferably refers to a time point within 7 days, preferably within 3 days, within 1 day, or less, before surgery. In these cases, preoperative preferably refers to at least 6 hours, more preferably at least 3 hours, before surgery.

[0284] When biomarkers are determined post-operatively as described herein, post-operatively preferably refers to a time point within 14 days, preferably 10 days, 7 days, 5 days, and most preferably 3 days after surgery.

[0285] As used herein, isolation of a sample while the patient is being monitored in the Post-Anesthesia Care Unit (PACU) preferably refers to isolation of a post-operative sample within 12 hours, preferably within 6 hours, after surgery.

[0286] As used herein, isolation of a sample on post-surgery day 1 (POD1) preferably refers to isolation of a post-operative sample 12 to 36 hours after surgery, preferably 18 to 30 hours after surgery, and most preferably about 24 hours after surgery.

[0287] As used herein, isolation of a sample on post-surgery day 2 (POD2) preferably refers to isolation of a post-operative sample 36 to 60 hours after surgery, preferably 42 to 54 hours after surgery, and most preferably about 48 hours after surgery.

[0288] As used herein, isolation of a sample on post-surgery day 3 (POD3) preferably refers to isolation of a post-operative sample 60 to 84 hours after surgery, preferably 66 to 78 hours after surgery, and most preferably about 72 hours after surgery.

[0289] When post-operative adverse events are predicted or diagnosed using the methods described herein, the time period for the occurrence of the post-operative adverse events preferably encompasses 60 days after surgery, more preferably 30 days after surgery.

[0290] As used herein, the term "medical procedure" refers to any clinical or diagnostic procedure performed by a medical professional (e.g., including but not limited to, a physician or physician's assistant, a nurse or registered nurse, or a veterinarian).

[0291] In the context of the present invention, "adverse events in postoperative patient health" refer to events that indicate complications or deterioration of the patient's health after undergoing surgery. Such adverse events include, but are not limited to, cardiac events, cardiovascular events, cerebrovascular events, infections or new infections, sepsis-like systemic infections, sepsis, organ failure, and deterioration of the patient's general clinical signs or symptoms, such as hypotension or hypertension, tachycardia or bradycardia, patient death, and patient death within 30 days after surgery.

[0292] Further examples of adverse events include situations in which clinical deterioration indicates the need for therapeutic measures such as focal irrigation procedures, antimicrobial therapy, antibiotic therapy, blood product infusions, colloid infusions, invasive mechanical ventilation, non-invasive mechanical ventilation, emergency surgery, organ replacement therapy such as renal or hepatic replacement, and vasopressor therapy.

[0293] As used herein, "diagnosis" in the context of the present invention relates to the recognition and (early) detection of a clinical condition. The assessment of severity may also be encompassed by the term "diagnosis".

[0294] "Prognosis" refers to the prediction of a subject's outcome or risk. It may also include estimating the chances of recovery or adverse outcome for the subject.

[0295] The method described herein comprises determining the level of at least one biomarker that correlates with the likelihood of adverse events in postoperative patient health.This preferably means that the likelihood of occurrence of adverse events can be evaluated by comparing the level of one of the biomarkers to a reference level (such as a threshold or cut-off value and / or a population average), and the reference level may correspond to the level of the biomarker in patients who do not develop or will not develop postoperative adverse events.

[0296] Thus, determination of the biomarkers described herein may be used to assess whether a patient is more or less likely to experience an adverse event following surgery.

[0297] The method includes diagnostics and prognoses. Thus, a level of a biomarker indicating a high likelihood of an adverse event may indicate a high likelihood that the patient suffered the adverse event post-operatively at the time of sample isolation, or that the patient will suffer the adverse event after sample isolation.

[0298] In terms of early diagnosis of postoperative adverse events or future prognosis, the method is particularly suitable for risk assessment or stratification.This means that the method of the present invention can distinguish high-risk patients who are more likely to suffer from (further) complications or will become more severe in the future from low-risk patients whose health condition is stable or even improving, so that patients are not expected to have suffered or will suffer from adverse events that may require certain therapeutic measures.

[0299] In the present invention, the terms "risk assessment" and "risk stratification" refer to grouping subjects into different risk groups according to the further prognosis of the subject. Risk assessment also refers to stratification for applying preventive and / or therapeutic measures. The term "therapy stratification" particularly relates to grouping or classifying patients into different groups, such as risk groups or treatment groups that receive certain different therapeutic measures according to the classification of the patient. The term "therapy stratification" also relates to grouping or classifying patients with symptoms of infectious disease or infectious disease into groups that do not need to receive certain therapeutic measures.

[0300] The method of the invention may also be used for monitoring, treatment monitoring, treatment guidance and / or treatment control. "Monitoring" relates to following a patient and any complications that may arise, for example to analyze the progress of the healing process or the impact of a particular treatment or therapy on the patient's health status.

[0301] The term "therapeutic monitoring" or "therapeutic control" in the context of the present invention refers to monitoring and / or adjusting the therapeutic treatment of the patient, for example by obtaining feedback on the effectiveness of the treatment. As used herein, the term "therapeutic guidance" refers to the application of a certain treatment, therapeutic action, or medical intervention based on the value / level of one or more biomarkers and / or clinical parameters and / or clinical scores. This includes adjusting or ceasing therapy.

[0302] The methods described herein relate to the diagnosis, prognosis, risk assessment, and / or risk stratification of adverse events in post-operative patient health based on the determination of the level of at least one biomarker selected from the group consisting of proADM, PCT, and proET-1.

[0303] The expressions "at least one biomarker selected from the group consisting of proADM, PCT, and proET-1" and "proADM, PCT, and / or proET-1" are to be understood to encompass all possible combinations, preferably including the determination of exactly one of the three biomarkers, i.e., proADM, PCT, or proET-1, as well as the determination of exactly two of the biomarkers, i.e., proADM and PCT, proADM and proET-1, or PCT and proET-1, or all three biomarkers, proADM, PCT, and proET-1.

[0304] It should further be understood that the phrase does not preclude the additional determination of further biomarkers or parameters.

[0305] In the context of the present invention, "determining the level of proADM or a fragment thereof" and the like are understood to refer to any means of determining proADM or a fragment thereof. The length of the fragment can be any length, for example at least about 5, 10, 20, 30, 40, 50, or 100 amino acids, as long as the fragment allows an unambiguous determination of the level of proADM or a fragment thereof. In a particularly preferred embodiment of the present invention, "determining the level of proADM" refers to determining the level of mid-region pro-adrenomedullin (MR-proADM). MR-proADM is a fragment and / or region of proADM.

[0306] The peptide adrenomedullin (ADM) was discovered as a 52 amino acid antihypertensive peptide isolated from the phenochromocytome (Kitamura et al., 1993). Adrenomedullin (ADM) is encoded as a precursor peptide ("preproadrenomedullin" or "preproADM") containing 185 amino acids. An exemplary amino acid sequence of pre-pro-ADM is provided in SEQ ID NO:1. SEQ ID NO:1: Amino acid sequence of pre-pro-ADM: [Table A]

[0307] ADM comprises positions 95-146 of the pre-proADM amino acid sequence and is a splice product thereof. "Pro-Adrenomedullin" ("proADM") refers to pre-proADM (amino acids 1-21) without the signal sequence, i.e., amino acid residues 22-185 of pre-proADM. "Mid-region pro-Adrenomedullin" ("MR-proADM") refers to amino acids 42-95 of pre-proADM. An exemplary amino acid sequence of MR-proADM is provided in SEQ ID NO:2. SEQ ID NO: 2: Amino acid sequence of MR-pro-ADM (AS 45 to 92 of pre-pro-ADM): ELRMSSSYPT GLADVKAGPA QTLIRPQDMK GASRSPEDSS PDAARIRV

[0308] It is also contemplated herein that peptides of pre-proADM or MR-proADM and fragments thereof can be used in the methods described herein. For example, the peptide or fragment thereof can include amino acids 22-41 of pre-proADM (PAMP peptide), or amino acids 95-146 of pre-proADM (mature adrenomedullin, including the biologically active form also known as bio-ADM). The C-terminal fragment of proADM (amino acids 153-185 of pre proADM) is called adrenotensin. A fragment of a proADM peptide or a fragment of MR-proADM can include, for example, at least about 5, 10, 20, 30, or more amino acids. Thus, a fragment of proADM can be selected from the group consisting of, for example, MR-proADM, PAMP, adrenotensin, and mature adrenomedullin, and preferably, as used herein, the fragment is MR-proADM.

[0309] Determination of these various forms of ADM or proADM and fragments thereof also encompasses measuring and / or detecting specific subregions of these molecules, for example, by using antibodies or other affinity reagents directed to specific portions of the molecules, or by measuring portions of the protein using mass spectrometry to determine the presence and / or amount of the molecules. Any one or more of the "ADM peptides or fragments" described herein can be used in the present invention.

[0310] The level of proADM in a subject's sample can be determined by immunoassay as described herein.As used herein, the level of ribonucleic acid or deoxyribonucleic acid coding for "proadrenomedullin" or "proADM" can also be determined.The method for determining proADM, for example, by using the product obtained from Thermo Fisher Scientific / B·R·A·H·M·S GmbH, is known to those skilled in the art.

[0311] In the context of the present invention, "determining the level of proendothelin-1 (proET-1) or a fragment thereof" and the like are understood to refer to determining proendothelin-1 or a fragment thereof. The length of the fragment can be any length, for example, at least about 5, 10, 20, 30, 40, 50, or 100 amino acids, so long as the fragment allows for an unambiguous determination of the level of endothelin-1.

[0312] Endothelin-1 is a family member of 21 amino acid peptides that are believed to play an important pathophysiological role in cardiovascular dysfunction (Haaf et al. 2014, Papassotiriou et al. 2014). The gene for ET-1 is found on chromosome 6, and its expression is regulated by several factors, such as angiotensin II, cytokines, hypoxia, thrombin, free radicals, endotoxins, and shear stress (Zhang et al. 2017, Bhandari et al. 2014). It is primarily synthesized by vascular endothelial cells, but also in smooth muscle cells, cardiomyocytes, and cardiac fibroblasts, as well as in various tissues throughout the body. ET-1 is initially synthesized as a precursor, preproET-1. Cleavage of preproET-1 generates proET-1, which is further cleaved by furin to generate two biologically inactive precursors, named big-1 and C-terminal of proET-1 (CT-proET-1). bigET-1 is finally converted by the metalloproteinase endothelin-converting enzyme (ECE-1) to generate ET-1 (Zhang et al. 2017).

[0313] As used herein, "proendothelin-1" or "proET-1" refers to a peptide spanning amino acid residues 18-212 of the amino acid precursor peptide of endothelin- (preproendothelin-1), or a fragment thereof. An exemplary sequence of the 212 amino acid precursor peptide of endothelin- (preproendothelin-1) is provided in SEQ ID NO: 3. An exemplary amino acid sequence of proET-1 is provided in SEQ ID NO: 1. proET-1 is cleaved into mature ET-1, big-ET-1, and C-terminal proET-1 (CT-proET-1). ET-1 relates to amino acid residues 53-73 of pre-pro-ET-1. CT-proET-1 relates to amino acid residues 168-212 of pre-pro-ET-1. An exemplary amino acid sequence of CT-proET-1 is provided in SEQ ID NO: 4. big-ET-1 includes amino acid residues 53-90 of pre-pro-ET-1. SEQ ID NO:3: Amino acid sequence of pre-pro-ET1: [Table B] SEQ ID NO: 4: Amino acid sequence of pro-ET1 [Table C] SEQ ID NO: 5: Amino acid sequence of CT-proET-1 [Table D]

[0314] In a particularly preferred embodiment, CT-proET-1 is measured to determine the level of proendothelin-1.The length of the proendothelin-1 fragment is therefore at least 12 amino acids, preferably more than 20 amino acids, more preferably more than 40 amino acids.

[0315] Determination of these various forms of CT-proET-1 or proET1 and fragments thereof also encompasses measuring and / or detecting specific subregions of these molecules, for example, by using antibodies or other affinity reagents directed to specific portions of the molecules, or by determining the presence and / or amount of the molecules by measuring portions of the protein using mass spectrometry. Any one or more of the "ET-1 peptides or fragments" described herein can be used in the present invention.

[0316] The level of proET-1 in a sample of a subject can be determined by immunoassay as described herein.As used herein, the level of ribonucleic acid or deoxyribonucleic acid encoding "proendothelin-1" or "proET-1" can also be determined.Methods for determining proET-1 are known to those skilled in the art, for example, from EP1564558.

[0317] In the context of the present invention, "determining the level of procalcitonin or a fragment thereof," "determining the level of PCT or a fragment thereof," and the like are understood to refer to determining procalcitonin or a fragment thereof. The length of the fragment can be any length, for example at least about 5, 10, 20, 30, 40, 50, or 100 amino acids, so long as the fragment allows for an unambiguous determination of the level of procalcitonin.

[0318] As used herein, "procalcitonin" or "PCT" refers to a peptide spanning amino acid residues 1-116, 2-116, 3-116, or fragments thereof, of the procalcitonin peptide. PCT is the peptide precursor of the calcitonin hormone. An exemplary sequence of the 1-116 procalcitonin peptide is provided in SEQ ID NO:6. SEQ ID NO:6: 1-116 Amino acid sequence of PCT [Table E]

[0319] Thus, the length of the procalcitonin fragment is at least 12 amino acids, preferably more than 50 amino acids, more preferably more than 110 amino acids. Determination of PCT may include determination of N-terminal PCT (SEQ ID NO: 7), calcitonin (SEQ ID NO: 8) or katacalcin (SEQ ID NO: 9), and may also include post-translational modifications such as glycosylation, lipidation, or derivatization. Procalcitonin is the precursor of calcitonin and katacalcin. Thus, under normal conditions, the PCT level in circulation is very low (less than about 0.05 ng / ml). SEQ ID NO: 7 (AS 1-57 of PCT, amino acid sequence of N-terminal PCT): [Table F] SEQ ID NO: 8 (amino acid sequence of calcitonin, PCT AS 60-91): [Table G] SEQ ID NO: 9 (amino acid sequence of katacalcin, PCT AS 96-116): [Table H]

[0320] The level of PCT in the sample of the subject can be determined by immunoassay as described herein.As used herein, the level of ribonucleic acid or deoxyribonucleic acid coding for "procalcitonin" or "PCT" can also be determined.The method for determining PCT is known to those skilled in the art, for example, by using the product obtained from Thermo Fisher Scientific / B·R·A·H·M·S GmbH.

[0321] Determination of procalcitonin and its fragments also encompasses measuring and / or detecting specific subregions of these molecules, for example, by using antibodies or other affinity reagents directed against specific portions of the molecules, or by determining the presence and / or amount of the molecules by measuring portions of the protein using mass spectrometry.

[0322] Thus, the methods and kits of the invention may also comprise determining at least one further biomarker, marker, clinical score and / or parameter in addition to proADM, PCT and / or proET-1.

[0323] As used herein, a parameter is a characteristic, feature, or measurable factor that can help define a particular system. A parameter is an important factor for the assessment of health and physiology, such as disease / disorder / clinical condition risk, preferably organ dysfunction. Furthermore, a parameter is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to therapeutic interventions. Exemplary parameters can be selected from the group consisting of Acute Physiology and Longitudinal Health Evaluation II (APACHE II), Simplified Acute Physiology Score (SAPSII score), quick sequential organ failure assessment score (SOFA score), quick sequential organ failure assessment score (qSOFA), body mass index, weight, age, sex, IGS II, water intake, white blood cell count, sodium, potassium, body temperature, blood pressure, dopamine, bilirubin, respiratory rate, oxygen tension, World Federation of Neurological Surgeons (WFNS) assessment, and Glasgow Coma Scale (GCS).

[0324] As used herein, terms such as "marker", "surrogate", "prognostic marker", "factor", or "biomarker" or "biological marker" are used interchangeably and refer to a measurable and quantifiable biological marker (e.g., a specific protein or enzyme concentration or fragment thereof, a specific hormone concentration or fragment thereof, or the presence of a biological substance or fragment thereof) that serves as an indicator of a health- and physiology-related evaluation, such as a disease / disorder / clinical condition risk, preferably an adverse event. A marker or biomarker is defined as a characteristic that can be objectively measured and evaluated as an indicator of a normal biological process, a pathogenic process, or a pharmacological response to a therapeutic intervention. Biomarkers may be measured in a sample (blood, plasma, urine, or tissue test).

[0325] The at least one additional marker and / or parameter of the subject is a level of lactate in the sample, the subject's Sequential Organ Failure Assessment Score (SOFA score), the subject's Simplified Acute Physiology Score (SAPSII), the subject's Acute Physiology and Longitudinal Health Evaluation II (APACHE II) score, the American Society of Anesthesiologists Physical Status (ASAPS), and a marker and / or parameter of the subject, such as soluble fms-like tyrosine kinase-1 (sFlt-1), histone H2A, histone H2B, histone H3, histone H4, arginine vasopressin (AVP), atrial natriuretic peptide (ANP), myoglobin, creatine kinase neutrophil gelatinase-binding lipocalin (NGAL), troponin, cardiac troponin T (cnTNT), brain natriuretic peptide (BNP), C-reactive protein (CRP). , pancreatic stone protein (PSP), triggering receptor expressed on myeloid cells 1 (TREM1), interleukin-6 (IL-6), interleukin-1, interleukin-24 (IL-24), interleukin-22 (IL-22), interleukin (IL-20), other ILs, presepsin (sCD14-ST), lipopolysaccharide-binding protein (LBP), alpha-1-antitrypsin, matrix metalloproteinase 2 (MMP2), metalloproteinase 2 (MMP8), Matrix metalloproteinase 9 (MMP9), matrix metalloproteinase 7 (MMP7, placental growth factor (PlGF), chromogranin A, S100A protein, S100B protein and tumor necrosis factor alpha (TNFα), neopterin, alpha-1-antitrypsin, proarginine vasopressin (AVP, proAVP, or copeptin), atrial natriuretic peptide (ANP, pro-ANP), endothelin-1, CCL1 / TCA3, CCL11 , CCL12 / MCP-5, CCL13 / MCP-4, CCL14, CCL15, CCL16, CCL17 / TARC, CCL18, CCL19, CCL2 / MCP-1, CCL20, CCL21, CCL22 / MDC, CCL23, CCL 24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL3L3, CCL4, CCL4L1 / LAG-1, CCL5, CCL6, CCL7, CCL8, CCL9, CX3CL1, CXCL1, CXCL10, CXCL11,CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CXCL2 / MIP-2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7 / Ppbp, CXCL9, IL8 / CXCL8, XCL1, XCL2, FAM19A1, FAM19A2 , FAM19A3, FAM19A4, FAM19A5, CLCF1, CNTF, IL11, IL31, IL6, leptin, LIF, OSM, IFNA1, IFNA10, IFNA13, IFNA14, IFNA2, IFNA4, IFNA7, IFNB1, IFNE, IFNG, IFNZ, I The level of FNA8, IFNA5 / IFNaG, IFNω / IFNW1, BAFF, 4-1BBL, TNFSF8, CD40LG, CD70, CD95L / CD178, EDA-A1, TNFSF14, LTA / TNFB, LTB, TNFa, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF15, TNFSF4, IL18, IL18BP, IL1A, IL1B, IL1F10, IL1F3 / IL1RA, IL1F5, IL1F6, IL1F7, IL1F8, IL1RL2, IL1F9, IL33, or fragments thereof.

[0326] As used herein, the "Continuous Organ Failure Assessment score" or "SOFA score" is a score used to track the status of a patient during their stay in the intensive care unit (ICU). The SOFA score is a scoring system for determining the degree of organ function or failure rate of a person. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Both the average and maximum SOFA scores are predictors of outcome. An increase in the SOFA score during the first 24-48 hours in the ICU predicts a mortality rate of at least 50% and up to 95%. A score below 9 confers a predicted mortality rate of 33%, while a score above 14 may approach or exceed 95%.

[0327] As used herein, the "quick SOFA score" (qSOFA score) is a scoring system that indicates a patient's risk of organ failure or death. The score is based on three criteria: 1) altered mental status, 2) a decrease in systolic blood pressure below 100 mmHg, and 3) a respiratory rate greater than 22 breaths per minute. Patients with two or more of these conditions are at higher risk of having organ failure or dying.

[0328] As used herein, "APACHE II" or "Acute Physiology and Chronic Health Evaluation II" is a scoring system for severity classification (Knaus et al., 1985). It can be applied within 24 hours of a patient's admission to the intensive care unit (ICU) and may be determined based on 12 different physiological parameters: AaDO2 or PaO2 (depending on FiO2), temperature (rectal), mean arterial pressure, arterial pH, heart rate, respiratory rate, sodium (serum), potassium (serum), creatinine, hematocrit, white blood cell count, and Glasgow Coma Scale.

[0329] As used herein, "SAPS II" or "Simplified Acute Physiology Score II" refers to a system for classifying the severity of a disease or disorder (see Le Gall JR et al., A new Simplified Acute Physiology Score (SAPS II) based on a European / North American multicenter study. JAMA. 1993; 270(24): 2957-63). The SAPS II score is composed of 12 physiological variables and 3 disease-related variables. A point score is calculated from 12 normal physiological measurements, information on previous health conditions, and some information obtained at the time of admission to the ICU. The SAPS II score can be determined at any time, preferably on the second day. The "worst" measurement is defined as the scale that correlates with the highest score. The SAPS II score ranges from 0 to 163 points. The classification system includes the following parameters: age, heart rate, systolic blood pressure, temperature, Glasgow Coma Scale, mechanical ventilation or CPAP, PaO2, FiO2, urine output, blood urea nitrogen, sodium, potassium, bicarbonate, bilirubin, white blood cells, chronic diseases, and type of admission. There is an sigmoidal correlation between mortality and total SAPS II score. Subject mortality is 10% with a SAPSII score of 29 points, mortality is 25% with a SAPSII score of 40 points, mortality is 50% with a SAPSII score of 52 points, mortality is 75% with a SAPSII score of 64 points, and mortality is 90% with a SAPSII score of 77 points (Le Gall, ibid.).

[0330] As used herein, "ASA", "ASA Physical Status", "ASAPS", or "ASA Score" are used to refer to the Physical Status Classification System developed by the American Society of Anesthesiologists (ASA) to provide clinicians with a simple classification of a patient's physiological status that may aid in predicting surgical risk. Preferably, the ASAPS is composed of six classes that indicate increasing surgical risk (Doyle et al. 2018). "ASA I": Normal, healthy patients. Example: Healthy, non-obese (BMI < 30), non-smoking patients with good exercise tolerance. "ASA II": Patients with mild systemic disease. Example: Patients with well-controlled disease without functional limitations (e.g., treated hypertension, obese with BMI < 35, frequent social alcohol users, or smokers). "ASA III": Patients with severe systemic disease that is not life-threatening. Example: Patients with some functional limitations as a result of disease (e.g., poorly treated hypertension or diabetes, morbid obesity, chronic renal failure, bronchospastic disease with intermittent exacerbations, stable angina, implanted pacemaker). "ASA IV": Patients with severe systemic disease that is consistently life-threatening. Example: Patients with functional limitations due to severe life-threatening disease (e.g., unstable angina, poorly controlled COPD, symptomatic CHF, recent (< 3 months) myocardial infarction or stroke). "ASA V": A moribund patient who is not expected to survive without surgery. The patient is not expected to survive beyond the next 24 hours without surgery. Examples: Ruptured abdominal aortic aneurysm, massive trauma, and extensive intracranial hemorrhage with significant impact. "ASA VI": A brain-dead patient whose organs are removed for the purpose of transplant into another patient.

[0331] As used herein, the term "sample" refers to a biological sample obtained or isolated from a patient or subject. As used herein, "sample" may refer to a sample of bodily fluid or tissue obtained for the purpose of diagnosis, prognosis, or evaluation of a subject of interest, such as a patient. Preferably, as used herein, the sample is a sample of bodily fluid, such as blood, serum, plasma, cerebrospinal fluid, urine, saliva, sputum, pleural effusion, cell, cell extract, tissue sample, tissue biopsy, stool sample, etc. In particular, the sample is blood, plasma, serum, or urine.

[0332] The embodiment of the present invention refers to the isolation of a first sample and the isolation of a second sample. In the context of the method of the present invention, the terms "first sample" and "second sample" refer to the relative determination of the chronological order of the isolation of the samples used in the method of the present invention. When the terms first sample and second sample are used in defining the method, they are not considered as an absolute determination of the number of samples taken. Thus, additional samples may be isolated from the patient before, during, or after the isolation of the first and / or second sample, or between the first or second sample, and these additional samples may or may not be used in the method of the present invention. Thus, the first sample may be considered as any sample obtained previously. The second sample may be considered as any further or later sample.

[0333] "Plasma" in the context of the present invention is the substantially cell-free supernatant of blood containing anticoagulants obtained after centrifugation. Exemplary anticoagulants include calcium ion-binding compounds such as EDTA or citrate, and thrombin inhibitors such as heparate or hirudin. Cell-free plasma can be obtained by centrifuging anticoagulated blood (e.g., citrated, EDTA or heparinized blood) at, for example, 2000-3000 g for at least 15 minutes.

[0334] "Serum" in the context of the present invention is the liquid fraction of whole blood that is collected after the blood has been allowed to clot. When the clotted blood (clot) is centrifuged, serum can be obtained as the supernatant.

[0335] As used herein, "urine" is the liquid product of the body secreted by the kidneys and excreted through the urethra through a process called urination (or micturition).

[0336] In a preferred embodiment of the invention, the method may be used for the diagnosis, prognosis, risk assessment and / or risk stratification of an infectious disease, preferably a blood infection, a respiratory infection, a urinary tract infection, a skin infection, more preferably a bloodstream infection, sepsis, severe sepsis and / or septic shock.

[0337] As used herein, "infection" within the scope of the present invention refers to a pathological process caused by the invasion of normally sterile tissues or body fluids by pathogenic or potentially pathogenic agents / pathogens, organisms, and / or microorganisms, and preferably relates to bacterial, viral, fungal, and / or parasitic infections. Thus, the infection may be a bacterial infection, a viral infection, and / or a fungal infection. The infection may be a localized or systemic infection. For the purposes of the present invention, a viral infection may be considered as a microbial infection.

[0338] Moreover, the subject suffering from infectious disease may suffer from two or more sources of infection at the same time.For example, the subject suffering from infectious disease may suffer from bacterial infection and viral infection, viral infection and fungal infection, bacterial infection and fungal infection, bacterial infection, fungal infection and viral infection, or may suffer from mixed infection, including one or more of the infections listed herein, possibly including superinfection, for example one or more bacterial infections in addition to one or more viral infections and / or one or more fungal infections.

[0339] As used herein, "infectious disease" includes all diseases or disorders associated with bacterial and / or viral and / or fungal infection.

[0340] In one embodiment, the infection to be detected or tested for is Bordetella, such as Bordetella pertussis, Borrelia, such as Borrelia burgdorferi, Brucella, such as Brucella abortus, Brucella canis, Brucella melitensis or Brucella suis, Campylobacter, such as Campylobacter jejuni, Chlamydia and Chlamydophila, such as Chlamydia pneumonia, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium, such as Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium, such as Corynebacterium diphtheria, Enterococcus, such as Enterococcus faecalis, Enterococcus faecium, Escherichia, such as Escherichia coli, Francisella Francisella such as Haemophilus influenzae, Helicobacter such as Helicobacter pylori, Legionella such as Legionella pneumophila, Leptospira such as Leptospira interrogans, Listeria such as Listeria monocytogenes, Mycobacterium such as Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycoplasma such as Mycoplasma pneumonia, Neisseria such as Neisseria gonorrhoeae, Neisseria meningitides, Pseudomonas such as Pseudomonas aeruginosa, RickettsiaThe bacterial strain may be selected from a species of Rickettsia such as rickettsia, Salmonella such as Salmonella typhi, Salmonella typhimurium, Shigella such as Shigella sonnei, Staphylococcus such as Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus such as Streptococcus agalactiae, Streptococcus pneumonia, Streptococcus pyogenes, Treponema such as Treponema pallidum, Vibrio such as Vibrio cholera, Yersinia such as Yersinia pestis, Yersinia enterocolitica or Yersinia pseudotuberculosis.

[0341] Pathogenic fungi are fungi that cause disease in humans or other organisms. Candida species are important human pathogens best known for causing opportunistic infections in immunocompromised hosts (e.g., transplant patients, AIDS sufferers, cancer patients). Infections are difficult to treat and can be very serious, with 30-40% of systemic infections resulting in death. Aspergillosis is another possible fungal pathogen. Aspergillus can cause disease in three major ways: through the production of mycotoxins, through the induction of an allergic response, and via local or systemic infection. In the latter two classifications, the immune status of the host is crucial. The most common pathogenic species are Aspergillus fumigatus and Aspergillus flavus. Aspergillus flavus produces aflatoxins, which are both toxins and carcinogens and can potentially contaminate food. Aspergillus fumigatus and Aspergillus clavatus can cause disease. Cryptococcus neoformans can cause disease in humans. Cryptococcus neoformans is a major pathogen of humans and animals. Cryptococcus laurentii and Cryptococcus albidus are known to occasionally cause moderate to severe disease in immunocompromised human patients. Cryptococcus gattii is endemic to tropical regions of the African and Australian continents and can cause disease. Histoplasma capsulatum can cause histoplasmosis in humans, dogs, and cats. Pneumocystis jirovecii (or Pneumocystis carinii) can cause a type of pneumonia in people with weakened immune systems, such as premature infants, the elderly, and AIDS patients. Stachybotrys chartarum or "black mold" can cause respiratory damage and severe headaches.

[0342] In one embodiment, the detected or tested infection is Acinetobacter baumannii, Klebsiella pneumoniae, Acinetobacter lwoffii, Listeria monocytogenes, Aeromonas caviae, Morganella morganii, Aeromonas hydrophila, Neisseria gonorrhoeae, Aspergillus flavus, Neisseria meningitidis, Aspergillus nidulans, Pasteurella multocida, Aspergillus niger, Pasteurella pneumotropica, Aspergillus terreus, Propionibacterium acnes, Bacillus anthracis, Proteus mirabillis, Bacillus cereus, Providencia rettgeri, Bacillus subtilis, Pseudomonas aeruginosa, Bacteroides fragilis, Salmonella choleraesuis, Brucella melitensis, Serratia liquefaciens, Burkholderia cepacia, Serratia marcescens, Candida albicans, Staphylococcus aureus, Candida dubliniensis, Staphylococcus epidermidis, Candida glabrata, Staphylococcus haemolyticus、Candida krusei、Staphylococcus hominis、Candida parapsilosis、Staphylococcus saccharolyticus、Candida tropicalis、Staphylococcus warn-eri、Capnocytophaga canimorsus、Stenotrophomonas maltophilia、Citrobacter braakii、Streptococcus agalactiae、Citrobacterfreundii, Streptococcus anginosus, Clostridium perfringens, Streptococcus bovis, Corynebacterium jeikeium, Streptococcus constellatus, Enterobacter aerogenes, Streptococcus dysgalactiae, Enterobacter cloacae, Streptococcus mutans, Enterobacter sakazakii, Streptococcus pneumoniae, Enterococcus faecalis, Streptococcus pyogenes, Enterococcus faecium, Streptococcus salivarius, Escherichia coli, Streptococcus sanguinis, Shigella sp., Streptococcus suis, Gemella haemolysans, Vibrio vulnificus, Gemella morbillorum, Yersinia enterocolitica, Haemophilus influenzae, Yersinia pestis, Kingella The bacterium may be selected from the group consisting of Klebsiella oxytoca, Yersinia kingae, Yersinia pseudotuberculosis and Klebsiella oxytoca.

[0343] As used herein, the term "bloodborne infection" may include systemic bloodstream infection, sepsis, severe sepsis, and / or septic shock.

[0344] "Sepsis" in the context of the present invention refers to a systemic response to an infection. Alternatively, sepsis may be viewed as a combination of SIRS and a confirmed infectious process or infection. Sepsis may be characterized as a clinical syndrome defined by the presence of both infection and a systemic inflammatory response (Levy et al. 2011). The term "sepsis" as used herein includes, but is not limited to, sepsis, severe sepsis, and septic shock.

[0345] The term "sepsis" as used herein includes, but is not limited to, sepsis, severe sepsis, and septic shock. Severe sepsis refers to sepsis associated with organ dysfunction, hypoperfusion abnormalities, or sepsis-induced hypotension. Hypoperfusion abnormalities include lactic acidosis, oliguria, and sudden changes in mental status. Sepsis-induced hypotension is defined by the presence of systolic blood pressure less than about 90 mmHg or its reduction from baseline of about 40 mmHg or more in the absence of other causes of hypotension (e.g., cardiogenic shock). Septic shock is defined as severe sepsis with sepsis-induced hypotension that persists despite adequate fluid resuscitation, together with the presence of hypoperfusion abnormalities or organ dysfunction (Bone et al., CHEST 101(6):1644-55, 1992).

[0346] Alternatively, the term sepsis may be defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In clinical operationalization, organ dysfunction may be represented by a 2-point or greater increase in the Sequential Organ Failure Assessment (SOFA) score and is associated with a greater than 10% in-hospital mortality rate. Septic shock may be defined as a subset of sepsis, in which particularly severe cardiovascular, cellular, and metabolic abnormalities are associated with a higher risk of death than sepsis alone. Patients with septic shock may be clinically identified by the need for vasopressors to maintain a mean arterial pressure of 65 mmHg or greater and serum lactate levels of more than 2 mmol / L (more than 18 mg / dL) in the absence of hypovolemia.

[0347] The term "sepsis" as used herein relates to all possible stages in the development of sepsis.

[0348] The term "sepsis" also includes severe sepsis or septic shock based on the SEPSIS-2 definition (Bone et al., 2009). The term "sepsis" also includes subjects that fall within the SEPSIS-3 definition (Singer et al., 2016). As used herein, the term "sepsis" refers to all possible stages in the development of sepsis.

[0349] "Cardiovascular event" is used herein synonymously with the term "cardiac event" and may refer to sudden cardiac death, acute coronary syndromes, including but not limited to plaque rupture, myocardial infarction, unstable angina, and non-cardiac acute arteriovenous events, such as leg thrombosis, aneurysm, stroke, and other arteriovenous ischemic events in which arteriovenous blood flow and oxygenation are interrupted. Cardiovascular events may also refer to elevated heart rate, bradycardia, tachycardia, or arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation, and premature ventricular or atrial contractions (PVCs or PACs). Preferably, the cardiovascular event is non-fatal cardiac arrest, congestive heart failure, new cardiac arrhythmias, angina, myocardial infarction, acute myocardial infarction, myocardial injury after non-cardiac surgery (MINS), or perioperative myocardial injury, or subacute ischemic heart disease.

[0350] For some embodiments, a cardiovascular event may refer to an event that presents with an abnormal electrocardiogram (ECG) or electrogram.

[0351] The term "electrocardiogram" is defined as the cardiac electrical signal from one or more skin surface electrodes placed in locations indicative of the electrical activity of the heart (depolarization and repolarization). An electrocardiogram segment refers to the recording of electrocardiogram data for either a particular period of time, such as 10 seconds, or a particular number of heart rates, such as 10 beats. The PQ segment of a patient's electrocardiogram is typically the flat segment of the electrocardiogram beat that occurs immediately before the R wave.

[0352] The term "electrogram" is defined as the cardiac electrical signal from one or more implanted electrodes placed in a location indicative of the electrical activity of the heart (depolarization and repolarization). An electrogram segment refers to a recording of electrogram data for either a specific time period, such as 10 seconds, or a specific heart rate, such as 10 beats. The PQ segment of a patient's electrogram is typically the flat segment of the electrogram that occurs immediately before the R wave. A beat is preferably a subsegment of an electrogram or electrocardiogram segment that contains exactly one R wave.

[0353] Cardiac signal parameters relate to measurements or calculations made during processing of one or more beats of electrogram data and may be used to determine whether a cardiovascular event has occurred. Cardiac signal parameters include PQ segment mean, ST segment mean, R wave peak value, ST deviation, ST shift, mean signal strength, T wave peak height, T wave mean, T wave deviation, heart rate, and RR interval.

[0354] As used herein, the term "myocardial infarction" preferably refers to at least partial necrosis of the myocardium caused by prolonged ischemia. Type I MI is caused by acute coronary syndrome. Myocardial blood flow is reduced due to rupture, ulceration, erosion, or detachment of unstable atherosclerotic plaques in one or more coronary vessels, followed by intraluminal thrombosis. Type II MI is caused by a long-term imbalance between myocardial oxygen supply and demand, and may occur as a result of conditions such as cardiac arrhythmias, anemia, respiratory failure, hypotension, hypertension, or by direct toxic effects of high levels of endogenous or exogenous circulating cortisol and catecholamines. Clinically, myocardial infarction is typically defined as a new elevation of the cardiac biomarker troponin, exceeding the upper level of the reference range by three times in the background of suspected myocardial ischemia accompanied by either ischemic symptoms or ischemic electrocardiogram (ECG) findings.

[0355] As used herein, the term "myocardial injury after non-cardiac surgery" or "MINS" preferably refers to myocardial injury resulting from ischemia after non-cardiac injury. MINS preferably encompasses a broader range of myocardial injury than myocardial infarction, and in particular, includes reversible myocardial injury in addition to necrosis.

[0356] Preferably, MINS refers to postoperative troponin elevation determined to be due to myocardial ischemia (without evidence of non-ischemic etiology), with or without ischemic symptoms. MINS preferably does not include perioperative myocardial injury resulting from etiology other than ischemia, such as sepsis or pulmonary embolism. The postoperative threshold for MINS depends on the type of troponin assay. For fifth generation cTnT, the threshold for assessing MINS may preferably be greater than 20 ng / L, with an increase of at least 5 ng / L or greater than 65 ng / L from baseline (Sessler et al. 2018).

[0357] "Cerebrovascular events" may preferably refer to events induced by cerebral ischemia, in particular ischemic events caused by insufficient oxygen supply to the brain, but may also encompass hemorrhagic events that occur when blood vessels in the brain rupture.

[0358] The event may be localized to a specific area of ​​the brain, as occurs in stroke or transient ischemic attack (TIA), or global, as occurs in delirium. Thus, a neurological adverse event may be characterized by confusion or may be diagnosed as a TIA or ischemic stroke. Oxygen delivery may be impaired due to the patient's health condition (as in certain blood diseases such as anemia), but may itself be caused by a surgical event. Cerebrovascular events may include any combination of events, particularly occlusion or stenosis of extracerebral or cerebral arteries, stroke, or transient ischemic attack.

[0359] "Major adverse cardiovascular or cerebrovascular event" or "MACCE" may preferably refer to a cerebrovascular or cardiovascular event selected from the group consisting of non-fatal cardiac arrest, acute myocardial infarction, congestive heart failure, new (post-operative) cardiac arrhythmia, angina pectoris, or stroke.

[0360] "Perioperative myocardial injury" or "PMI" preferably refers to any myocardial injury that occurs during the perioperative period. The perioperative period is the period of surgical treatment of a patient. This typically includes admission to the ward, anesthesia, surgery, and recovery. The perioperative period may also include the time associated with, occurring, or being the period around the time of surgery. Perioperative myocardial injury (PMI) appears to be a cause of death after non-cardiac surgery. Since the majority of PMIs are asymptomatic, in the absence of systematic screening, PMIs are routinely overlooked (see Puelacher et al. 2018). Thus, the present invention provides a method useful in determining the presence and / or risk of PMI using the methods described herein. In some embodiments, the perioperative period is between the preoperative and postoperative (post-operative) periods. The perioperative period may, in some embodiments, include a portion of the preoperative period, e.g., the time immediately prior to surgery, e.g., 1, 2, 3, or 4 hours starting from admission to the ward and preparation. In some embodiments, the present invention relates to intraoperative myocardial injury. The peroperative or intraoperative phase begins when the patient is transferred to the operating table and ends with the transfer of the patient to the postanesthesia care unit (PACU). The perioperative phase, in some embodiments, may include a portion of the postoperative period, e.g., the time immediately following surgery, e.g., the first 1, 2, 3, or 4 hours of recovery.

[0361] As used herein, "non-fatal cardiac arrest" preferably refers to the absence of cardiac rhythm or the presence of a chaotic rhythm that requires any part of basic or advanced cardiopulmonary resuscitation. "Acute myocardial infarction" preferably refers to an increase and gradual decrease in troponin levels, or a faster increase and decrease in the case of creatine kinase isoenzymes as a marker of myocardial necrosis, accompanied by at least one of the following: ischemic symptoms, abnormal Q waves on ECG, ST segment elevation or depression, irregular decrease in elevated troponin levels detected at its peak after coronary intervention (e.g., coronary angioplasty), or surgery in the patient. "Congestive heart failure" preferably refers to new in-hospital signs or symptoms after surgery of dyspnea or fatigue, orthopnea, paroxysmal nocturnal dyspnea, elevated jugular venous pressure, pulmonary rales on physical examination, cardiac hypertrophy, or pulmonary vascular congestion. "New cardiac arrhythmia" preferably refers to atrial flutter, atrial fibrillation, or second- or third-degree atrioventricular conduction block, which may be supported by an electrocardiogram. "Angina" preferably refers to a dull, diffuse substernal chest discomfort brought on by exertion or emotion and relieved by rest or nitroglycerin. "Stroke" preferably refers to an embolic, thrombotic, or hemorrhagic event lasting at least 30 in, with or without persistent residual motor, sensory, or cognitive dysfunction; if neurological symptoms persist for more than 24 hours, a person is preferably diagnosed with a stroke; if lasting less than 24 hours, the event is defined as a transient ischemic attack (TIA).

[0362] In the context of the present invention, the term "medical treatment" or "treatment" includes various treatment and therapeutic strategies, including, but not limited to, for infections, preferably sepsis, anti-inflammatory strategies, antibacterial therapy, ADM antagonists such as therapeutic antibodies, administration of si-RNA or DNA, extracorporeal blood purification or apheresis, dialysis, removal of harmful substances via adsorbents to prevent cytokine storm, removal of inflammatory mediators, plasma apheresis, administration of vitamins such as vitamin C, ventilation such as mechanical ventilation and non-mechanical ventilation to provide sufficient oxygen to the body, e.g., focal irrigation procedures, infusion of blood products, infusion of colloids, renal or hepatic replacement, antibiotic therapy, invasive mechanical ventilation, non-invasive mechanical ventilation, renal replacement therapy, vasopressor use, fluid therapy, apheresis, and measures for organ protection, and for cardiovascular or cerebrovascular events, anticoagulation therapy, oxygen therapy, lytic therapy such as thrombolysis, percutaneous coronary intervention, percutaneous transluminal angioplasty, coronary artery bypass graft surgery, and / or stent implantation. In some embodiments, medical treatment of cardiovascular and cerebrovascular events includes administration of nitroglycerin, acetylsalicylic acid, beta-blockers, ACE inhibitors, and / or clopidogrel.

[0363] With regard to perioperative myocardial infarction, as a means of prevention, medical therapy may include administration of statins, beta-blockers, alpha2-adrenergic agonists, or other anti-ischemic drugs such as calcium channel blockers or nitrates, among others.

[0364] "Renal replacement therapy" (RRT) refers to therapies used to replace the normal blood filtering function of the kidneys. Renal replacement therapy may refer to dialysis (e.g., hemodialysis or peritoneal dialysis), hemofiltration, and hemodiafiltration. Such techniques are various modalities in which blood is passed through a machine, cleaned, and then returned to the body. Renal replacement therapy may also refer to kidney transplantation, which is the ultimate form of replacement in that the old kidney is replaced by a donor kidney. Hemodialysis, hemofiltration, and hemodiafiltration may be continuous or intermittent and may use arteriovenous (blood leaves the arteries and returns via veins) or venovenous (blood leaves the veins and returns via veins) routes. This results in different types of RRT. For example, the renal replacement therapy may be selected from the group of, but is not limited to, continuous renal replacement therapy (CRRT), continuous hemodialysis (CHD), continuous arteriovenous hemodialysis (CAVHD), continuous venovenous hemodialysis (CVVHD), continuous hemofiltration (CHF), continuous arteriovenous hemofiltration (CAVH or CAVHF), continuous venovenous hemofiltration (CVVH or CVVHF), continuous hemodiafiltration (CHDF), continuous arteriovenous hemodiafiltration (CAVHDF), continuous venovenous hemodiafiltration (CVVHDF), intermittent renal replacement therapy (IRRT), intermittent hemodialysis (IHD), intermittent venovenous hemodialysis (IVVHD), intermittent hemofiltration (IHF), intermittent venovenous hemofiltration (IVVH or IVVHF), intermittent hemodiafiltration (IHDF), and intermittent venovenous hemodiafiltration (IVVHDF).

[0365] Artificial and mechanical ventilation are effective approaches to enhance proper gas exchange and ventilation and to save lives during severe hypoxemia. Artificial ventilation refers to supporting or stimulating the breathing of a subject. Artificial ventilation may be selected from the group consisting of mechanical ventilation, manual ventilation, extracorporeal membrane oxygenation (ECMO), and non-invasive ventilation (NIV). Mechanical ventilation refers to methods of mechanically supporting or replacing spontaneous breathing. This may involve a machine called a ventilator. Mechanical ventilation may be high frequency oscillatory ventilation or partial liquid ventilation.

[0366] "Fluid management" refers to the monitoring and control of a subject's fluid status and administration of fluids to stabilize circulation or organ vitality, for example, by oral, enteral, or intravenous fluid administration. This includes stabilizing fluid and electrolyte balance, or preventing or correcting hypervolemia or hypovolemia, and providing blood products.

[0367] A surgical emergency / emergency operation is required when a subject is in a medical emergency and may require immediate surgical intervention to survive or maintain health.Subjects requiring emergency operation may be selected from the group consisting of subjects suffering from acute trauma, active uncontrolled infection, organ transplantation, organ protection or stabilization surgery, or cancer.

[0368] Cleaning procedures are hygienic methods for preventing infection of subjects, especially nosocomial infections, and include disinfection of all organic and inorganic surfaces that may come into contact with patients, such as skin, objects in the hospital room, medical devices, diagnostic devices, or room air. Cleaning procedures include measures such as the use of protective clothing and units, such as mouth guards, gowns, gloves, or sanitary locks, and restrictions on patient visits. In addition, cleaning procedures include washing the patient himself and his clothes or the patient.

[0369] In case of serious adverse events such as severe infection or sepsis, or severe cardiovascular or cerebrovascular events, it is crucial to perform early diagnosis of such adverse events as well as prognosis and risk assessment in order to initiate optimal therapy and management. Therapeutic approaches are individual and need to differ from case to case. Therapeutic monitoring is necessary for best practice therapy and is influenced by the timing of treatment, the use of combination therapy, and optimization of medication or surgical measures. Incorrect or omitted therapy or management will increase the mortality rate by the hour.

[0370] The medical treatment of the present invention may be an antibiotic treatment, in which one or more "antibiotics" or "antibiotic preparations" may be administered when an infection is diagnosed or when symptoms of an infection are determined.

[0371] Antibiotics or antibiotic formulations according to the present invention may also include antibacterial, antifungal, or antiviral compounds used to treat diagnosed infections or sepsis. The terms antibacterial, antibiotic, and anti-infective as may be used herein encompass a wide variety of pharmaceuticals including antibacterial, antifungal, antiviral, and antiparasitic drugs. Dividing pathogens by classification, antibiotic formulations commonly applied to the treatment of any given infection are as follows:

[0372] Gram-positive bacteria coverage: Penicillins, (ampicillin, amoxicillin), penicillinase resistant, (dicloxacillin, oxacillin), cephalosporins (1st and 2nd generation), macrolides (erythromycin, clarithromycin, azithromycin), quinolones (gatifloxacin, moxifloxacin, levofloxacin), vancomycin, sulfonamides / trimethoprim, clindamycin, tetracycline, chloramphenicol, linezolid, synercid.

[0373] Gram-negative coverage: Broad-spectrum penicillins (ticarcillin, clavulanic acid, piperacillin, tazobactam), cephalosporins (2nd, 3rd, and 4th generation), aminoglycosides, macrolides, azithromycin, quinolones (ciprofloxacin), monobactams (azetreonam), sulfonamides / trimethoprim, carbapenems (imipenem), chloramphenicol.

[0374] Pseudomonas Coverage: Ciprofloxacin, aminoglycosides, some third generation cephalosporins, fourth generation cephalosporins, broad-spectrum penicillins, carbapenems.

[0375] Fungal treatments: allylamines, amphotericin B, fluconazole and other azoles, itraconazole, voriconazole, posaconazole, ravuconazole, echinocandins, flucytosine, sordarin, chitin synthase inhibitors, topoisomerase inhibitors, lipopeptides, pradimicin, liposomal preparations of nystatin, voriconazole, echinocandins, imidazoles, triazoles, thiazoles, polyenes.

[0376] Antiviral Treatment: Abacavir, Acyclovir (Aciclovir), Activated Caspase Oligomerizer, Adefovir, Amantadine, Amprenavir (Agenerase), Ampligen, Arbidol, Atazanavir, Atripla, Balavir, Cidofovir, Combivir, Dolutegravir, Darunavir, Delavirdine, Didanosine, Double-stranded RNA, Docosanol, Edoxudine, Efavirenz, Emtricitabine, Enfuvirtide, Entecavir, Ecoliever, Famciclovir, Fixed-dose combinations (antiretrovirals), Fomivirsen, Fosamprenavir, Foscarnet, Phosphonet, Fusion inhibitors, Ganciclovir, Ibacitabine, Imunovir, Idoxuridine, Imiquimod, Indinavir, Inosine, Integrase inhibitors, Interferon III, Interferon II, Interferon I, Interferon, Lamivudine, Lopinavir, Robiride, Maraviroc, Moroxydine, Methisazone, Morpholino, Nelfinavir, Nevirapine, Nexavir, Nitazoxanide, Nucleoside analogues, Novir, Oseltamivir (Tamiflu), Peginterferon alfa-2a, Penciclovir, Peramivir, Pleconaril, Podophyllotoxin, Protease inhibitors (pharmacology), Raltegravir, Reverse transcriptase inhibitors, Ribavirin, Ribozyme, Rifampicin, Rimantadine, Ritonavir, RNase H, protease inhibitors, pyramidine, saquinavir, sovosbuvir, stavudine, synergistic enhancer (antiretroviral), telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, Truvada, valacyclovir (Valtrex), valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir (Relenza), zidovudine.

[0377] In addition, antibiotic preparations include bacteriophages, synthetic antimicrobial peptides, or iron antagonists / chelators for the treatment of bacterial infections. Also, therapeutic antibodies or antagonists against pathogenic structures, such as anti-VAP antibodies, anti-resistant clonal vaccination, administration of immune cells such as in vitro stimulated or modified T effector cells, are antibiotic preparations that represent treatment options for critically ill patients, such as septic patients. Further antibiotic preparations / treatments or therapeutic strategies against infections or for the prevention of new infections include the use of disinfectants, decontamination products, antivirals like liposomes, hygiene, wound care, surgery.

[0378] It is also possible to combine several of the aforementioned antibiotic agents or treatment strategies.

[0379] According to the present invention, proADM, PCT, and / or proET-1, and / or optionally other markers or clinical scores are used as markers for prognosis, diagnosis, risk assessment, and risk stratification of adverse events in post-operative patient health, and optionally for further treatment guidance, treatment stratification, and / or therapy control.

[0380] A person skilled in the art will be able to obtain or develop means for identifying, measuring, determining and / or quantifying any one of the above-mentioned proADM, PCT and / or proET-1 molecules, or fragments or variants thereof, as well as other markers of the present invention according to standard molecular biology practices.

[0381] The levels of proADM, PCT, and / or proET-1, or fragments thereof, as well as the levels of other markers of the present invention, can be determined by any assay that reliably determines the concentration of the marker. In particular, mass spectrometry (MS) and / or immunoassays can be used as illustrated in the accompanying examples. As used herein, an immunoassay is a biochemical test that measures the presence or concentration of a macromolecule / polypeptide in a solution through the use of an antibody or an antibody-binding fragment or an immunoglobulin.

[0382] The method of determining proADM, PCT, and / or proET-1, or other markers used in the context of the present invention is contemplated in the present invention.As an example, a method selected from the group consisting of mass spectrometry (MS), luminescence immunoassay (LIA), radioimmunoassay (RIA), chemiluminescence and fluorescence immunoassay, enzyme immunoassay (EIA), enzyme-linked immunoassay (ELISA), luminescence-based bead array, magnetic bead-based array, protein microarray assay, rapid test format such as instant immunochromatography strip test, rare earth cryptate assay, and automated system / analyzer may be used.

[0383] The determination of proADM, PCT, and / or proET-1, and optionally other markers, based on antibody recognition is a preferred embodiment of the present invention. As used herein, the term "antibody" refers to immunoglobulin molecules and immunologically active parts of immunoglobulin (Ig) molecules, i.e. molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen. According to the present invention, the antibody may be a monoclonal or polyclonal antibody. In particular, antibodies that specifically bind at least proADM, PCT, and / or proET-1, or fragments thereof, are used.

[0384] An antibody is considered specific if its affinity for a molecule of interest, such as proADM, PCT, and / or proET-1, or a fragment thereof, is at least 50 times higher, preferably 100 times higher, and most preferably at least 1000 times higher, than for other molecules contained in the sample containing the molecule of interest. How to develop and select an antibody with a given specificity is well known in the art. In the context of the present invention, monoclonal antibodies are preferred. The antibody or antibody-binding fragment specifically binds to a marker or a fragment thereof as defined herein. In particular, the antibody or antibody-binding fragment binds to a peptide of proADM, PCT, and / or proET-1 as defined herein. Thus, the peptide as defined herein may also be an epitope to which the antibody specifically binds. Furthermore, the methods and kits of the present invention use antibodies or antibody-binding fragments that specifically bind to ADM or proADM, in particular MR-proADM, PCT, and / or proET-1, in particular CT-proET1.

[0385] Furthermore, the methods and kits of the present invention use antibodies or antibody-binding fragments that specifically bind to proADM, PCT, and / or proET-1 or fragments thereof, and optionally other markers of the present invention.Exemplary immunoassays can be luminescence immunoassays (LIA), radioimmunoassays (RIA), chemiluminescence and fluorescence immunoassays, enzyme immunoassays (EIA), enzyme-linked immunoassays (ELISA), luminescence-based bead arrays, magnetic bead-based arrays, protein microarray assays, rapid test formats, rare earth cryptate assays.In addition, assays suitable for point-of-care testing and rapid test formats, such as immunochromatographic strip tests, can be used.Automated immunoassays, such as KRYPTOR assays, are also contemplated.

[0386] Alternatively, instead of antibodies, other capture molecules or molecular scaffolds that specifically and / or selectively recognize proADM, PCT, and / or proET-1 may be included within the scope of the present invention. As used herein, the term "capture molecule" or "molecular scaffold" includes molecules that may be used to bind target molecules or molecules of interest, i.e., analytes (e.g., proADM, proADM, MR-proADM, PCT, proET-1, or CT-proET-1) from a sample. For this purpose, the capture molecule must be appropriately shaped both spatially and with respect to surface features such as surface charge, hydrophobicity, hydrophilicity, the presence or absence of Lewis donors and / or acceptors, to specifically bind to the target molecule or molecule of interest. Thus, the binding may be mediated, for example, by ionic, van der Waals forces, pi-pi, sigma-pi, hydrophobic or hydrogen bond interactions, or a combination of two or more of the aforementioned interactions or covalent interactions between the capture molecule or molecular scaffold and the target molecule or molecule of interest. In the context of the present invention, the capture molecule or molecular scaffold can be selected from the group consisting of, for example, nucleic acid molecule, carbohydrate molecule, PNA molecule, protein, peptide, and glycoprotein.The capture molecule or molecular scaffold can include, for example, aptamer, DAR pin (Designed Ankyrin Repeat Protein).Affimer and the like are included.

[0387] In certain aspects of the invention, the method comprises: a) subjecting a sample to a first antibody or an antigen-binding fragment or derivative thereof specific for a first epitope of i.proADM, PCT, and / or proET-1; and ii. contacting with a second antibody or antigen-binding fragment or derivative thereof specific for a second epitope of proADM, PCT, and / or proET-1; b) detecting binding of the two antibodies or antigen-binding fragments or derivatives thereof to proADM, PCT, and / or proET-1.

[0388] Preferably, one antibody is labeled and the other antibody is bound to a solid phase or can be selectively bound to a solid phase. In a particularly preferred embodiment of the assay, one of the antibodies is labeled while the other is either bound to a solid phase or can be selectively bound to a solid phase. The first and second antibodies can be present dispersed in a liquid reaction mixture, a first label component that is part of a labeling system based on fluorescence or chemiluminescence quenching or amplification is bound to the first antibody and a second label component of the labeling system is bound to the second antibody, so that after binding of both antibodies to be detected to proADM, PCT and / or ET-1 or fragments thereof, a measurable signal is generated that allows the detection of the resulting sandwich complex in the measurement solution. The labeling system can include rare earth cryptates or chelates, in particular in combination with fluorescent or chemiluminescent dyes of the cyanine type.

[0389] In a preferred embodiment, the method is carried out as a heterogeneous sandwich immunoassay, in which one of the antibodies is immobilized on a solid phase selected at will, for example on a coated test tube (e.g. polystyrol test tube; coated tube; CT) or on a microtiter plate, for example made of polystyrol, or on particles, for example magnetic particles, so that the other antibody has a group that is useful for the detection of the formed sandwich structure, which resembles a detectable label or allows it to selectively bind to the label. A temporary delay or subsequent immobilization using a suitable solid phase is also possible.

[0390] The method according to the invention can further be embodied as a homogeneous method, in which the sandwich complex formed by the antibody / antibodies to be detected and the markers proADM, PCT, and / or ET-1, or fragments thereof, remains suspended in a liquid phase. In this case, when two antibodies are used, it is preferred that both antibodies are labeled as part of the detection system, which results in the generation or induction of a signal when both antibodies are integrated into a single sandwich. Such techniques are especially embodied as fluorescence enhancement or fluorescence quenching detection methods. Particularly preferred embodiments relate to the use of detection reagents used in pairs, such as those described in US4882733, EP0180492, or EP0539477, and the prior art cited therein. In this way, measurements are possible in which only reaction products containing both labeling components are detected directly in a single immune complex in the reaction mixture. For example, such techniques are provided under the trade names TRACE® (Time Resolved Amplified Cryptate Emission), or KRYPTOR®, which implement the teachings of the above-cited applications. Therefore, in a particularly preferred embodiment, diagnostic device is used to carry out the method provided herein.For example, the level of proADM, PCT, and / or ET-1 or its fragment and / or the level of any additional marker of the method provided herein are determined.In a particularly preferred embodiment, diagnostic device is KRYPTOR® or a correlated automated device.

[0391] The level of the marker of the present invention, for example, proADM, PCT, and / or ET-1, or fragments thereof, or other markers, can also be determined by methods based on mass spectrometry (MS).Such methods can include detecting the presence, amount, or concentration of one or more modified or unmodified fragment peptides, for example, of proADM, PCT, or proET-1 in the biological sample or, for example, in the protein digest (for example, trypsin digest) from the sample, and optionally separating the sample using a chromatographic method, and subjecting the prepared and optionally separated sample to MS analysis.For example, selected reaction monitoring (SRM), multiple reaction monitoring (MRM), or parallel reaction monitoring (PRM) mass spectrometry can be used for MS analysis, particularly to determine the amount of proADM, PCT, or proET-1, or fragments thereof.

[0392] As used herein, the term "mass spectrometry" or "MS" refers to analytical techniques for identifying compounds by their mass. To increase the mass resolution and mass determination capabilities of mass spectrometry, samples may be treated prior to MS analysis. Thus, the present invention relates to immunoenrichment techniques, methods relating to sample preparation, and / or MS detection methods that can be combined with chromatographic methods, preferably liquid chromatography (LC), more preferably high performance liquid chromatography (HPLC) or ultra-high performance liquid chromatography (UHPLC). Sample preparation methods include techniques for dissolution, fractionation, digestion of the sample into peptides, depletion, concentration, dialysis, desalting, alkylation, and / or peptide reduction. However, these steps are optional. Selective detection of analyte ions may be performed using tandem mass spectrometry (MS / MS). Tandem mass spectrometry is characterized by a mass selection step (as used herein, the term "mass selection" refers to the isolation of ions with a specific m / z or a narrow range of m / z), followed by fragmentation of the selected ions, and mass analysis of the resulting product (fragment) ions.

[0393] Those skilled in the art will recognize how to quantitate the levels of markers in a sample by mass spectrometry. For example, relative quantification "rSRM" or absolute quantification can be used as described above.

[0394] Furthermore, levels (including reference levels) can be determined by mass spectrometry-based methods, such as methods that determine relative quantification or methods that determine absolute quantification of a protein of interest or a fragment thereof.

[0395] Relative quantification "rSRM" can be achieved by: 1. Determine the increased or decreased presence of a target protein by comparing the SRM (selected reaction monitoring) signature peak area from a given target fragment peptide detected in a sample with the same SRM signature peak area of ​​the target fragment peptide in at least a second, third, fourth, or more biological samples.

[0396] 2. Determine the increased or decreased presence of a target protein by comparing the SRM signature peak area from a given target peptide detected in a sample with the SRM signature peak area generated from fragment peptides from other proteins in other samples derived from different, separate biological sources, where the SRM signature peak area comparison between the two samples for the peptide fragments is normalized, for example, to the amount of protein analyzed in each sample.

[0397] 3. To normalize changes in the levels of histone proteins to the levels of other proteins that do not change their expression levels under various cellular conditions, the increased or decreased presence of the target protein is determined by comparing the SRM signature peak area for a given target peptide to the SRM signature peak areas from other fragment peptides derived from different proteins within the same biological sample.

[0398] 4. These assays can be applied to both unmodified fragment peptides and modified fragment peptides of the target protein, where modifications include phosphorylation and / or glycosylation, acetylation, methylation (mono-, di-, tri-), citrullination, and ubiquitination, and the relative levels of modified peptides are determined in the same way as the relative amounts of unmodified peptides are determined.

[0399] Absolute quantification of a given peptide may be achieved by: 1. Compare the SRM / MRM signature peak area for a given fragment peptide from a target protein in an individual biological sample with the SRM / MRM signature peak area of ​​an internal fragment peptide standard spiked into a protein lysate from the biological sample. The internal standard may be a labeled synthetic version of the fragment peptide from the target protein being investigated or a labeled recombinant protein. This standard is spiked into the sample in known amounts before (required for recombinant proteins) or after digestion, and the SRM / MRM signature peak area is determined separately for both the internal fragment peptide standard and the native fragment peptide in the biological sample, after which a comparison of both peak areas can be made. This can be applied to unmodified and modified fragment peptides, where modifications include phosphorylation and / or glycosylation, acetylation, methylation (e.g., mono-, di-, or trimethylation), citrullination, ubiquitination, and the absolute level of the modified peptide can be determined in the same way as determining the absolute level of the unmodified peptide.

[0400] 2. Peptides can also be quantified using an external calibration curve. The normal curve approach uses a fixed amount of a heavy peptide as an internal standard and various amounts of a light synthetic peptide spiked into the sample. A representative matrix similar to that of the test sample must be used to construct a standard curve to account for matrix effects. Besides, the inverse curve method avoids the problem of endogenous analytes in the matrix, where a fixed amount of a light peptide is spiked on top of the endogenous analyte to create the internal standard, and various amounts of a heavy peptide are spiked to create a set of concentration standards. The test samples to be compared with either the normal curve or the inverse curve are spiked with the same amount of standard peptide as the internal standard spiked into the matrix used to create the calibration curve.

[0401] The present invention further relates to kits, the use of the kits, and methods in which such kits are used. The present invention relates to kits for carrying out the methods provided herein above and below. The definitions provided herein, e.g., for the methods, also apply to the kits of the present invention. In particular, the present invention relates to kits for prognosis, diagnosis, risk assessment, or risk stratification of adverse events in post-operative patient health, comprising: - a detection reagent for determining the level of at least one biomarker selected from the group consisting of proADM, PCT, and proET-1, or fragments thereof; - reference data regarding the likelihood of postoperative adverse events, in particular reference data regarding threshold or cut-off values, which reference data is preferably stored on a computer readable medium and / or used in the form of a computer executable code configured to compare the determined level of at least one biomarker selected from proADM, PCT and proET-1, or a fragment thereof, with the threshold or cut-off value.

[0402] As used herein, "reference data" includes reference levels of proADM, PCT, and / or proET-1, and optionally further markers as described herein. The levels of proADM, PCT, and / or proET-1 in a subject's sample can be compared with the reference levels contained in the reference data of the kit. The reference levels are described herein above and are also illustrated in the accompanying examples. The reference data can also include a reference sample with which the levels of proADM, and optionally PCT, lactate, and / or C-reactive protein are compared. The reference data can also include instructions on how to use the kit of the present invention.

[0403] In addition, the kit may include items useful for obtaining a sample, such as a blood sample, for example, the kit may include a container that includes a device for attaching the container to a cannula or syringe, e.g., a syringe suitable for blood isolation that exhibits an internal pressure below atmospheric pressure suitable for drawing a predetermined amount of sample into the container, and / or additionally includes a filtration system containing detergents, chaotropic salts, ribonuclease inhibitors, chelating agents such as guanidinium isothiocyanate, guanidinium hydrochloride, sodium dodecyl sulfate, polyoxyethylene sorbitan monolaurate, RNAse inhibitor proteins, and mixtures thereof, and / or nitrocellulose, silica matrix, ferromagnetic spheres, a cup retrieve spill over, trehalose, fructose, lactose, mannose, poly-ethylene-glycol, glycerol, EDTA, TRIS, limonene, xylene, benzoyl, phenol, mineral oil, aniline, pyrrole, citrate, and mixtures thereof.

[0404] As used herein, a "detection reagent" or the like is a reagent suitable for determining a marker described herein, e.g., proADM, PCT, and / or proET-1. Such an exemplary detection reagent is, for example, a ligand, e.g., an antibody or a fragment thereof, that specifically binds to a peptide or epitope of a marker described herein. Such a ligand can be used in an immunoassay, as described above. Additional reagents used in an immunoassay to determine the level of a marker can also be included in the kit and are considered detection reagents herein. Detection reagents can also relate to reagents used to detect a marker or a fragment thereof by MS-based methods. Thus, such detection reagents can also be reagents used to prepare a sample for MS analysis, e.g., enzymes, chemicals, buffers, etc. Mass spectrometers can also be considered detection reagents. Detection reagents according to the present invention can also be, for example, calibration solutions that can be used to determine and compare the levels of markers.

[0405] The sensitivity and specificity of diagnostic and / or prognostic tests do not only depend on the analytical "quality" of the test, but they also depend on the definition of what constitutes an abnormal result. In practice, receiver operating characteristic curves (ROC curves) are typically calculated by plotting the value of a variable against its relative frequency in a "normal" population (i.e., apparently healthy individuals without infection) and a "disease" population, e.g., subjects with an infection. For any particular marker (such as proADM, PCT, and / or proET-1), the distributions of marker levels for subjects with or without the disease / condition are likely to overlap. Under such conditions, the test will not completely distinguish between normal and disease with 100% accuracy, and the area of ​​overlap may indicate where the test cannot distinguish between normal and disease. A threshold is selected below which the test is considered abnormal and above which the test is considered normal, or below or above which the test indicates a particular condition, e.g., an infection or a cardiovascular or cerebrovascular event. The area under the ROC curve is a measure of the probability that a perceived measurement will allow correct identification of a condition. Even if the test result does not necessarily give an exact number, the ROC curve can be used. As long as the results can be ranked, the ROC curve can be created. For example, the results of the test on the "disease" sample can be ranked according to degree (e.g., 1=low, 2=normal, and 3=high). This ranking can be correlated with the results of the "normal" population, and the ROC curve can be created. These methods are well known in the art. See, for example, Hanley et al. 1982.Radiology 143:29-36. Preferably, the threshold value is selected to provide a ROC curve area of ​​greater than about 0.5, more preferably greater than about 0.7, even more preferably greater than about 0.8, even more preferably greater than about 0.85, and most preferably greater than about 0.9. The term "about" in this context refers to + / - 5% of a given measurement.

[0406] The horizontal axis of the ROC curve represents (1-specificity), which increases with the false positive rate. The vertical axis of the curve represents sensitivity, which increases with the true positive rate. Thus, for a particular cutoff selected, the value of (1-specificity) may be determined and the corresponding sensitivity may be obtained. The area under the ROC curve is a measure of the probability that the measured marker level will allow for correct identification of a disease or condition. Thus, the area under the ROC curve can be used to determine the validity of a test.

[0407] The method of the present invention may be partially implemented by computer. For example, the step of comparing the detected level of markers, such as proADM, PCT, and / or proET-1, or fragments thereof, with a reference level may be performed by a computer system. In the computer system, the determined level of the marker may be combined with other marker levels and / or parameters of the subject to calculate a score that is an index for diagnosis, prognosis, risk assessment, and / or risk stratification. For example, the determined value may be input into the computer system (manually by a medical professional or automatically from the device where the respective marker level is determined). The computer system may be directly at the point of care (e.g., primary care, ICU, or ED) or may be at a remote location connected via a computer network (e.g., via the Internet, or a specialized medical cloud system, optionally combined with other IT systems or platforms such as a hospital information system (HIS)). Typically, the computer system will store values ​​(e.g., marker levels, or parameters such as age, blood pressure, weight, sex, or clinical scoring systems such as SOFA, qSOFA, BMI, etc.) in a computer readable medium and calculate a score based on predefined and / or prestored reference levels or values. The resulting score will be displayed and / or printed for a user (typically a medical professional such as a physician). Alternatively or additionally, an associated prognosis, diagnosis, evaluation, treatment guideline, patient management guideline, or stratification will be displayed and / or printed for a user (typically a medical professional such as a physician).

[0408] In one embodiment of the present invention, a software system in which machine learning algorithms exist can be used to identify hospitalized patients at risk for sepsis, severe sepsis, and septic shock, preferably using data from an electronic health record (EHR). The machine learning approach can be trained with a random forest classifier using EHR data from the patient (lab results, biomarker expression, vitals, demographics, etc.). Machine learning is a type of artificial intelligence that gives computers the ability to learn complex patterns of data without being explicitly programmed, unlike simple rule-based systems. Previous studies have used electronic health record data to raise warnings and detect general clinical deterioration. In one embodiment of the present invention, the processing of proADM, PCT, and / or proET-1 levels may be incorporated into appropriate software for comparison with existing data sets, for example, proADM, PCT, and / or proET-1 levels may also be processed in machine learning software to aid in the diagnosis or prognosis of the occurrence of adverse events.

[0409] As used herein, the terms "comprising" and "including" or grammatical variations thereof should be interpreted as specifying stated features, integers, steps, or components, but not excluding the addition of one or more additional features, integers, steps, components, or groups thereof. This term encompasses the terms "consisting of" and "consisting essentially of."

[0410] Thus, the terms "comprising" / "including" / "having" mean that any additional components (or similar features, integers, steps, etc.) may / can be present. The term "consisting of" means that no additional components (or similar features, integers, steps, etc.) are present.

[0411] The term "consisting essentially of" or grammatical variations thereof, as used herein, should be construed to identify the stated features, integers, steps, or components, but not to preclude the addition of one or more additional features, integers, steps, components, or groups thereof, but only if those additional features, integers, steps, components, or groups thereof do not materially alter the basic and novel characteristics of the composition, device, or method being claimed.

[0412] Thus, the term "consisting essentially of" means that certain additional components (or similar features, integers, steps, etc.) may be present, i.e., that do not substantially affect the essential characteristics of the composition, device, or method. In other words, the term "consisting essentially of" (which may be used synonymously herein with the term "substantially comprising") allows for the presence of other components in the composition, device, or method in addition to the required components (or similar features), provided that the essential characteristics of the device or method are not substantially affected by the presence of the other components.

[0413] The term "method" refers to manners, means, techniques, and procedures for accomplishing a given task, and includes, but is not limited to, manners, means, techniques, and procedures that are either known to practitioners in the chemical, biological, and biophysical arts or that can be readily developed by practitioners from known manners, means, techniques, and procedures. EXAMPLES

[0414] The present invention will now be further described by reference to the following non-limiting examples, which set forth non-limiting working embodiments presented to further illustrate the present invention.

[0415] Example Method: Study design and patients: This study is part of the MINSS study "Myocardial Injury in Noncardiac Surgery in Sweden" which aimed to find the relationship between perioperative variables and the occurrence of adverse outcomes in Swedish patients undergoing elective and major abdominal surgery. The MINSS study is a multicenter prospective cohort study in several Swedish hospitals, followed from April 2017 to October 2018. Patients aged 50 years or older undergoing elective abdominal surgery graded as major or major / complex by the Surgical Outcome Risk Tool, SORT (Protopapa et al. 2014), were eligible. In addition, the procedure had to be performed under general anesthesia and required at least one night of hospitalization.

[0416] Eligible patients were identified by daily screening of patient lists at the preoperative evaluation clinic. Before consenting to participate, patients were informed of the study's aims, methods, expected benefits, possible risks, and the option to withdraw at any time.

[0417] Written informed consent was obtained from all patients prior to inclusion.

[0418] Participants could only be included once and were excluded if they were unable to provide informed consent or if they underwent one of the following types of abdominal surgery: transplant, trauma, endocrine, vascular, or endovascular.

[0419] Included patients were excluded if the elective surgery was cancelled due to patient death or if another non-elective surgery was performed before the elective surgery.

[0420] Study Evaluation Items MACCE within 30 days and MINS within 3 days of surgery were predefined study outcomes. MINS is defined as a peak fifth generation cTnT >65 ng / L or >20 ng / L, increased >5 ng / L from preoperative levels. MACCE was defined as one or more of the outcomes listed in Table 9 (Devereaux et al. 2005).

[0421] Date Collection and Analysis A 12-lead ECG was obtained at five sampling points: preoperative (<24 hours before anesthesia), postoperative (within 24 hours of surgery), and days 1, 2, and 3 after surgery. Concurrently, arterial or venous blood samples were obtained using 8.5 ml EDTA tubes. Blood samples were sent to a local clinical chemistry laboratory where the samples were centrifuged and the plasma was frozen in aliquots at -80°C and stored until batch analysis of plasma concentrations of CT-proET-1, MR-proADM, PCT, and cTnT.

[0422] New ECG changes according to Table 2 were considered to be indicative of myocardial ischemia. All ECGs were analyzed by an investigator blinded to the results of hsTnT and CT-proET-1.

[0423] The occurrence of MACCE was reviewed through charts on days 1, 2, and 3 and 30 days after surgery via telephone interview and / or by reviewing the patients' medical records. The incidence of MINS was calculated from the analyzed cTnT plasma levels. Mortality was assessed using Swedish population registries.

[0424] The occurrence of infection or sepsis was reviewed by trained reviewers and microbial identification on days 1, 2, and 3, and 30 days after surgery via telephone interview and / or by reviewing the patient's medical records.

[0425] In addition, the patients' general health status was assessed using the American Society of Anesthesiologists (ASA) physical status classification system. [Table 1]

[0426] If a patient was discharged, dropped out, or died before all samples were obtained, the patient was not excluded and the collected samples were analyzed unless the patient asked not to be included in the data analysis.

[0427] Biomarker measurements: CT-proET-1 was measured using an immunofluorescence assay on a BRAHMS Kryptor Compact plus (BRAHMS GmbH, Heringsdorf, Germany) with TRACE technology (Time Resolved Amplified Cryptate Emission). Two fluorescent tracers, donor (Europium cryptate) and acceptor (XL665), each conjugated to an antibody, were used. When the antibodies bind to their antigen CT-proET-1, the tracer is activated and energy is transferred from the cryptate to the XL665, resulting in the emission of a signal at 665 nm. Fluorescence is proportional to the CT-proET1 concentration. The 99th percentile of CT-proET1 in the healthy population was 72.9 pmol / L, with an analytical lower detection limit of 3 pmol / L and a read zone up to 5000 pmol / L.

[0428] Cardiac troponin T (cnTNT) was analyzed using a highly sensitive electrochemiluminescence immunoassay on a Cobas e 602 / cobas e 601 / cobas e 411 (Roche Diagnostics Mannheim, Germany). Two antibodies specific for cTnT are used, one labeled with biotin and the other with a ruthenium complex that together form a sandwich complex. Streptavidin is added to the sample before it is transferred to the measurement cell and unbound material is removed by the ProCell. By applying an electric field, electrochemiluminescence at 620 nm is emitted by the ruthenium complex, which is detected by a photomultiplier tube to determine the hsTnT concentration. The lower limit of detection of this assay is 5 ng / L, with a 99th percentile of 14 ng / L in a healthy reference population.

[0429] PCT was measured using a commercial double sandwich immunoassay on the KRYPTOR platform (Thermo Fisher Scientific, Germany) with a measurement range of 0.02–5000 ng / ml and a functional assay sensitivity and lower limit of detection of at least 0.06 ng / ml and 0.02 ng / ml, respectively.

[0430] MR-proADM plasma concentrations were measured using a Kryptor® (Thermo Fisher Scientific, Germany) with a detection limit of 0.05 nmol / L.

[0431] Statistical analysis: Data analysis was performed using Graphpad PRISM 8. Data distribution was examined using the D'Agostino & Parson test. Comparisons between different groups were performed using Fisher's exact test and Kruskal-Wallis test. A p value of less than 0.05 was considered significant.

[0432] Example 1: Patient characteristics Patient characteristics at study entry are summarized in Table 1 .

[0433] A total of 387 patients who underwent surgery were analyzed. The mean age of the enrolled patients was 70 years, with 44% women and 56% men. Using the American Society of Anesthesiologists Physical Status Score (ASAPS), 265 (68%) patients were classified as high-risk patients (ASA III-IV) and 116 (30%) patients were classified as low-risk patients (ASA I-III).

[0434] Of all patients, 37 (9.6%) suffered a postoperative major adverse cardiac or cerebrovascular event (MACCE) and 94 (24%) suffered a myocardial injury after noncardiac surgery (MINS), of which 14 patients experienced both. Regarding postoperative infections, 105 (27%) developed an infection, of which 11 had a blood infection. Overall mortality was 1.3% (5 deaths).

[0435] Example 2: Correlation between postoperative occurrence of MACCE and biomarkers Table 2 summarizes patient characteristics with respect to the occurrence of MACCE. Biomarker levels were determined for all patients preoperatively (preOP), in the postanesthesia care unit (PACU), and on days 1 (POD1), 2 (POD2), and 3 (POD3) after surgery.

[0436] Figures 1-3 summarize the results for MR-proADM, PCT, and CT-proET-1. The levels of all biomarkers were higher in the group of patients who suffered from MACCE after surgery. This trend is evident at all sample points: preOP, PACU, and PODs 1-3.

[0437] Differences are observed for MR-proADM at all observed sample points, which become more pronounced postoperatively, starting from PACU until POD 3 (Figure 1). The levels of MR-proADM in MACCE patients are continuously elevated from preOP through PACU to POD 1-3, whereas the levels of MR-proADM in patients without MACCE remain constant or even decrease after POD 1.

[0438] Similar results are seen for PCT as a marker of MACCE occurrence (Figure 2). Notably, a steady and rapid 4-fold increase in PCT levels starting from PACU up to POD3 is seen in patients with MACCE, whereas patients who did not experience MACCE showed a mild increase on POD1, with levels remaining constant or decreasing at later dates from POD1 to POD3.

[0439] For preoperative and PACU CT-proET-1, the difference between patients with and without MACCE is particularly striking with p-values ​​of 0.03 (preOP) and 0.0001 (PACU) (Figure 3). However, even at later sample points, a clear difference in proET-1 levels in relation to the incidence of MACCE can hold: p-values ​​are 0.006 at POD2 and 0.007 at POD3. Notably, at sample points POD1-3, the levels of CT-proET1 decrease in patients without MACCE, whereas they are maintained or even increased in patients with MACCE.

[0440] A single cutoff value of 84.7 pmol / L for CT-proET1 across all sample points (preOP, PACU, POD1-3) yielded a highly statistically significant Fisher's exact test of p=<0.0001 (see Table 3).

[0441] These results indicate that MR-proADM, CT-proET1, and PCT can be useful for reliable prediction or diagnosis of the incidence of MACCE in postoperative patients. Prediction or diagnosis can be established using a single threshold for all sample points or at individual sample points (e.g., preOP, PACU, POD1-3) by comparing with sample point-specific values.

[0442] In addition, the different time courses of biomarker levels in patients with and without MACCE allow for more reliable prognosis or diagnosis when samples are taken at two or more time points and the percentage or absolute difference for different sample points is analyzed. In patients with MACCE, the biomarker levels continuously increase, whereas in patients without MACCE, after a mild increase after surgery, the biomarker levels remain unchanged or even decrease over the 72 hours after surgery until POD3.

[0443] Example 3: Correlation of postoperative occurrence of MACCE with ECG changes or creatine levels To test the prognostic or diagnostic reliability of additional markers or parameters at the time of analysis, the ECGs of 146 patients were analyzed. Table 4 presents the distribution of ECG changes in patients with and without MACCE. Although the number of ECGs analyzed may not be a clear statistical description, the current distribution of ECG changes does not seem to be a good predictor of MACCE, in contrast to the biomarkers MR-proADM, PCT, and / or CT-1.

[0444] Creatinine levels were also analyzed in relation to the incidence of MACCE, since renal function is known to affect CT-proET1 levels. Figure 4 shows that the Kruskal-Wallis test revealed no significant difference in creatinine levels between patients with and without MACCE. Thus, the finding that CT-proET1 levels or one of the other biomarkers predicts MACCE in patients does not appear to be influenced by the renal function of the patients.

[0445] Example 4: Correlation between postoperative occurrence of MINS and biomarkers Table 5 summarizes patient characteristics with respect to the occurrence of MINS. Biomarker levels were determined for all patients preoperatively (preOP), in the postanesthesia care unit (PACU), and on days 1 (POD1), 2 (POD2), and 3 (POD3) after surgery.

[0446] Figures 5-7 summarize the results for MR-proADM, PCT, and CT-proET-1. The levels of all biomarkers were higher in the group of patients who suffered from MINS after surgery. This trend is evident at all sample points: preOP, PACU, and PODs 1-3.

[0447] For MR-proADM, the difference in levels between patients with and without MINS is visible at early and even preoperative sample points in the PACU, and the difference becomes more pronounced postoperatively from POD1 to POD3 (Figure 5). The levels of MR-proADM in MACCE patients continuously increase until POD1 and are maintained at high levels of approximately 1.75 nmol / L on POD2 and POD3, whereas the levels of MR-proADM in patients without MACCE steadily decrease after POD1.

[0448] Similar results hold for PCT as a marker of MINS development (Figure 6). Notably, from PACU to POD1, levels rise 4-fold from approximately 0.25 μg / L to over 1 μg / L and continue to rise until sample point POD3. On the contrary, levels of PCT in patients without MINS on postoperative days 1-3 remain constant, well below 1 μg / L, and levels on POD3 decrease relative to POD1.

[0449] For CT-proET-1, the differences between patients with and without MACCE are particularly striking, with p-values ​​less than 0.001 in preOP and less than 0.0001 in PACU and POD1 to POD3. Notably, at sample points POD1 to POD3, the levels of CT-proET1 are decreased in patients without MACCE, which allows further differentiation from MACCE patients (Figure 7).

[0450] These results indicate that MR-proADM, CT-proET1, and PCT can be useful for reliable prediction or diagnosis of the incidence of MINS in postoperative patients. Prediction or diagnosis can be established using a single threshold for all sample points or at individual sample points (e.g., preOP, PACU, POD1-3) by comparing with sample point-specific values.

[0451] In addition, the different time courses of biomarker levels in patients with and without MINS allow for more reliable prognosis or diagnosis when samples are taken at two or more time points and the percentages or absolute differences for the different sample points are analyzed.

[0452] Example 5: Correlation of biomarkers with postoperative occurrence of any infection Table 6 summarizes patient characteristics with respect to the occurrence of infection. Biomarker levels were determined for all patients preoperatively (preOP), in the postanesthesia care unit (PACU), and on days 1 (POD1), 2 (POD2), and 3 (POD3) after surgery.

[0453] Figures 8-10 summarize the results for MR-proADM, PCT, and CT-proET-1. The levels of all biomarkers, especially MR-proADM and PCT, were higher in the group of patients who suffered from infection after surgery. This trend is evident at all sample points: preOP, PACU, and PODs 1-3.

[0454] The levels of MR-proADM in patients with postoperative infections were higher for early PACU sample points and even mildly preoperatively compared to those in patients without infections. This difference becomes more pronounced postoperatively, starting on POD1, and especially on POD2 and POD3 (Figure 8). At the same time, the levels of MR-proADM in patients without any infections decline from approximately 1.25 nmol / L after POD1 to less than 1.2 nmol / L on POD3. In patients with any infections, the levels remain robustly above 1.5 nmol / L on all PODs 1-3.

[0455] In the case of PCT as a marker of the development of any infection, striking and significant differences are seen from POD1 through POD3 postoperatively (Figure 9). While the levels of PCT in postoperative patients without infection remain around or below 0.75 μg / L, those in patients with any infection continuously increase from POD1 (approximately 1.0 μg / L) to above approximately 1.25 μg / L on PODs 2 and 3. Notably, mild differences are also evident preoperatively and early in the PACU.

[0456] In the case of CT-proET-1, the difference between patients with and without infection is less pronounced than in the case of the markers PCT and MR-proADM. However, clear differences allow a reliable discrimination, especially at the later sample points, 2-3 days after surgery (Figure 10).

[0457] These results suggest that MR-proADM and PCT, and possibly also CT-proET-1, in particular, may be useful for reliable prediction or diagnosis of the incidence of infections in postoperative patients. Prediction or diagnosis may be established using a single threshold for all sample points or at individual sample points (e.g., preOP, PACU, POD1-3) by comparison with sample point-specific values.

[0458] In addition, the different time courses of biomarker levels in patients with and without any infection allow for a more reliable prognosis or diagnosis when samples are taken at least at two time points and the percentages or absolute differences for the different sample points are analyzed.

[0459] Example 6: Correlation between postoperative occurrence of blood infection and biomarkers Table 7 summarizes patient characteristics with respect to the occurrence of blood infections. Biomarker levels were determined for all patients preoperatively (preOP), in the postanesthesia care unit (PACU), and on days 1 (POD1), 2 (POD2), and 3 (POD3) after surgery.

[0460] Figures 11-13 summarize the results for MR-proADM, PCT, and CT-proET-1. The levels of all biomarkers, especially MR-proADM and PCT, were higher in the group of patients who suffered from blood infections after surgery. This trend is evident at all sample points: preOP, PACU, and PODs 1-3.

[0461] The levels of MR-proADM in patients with postoperatively developed blood infections were significantly higher for the early PACU sample points and even preoperatively compared to the levels in patients without infections. This difference becomes more pronounced postoperatively from POD1 to POD3 (Figure 11). At the same time, the levels of MR-proADM in patients without any infections decrease from about 1.3 nmol / L after POD1 to less than 1.2 nmol / L on POD3. For patients with blood infections, the levels remain robust at more than about 1.75 nmol / L on all PODs 1-3.

[0462] Particularly striking differences in the levels of PCT are seen postoperatively from POD1 through POD3, as well as in the development of any infection versus the development of a blood infection (Figure 12). While the levels of PCT in postoperative patients without a blood infection remain around or below 0.75 μg / L, those in patients with a blood infection continually increase from POD1 (approximately 2.0 μg / L) to above approximately 2.5 μg / L on PODs 2 and 3. Notably, mild differences are also evident preoperatively and early in the PACU.

[0463] For CT-proET-1, the differences between patients with and without blood infections are less pronounced than for the markers PCT and MR-proADM. However, clear differences allow differentiation, especially at the later sample points, 2-3 days after surgery. Levels of CT-proET-1 in patients with blood infections exceeded 100 pmol / L on PODs 2 and 3, whereas levels in patients without blood infections were around or below 0.75 pmol / L on PODs 2 and 3 (Figure 13).

[0464] These results suggest that MR-proADM and PCT, and possibly also CT-proET-1, in particular, may be useful for reliable prediction or diagnosis of the incidence of blood infections in postoperative patients. Prediction or diagnosis may be established using a single threshold for all sample points or at individual sample points (e.g., preOP, PACU, POD1-3) by comparison with sample point-specific values.

[0465] In addition, the different time courses of biomarker levels in patients with and without blood infections allow for more reliable prognosis or diagnosis when samples are taken at two or more time points and the percentages or absolute differences for the different sample points are analyzed.

[0466] Example 7: Correlation of biomarkers with postoperative incidence of infection and MACCE Table 8 summarizes patient characteristics with respect to the postoperative occurrence of infection and MACCE. Biomarker levels were determined for all patients preoperatively (preOP), in the postanesthesia care unit (PACU), and on days 1 (POD1), 2 (POD2), and 3 (POD3) after surgery.

[0467] Figures 14-19 summarize the results for MR-proADM, PCT, and CT-proET-1.

[0468] Notably, levels of all biomarkers were particularly high in the group of patients who had both infection and MACCE, and this trend was evident at all sample points: preOP, PACU, and PODs 1-3.

[0469] In the case of MR-proADM, the levels of patients who suffered from infection and MACCE exhibit clear differences versus patients who suffered from neither of these events or only one of the adverse events across all sample points (Figure 14). The differences are especially pronounced postoperatively. Patients who did not develop infections and did not experience MACCE postoperatively had MR-proADM levels below 1 nmol / L in the PACU or on PODs 1-3, whereas patients who suffered from both adverse events had a steady increase in MR-proADM levels from approximately 1.5 nmol / L in the PACU to approximately 2.3 nmol / L on POD 3. Notably, MR-proADM levels in patients with MACCE and either infection are also consistently higher than those in patients with MACCE but no infection (Figure 17). Thus, MR-proADM may serve as a reliable marker for the prognosis or diagnosis of either one of both postoperative adverse events and their combination.

[0470] PCT appears to be a particularly valuable marker for the combined prognosis or diagnosis of infection or MACCE. This is especially true for postoperative sample points from POD1 to POD3 (Figure 15). PCT levels in patients who developed infection and suffered a MACCE event were consistently above 2 μg / L from POD1 to POD3, and further averaged about 3 μg / L to 3.5 μg / L on POD2 and POD3. On the contrary, for patients who experienced neither MACCE nor infection after surgery, PCT levels were determined to be around or below 0.5 μg / L. The difference of more than 4-fold on POD1 and the difference of more than 6-7-fold on POD2 or POD3 indicate a strong synergistic effect for the combined diagnosis or prediction of infection and MACCE using PCT as a marker. Notably, for postoperative sample points, PCT levels in patients with MACCE and any infection are also found to be consistently higher than those in patients with MACCE but without infection (Figure 18).

[0471] Similarly, in the case of CT-proET-1 across all sample points, it was determined that the levels in patients who suffered both infection and MACCE postoperatively were significantly higher than those who did not experience either of these adverse events (Figure 16). For the former group, CT-proET-1 levels remained at or below about 80 pmol / L, while in the latter group, CT-proET-1 levels were at or above about 125 pmol / L postoperatively from PACU to POD3. Furthermore, CT-proET-1 levels in patients with MACCE and any infection are higher than those in patients with MACCE but no infection at either preoperative or postoperative sample points (Figure 19). Thus, this data strongly supports the prognostic and diagnostic ability of CT-proET-1 for either infection or MACCE as a postoperative adverse event and their combination.

[0472] The present data show that the prognosis and / or diagnosis of infection and MACCE using one of the described biomarkers can be achieved with particularly high accuracy and reliability.Such a strong predictive power is not expected from the predictive potential of the marker for one of the adverse events, which indicates the functional synergy of these biomarkers for the diagnosis or prediction of these prominent adverse events.

[0473] A prediction or diagnosis can be established using a single threshold for all sample points or at individual sample points (eg, preOP, PACU, POD1-3) by comparison to sample point specific values.

[0474] In addition, the different time courses of biomarker levels in patients with and without infection and MACCE allow for more reliable prognosis or diagnosis when samples are taken at two or more time points and the percentages or absolute differences for the different sample points are analyzed. [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

Table 11

Claims

1. 1. A method for diagnosis, prognosis, risk assessment, and / or risk stratification of adverse events in post-operative patient health, comprising: providing at least one sample from a patient who has undergone, is undergoing or is about to undergo surgery, said at least one sample being isolated from said patient pre-, intra- or post-operatively; - determining the level of at least one biomarker in said at least one sample, - the method, wherein said level of said at least one biomarker or a fragment thereof correlates with the likelihood of said adverse event, said at least one biomarker being proADM or a fragment thereof and said adverse event being an infection.

2. 10. The method of claim 1, wherein the adverse event is a fungal, bacterial, or viral infection.

3. 3. The method of claim 1 or 2, wherein the infection is a blood infection, a respiratory infection, a urinary tract infection, a skin infection, or an abdominal infection.

4. The method of any one of claims 1 to 3, wherein the adverse event is bloodstream infection, sepsis, severe sepsis, and / or septic shock.

5. 2. The method of claim 1, wherein the adverse events are cardiovascular or cerebrovascular events and infections.

6. 2. The method of claim 1, wherein the adverse events are myocardial injury after non-cardiac surgery (MINS) and infection.

7. 2. The method of claim 1, wherein the adverse events are major cardiovascular or cerebrovascular events (MACCE) and infections.

8. 2. The method of claim 1, wherein the adverse events are cardiovascular or cerebrovascular events and blood infections.

9. 2. The method of claim 1, wherein the adverse events are myocardial injury after non-cardiac surgery (MINS) and blood infections.

10. 2. The method of claim 1, wherein the adverse events are major cardiovascular or cerebrovascular events (MACCE) and blood infections.

11. 11. The method of any one of claims 1 to 10, wherein a first sample is isolated from the patient at a first time point and a second sample is isolated from the patient at a second time point, preferably with at least 6 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between said first and second time points.

12. 12. The method of any one of claims 1 to 11, wherein a first sample is isolated from the patient at a first time point and a second sample is isolated from the patient at a second time point, and the likelihood of an adverse event is correlated with an absolute difference, percentage, and / or rate of change in the level of the biomarker between the first and second time points.

13. 13. The method of any one of claims 1 to 12, wherein a first sample is isolated from the patient post-operatively at a first time point and a second sample is isolated from the patient post-operatively at a second time point, preferably with at least 12, 24, 36, 48 or more hours having elapsed between said first and second time points, and wherein an increase or plateauing in levels of proADM or a fragment thereof indicates a high likelihood of said adverse event.

14. The method of any one of claims 1 to 13, wherein determining the level of proADM or a fragment thereof comprises determining the level of MR-proADM or mature ADM in said sample.

15. The method of any one of claims 1 to 14, further comprising treatment guidance, stratification and / or control.

16. The method according to any one of claims 1 to 15, wherein the level of said at least one biomarker correlates with a likelihood of infection indicating initiation of treatment with an anti-infective agent, preferably an antibiotic.

17. 17. The method of any one of claims 1 to 16, wherein the level of the at least one biomarker correlates with a likelihood of a post-operative adverse event indicating that the patient will require frequent or increased levels of monitoring and / or critical care.

18. 18. The method of any one of claims 1 to 17, wherein determining the level of at least one biomarker comprises determining the level of proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold indicates an increased likelihood of infection.

19. 19. The method of any one of claims 1 to 18, wherein determining the level of at least one biomarker comprises determining the level of said proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold indicates an increased likelihood of a blood-borne infection.

20. 20. The method according to any one of claims 1 to 19, wherein determining the level of at least one biomarker comprises determining the level of said proADM or a fragment thereof, wherein a level of proADM or a fragment thereof above a threshold value indicates an increased likelihood of infection, preferably a blood infection, and of adverse cardiovascular or cerebrovascular events, preferably MACCE, PMI and / or MINS.

21. A kit for carrying out the method according to any one of claims 1 to 20, said kit comprising: - a detection reagent for determining the level of said at least one biomarker, said at least one biomarker being proADM or a fragment thereof; reference data on the likelihood of a postoperative adverse event, in particular reference data on threshold or cut-off values, said reference data being preferably stored on a computer readable medium and / or said reference data being preferably used in the form of a computer executable code configured to compare said determined level of proADM or a fragment thereof with said threshold or cut-off value, said adverse event being an infection, The kit comprising:

22. 1. A method for diagnosis, prognosis, risk assessment, and / or risk stratification of adverse events in post-operative patient health, comprising: providing at least one sample from a patient who has undergone, is undergoing or is about to undergo surgery, said at least one sample being isolated from said patient pre-, intra- or post-operatively; - determining the level of at least one biomarker in said at least one sample, - the method, wherein said level of said at least one biomarker or a fragment thereof correlates with the likelihood of said adverse event, said at least one biomarker being PCT or a fragment thereof and said adverse event being a cardiovascular or cerebrovascular event.

23. 23. The method of claim 22, wherein the cardiovascular event is myocardial infarction (MI).

24. 23. The method of claim 22, wherein the cardiovascular event is myocardial injury after non-cardiac surgery (MINS).

25. 23. The method of claim 22, wherein the cardiovascular event is a major adverse cardiovascular or cerebrovascular event (MACCE).

26. 23. The method of claim 22, wherein the adverse event is perioperative myocardial injury (PMI).

27. 23. The method of claim 22, wherein the cerebrovascular event is a stroke and / or a transient ischemic attack.

28. 23. The method of claim 22, wherein the adverse events are cardiovascular or cerebrovascular events and infections.

29. 23. The method of claim 22, wherein the adverse events are myocardial injury after non-cardiac surgery (MINS) and infection.

30. 23. The method of claim 22, wherein the adverse events are major cardiovascular or cerebrovascular events (MACCE) and infections.

31. 23. The method of claim 22, wherein the adverse events are cardiovascular or cerebrovascular events and blood infections.

32. 23. The method of claim 22, wherein the adverse events are myocardial injury after non-cardiac surgery (MINS) and blood infections.

33. 23. The method of claim 22, wherein the adverse events are major cardiovascular or cerebrovascular events (MACCE) and blood infections.

34. 34. The method of any one of claims 22 to 33, wherein a first sample is isolated from the patient at a first time point and a second sample is isolated from the patient at a second time point, preferably with at least 6 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between said first and second time points.

35. 35. The method of any one of claims 22-34, wherein a first sample is isolated from the patient at a first time point and a second sample is isolated from the patient at a second time point, and the likelihood of an adverse event is correlated with an absolute difference, percentage, and / or rate of change in the level of the biomarker between the first and second time points.

36. 36. The method of any one of claims 22 to 35, wherein a first sample is isolated from the patient post-operatively at a first time point and a second sample is isolated from the patient post-operatively at a second time point, preferably at least 12, 24, 36, 48 or more hours having elapsed between said first and second time points, and wherein an increase or plateauing in the level of PCT or a fragment thereof indicates a high likelihood of said adverse event.

37. 37. The method of any one of claims 22 to 36, wherein determining the level of PCT or a fragment thereof comprises determining the level of PCT1-116, PCT2-116, or PCT3-116 in the sample.

38. The method of any one of claims 22 to 37, further comprising treatment guidance, stratification and / or control.

39. 39. The method of any one of claims 22 to 38, wherein the level of the at least one biomarker correlates with the likelihood of an adverse cardiovascular or cerebrovascular event indicating further diagnostic evaluation selected from CT scan, MRI scan, angiogram, arteriogram, X-ray, echocardiogram, ECG, and EEG.

40. 40. The method of any one of claims 22 to 39, wherein the level of the at least one biomarker correlates with the likelihood of an adverse cardiovascular or cerebrovascular event indicating initiation or readiness for anticoagulant therapy, oxygen therapy, lytic therapy, percutaneous coronary intervention, percutaneous transluminal angioplasty, coronary artery bypass grafting, and / or stent implantation.

41. 41. The method of any one of claims 22 to 40, wherein the level of the at least one biomarker correlates with a likelihood of a post-operative adverse event indicating that the patient will require frequent or increased levels of monitoring and / or critical care.

42. 42. The method according to any one of claims 22 to 41, wherein determining the level of at least one biomarker comprises determining the level of said PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold is indicative of an increased likelihood of an adverse cardiovascular or cerebrovascular event, preferably MACCE.

43. 43. The method according to any one of claims 22 to 42, wherein determining the level of at least one biomarker comprises determining the level of said PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold is indicative of an increased likelihood of a cardiovascular or cerebrovascular adverse event, preferably MINS.

44. 44. The method according to any one of claims 22 to 43, wherein determining the level of at least one biomarker comprises determining the level of said PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold indicates an increased likelihood of an adverse cardiovascular or cerebrovascular event, preferably a PMI.

45. 45. The method according to any one of claims 22 to 44, wherein determining the level of at least one biomarker comprises determining the level of said PCT or a fragment thereof, wherein a level of PCT or a fragment thereof above a threshold is indicative of an increased likelihood of infection, preferably a blood infection, and of adverse cardiovascular or cerebrovascular events, preferably MACCE, PMI and / or MINS.

46. A kit for carrying out the method according to any one of claims 22 to 45, said kit comprising: - a detection reagent for determining the level of said at least one biomarker, said at least one biomarker being PCT or a fragment thereof; - reference data on the likelihood of a postoperative adverse event, in particular on threshold or cut-off values, said reference data being preferably stored on a computer readable medium and / or preferably in the form of a computer executable code configured to compare the determined level of the at least one biomarker selected from the group consisting of the PCT or a fragment thereof with said threshold or cut-off value, said adverse event being an infection; The kit comprising:

47. 1. A method for diagnosis, prognosis, risk assessment, and / or risk stratification of adverse events in post-operative patient health, comprising: providing at least one sample from a patient who has undergone, is undergoing or is about to undergo surgery, said at least one sample being isolated from said patient pre-, intra- or post-operatively; - determining the level of at least one biomarker in said at least one sample, - the method, wherein said level of said at least one biomarker or a fragment thereof correlates with the likelihood of said adverse event, and said at least one biomarker is proET-1 or a fragment thereof.

48. 48. The method of claim 47, wherein the adverse event is a cardiovascular or cerebrovascular event.

49. 48. The method of claim 47, wherein the cardiovascular event is myocardial infarction (MI).

50. 48. The method of claim 47, wherein the cardiovascular event is myocardial injury after non-cardiac surgery (MINS).

51. 48. The method of claim 47, wherein the cardiovascular event is a major adverse cardiovascular or cerebrovascular event (MACCE).

52. 48. The method of claim 47, wherein the adverse event is perioperative myocardial injury (PMI).

53. 48. The method of claim 47, wherein the cerebrovascular event is a stroke and / or a transient ischemic attack.

54. 48. The method of claim 47, wherein the adverse event is an infection.

55. 48. The method of claim 47, wherein the adverse event is a fungal, bacterial, or viral infection.

56. 56. The method of claim 54 or 55, wherein the infection is a blood infection, a respiratory infection, a urinary tract infection, a skin infection, or an abdominal infection.

57. 57. The method of any one of claims 54 to 56, wherein the adverse event is bloodstream infection, sepsis, severe sepsis, and / or septic shock.

58. The method according to claims 54 to 57, wherein the adverse events are cardiovascular or cerebrovascular events and infections.

59. The method of claims 54 to 58, wherein the adverse events are myocardial injury after non-cardiac surgery (MINS) and infection.

60. The method according to claims 54 to 59, wherein the adverse events are major cardiovascular or cerebrovascular events (MACCE) and infections.

61. The method according to claims 48 to 53, wherein the adverse events are cardiovascular or cerebrovascular events and blood infections.

62. 48. The method of claim 47, wherein the adverse events are myocardial injury after non-cardiac surgery (MINS) and blood infections.

63. 48. The method of claim 47, wherein the adverse events are major cardiovascular or cerebrovascular events (MACCE) and blood infections.

64. 64. The method of any one of claims 47 to 63, wherein a first sample is isolated from said patient at a first time point and a second sample is isolated from said patient at a second time point, preferably with at least 6 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between said first and second time points.

65. 65. The method of any one of claims 47-64, wherein a first sample is isolated from the patient at a first time point and a second sample is isolated from the patient at a second time point, and the likelihood of an adverse event is correlated with an absolute difference, percentage, and / or rate of change in the level of the biomarker between the first and second time points.

66. 66. The method of any one of claims 47 to 65, wherein a first sample is isolated from said patient post-operatively at a first time point and a second sample is isolated from said patient post-operatively at a second time point, preferably at least 12, 24, 36, 48 or more hours having elapsed between said first and second time points, and wherein an increase or plateauing in levels of proET-1 or a fragment thereof indicates a high likelihood of said adverse event.

67. The method of any one of claims 47 to 66, wherein determining the level of proET-1 or a fragment thereof comprises determining the level of CT-proET-1 in said sample.

68. 68. The method of any one of claims 47 to 67, further comprising treatment guidance, stratification and / or control.

69. The method according to any one of claims 47 to 68, wherein said level of said at least one biomarker correlates with a likelihood of infection indicating initiation of treatment with an anti-infective agent, preferably an antibiotic.

70. 70. The method of any one of claims 47-69, wherein the level of the at least one biomarker correlates with the likelihood of an adverse cardiovascular or cerebrovascular event indicating further diagnostic evaluation selected from CT scan, MRI scan, angiogram, arteriogram, X-ray, echocardiogram, ECG, and EEG.

71. 71. The method of any one of claims 47 to 70, wherein the level of the at least one biomarker correlates with the likelihood of an adverse cardiovascular or cerebrovascular event indicating initiation or readiness for anticoagulant therapy, oxygen therapy, lytic therapy, percutaneous coronary intervention, percutaneous transluminal angioplasty, coronary artery bypass grafting, and / or stent implantation.

72. 72. The method of any one of claims 47-71, wherein the level of the at least one biomarker correlates with a likelihood of a post-operative adverse event indicating that the patient will require frequent or increased levels of monitoring and / or critical care.

73. 73. The method according to any one of claims 47 to 72, wherein determining the level of at least one biomarker comprises determining the level of said proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value is indicative of an increased likelihood of an adverse cardiovascular or cerebrovascular event, preferably MACCE.

74. 74. The method according to any one of claims 47 to 73, wherein determining the level of at least one biomarker comprises determining the level of said proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value indicates an increased likelihood of an adverse cardiovascular or cerebrovascular event, preferably MINS.

75. 75. The method according to any one of claims 47 to 74, wherein determining the level of at least one biomarker comprises determining the level of said proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value is indicative of an increased likelihood of an adverse cardiovascular or cerebrovascular event, preferably a PMI.

76. 76. The method of any one of claims 47 to 75, wherein determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold indicates an increased likelihood of infection.

77. 77. The method of any one of claims 47 to 76, wherein determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold indicates a high likelihood of a blood-borne infection.

78. 78. The method according to any one of claims 47 to 77, wherein determining the level of at least one biomarker comprises determining the level of said proET-1 or a fragment thereof, wherein a level of proET-1 or a fragment thereof above a threshold value is indicative of an increased likelihood of infection, preferably a blood infection, and of adverse cardiovascular or cerebrovascular events, preferably MACCE, PMI and / or MINS.

79. A kit for carrying out the method according to any one of claims 47 to 78, said kit comprising: - a detection reagent for determining the level of said at least one biomarker, said at least one biomarker being proET-1 or a fragment thereof; - reference data regarding the likelihood of a post-operative adverse event, in particular reference data regarding threshold or cut-off values, said reference data being preferably stored on a computer readable medium and / or said reference data being preferably used in the form of a computer executable code configured to compare the determined level of said at least one biomarker with said threshold or cut-off value.

80. 80. The method of any one of claims 1 to 79, wherein the patient has undergone, is undergoing or is about to undergo non-cardiac surgery.

81. 81. The method of any one of claims 1 to 80, wherein the patient has undergone, is undergoing or is about to undergo abdominal surgery.

82. The method of any one of claims 1 to 81, wherein the patient is 50 years of age or older.

83. A method according to any one of claims 1 to 82, wherein the sample is isolated pre-operatively, within 7 days, preferably within 3 days, 1 day, 12 hours or less, before the surgery.

84. 84. The method of any one of claims 1 to 83, wherein the sample is isolated from the patient post-operatively, at least 12 hours, 24 hours, 48 ​​hours, 72 hours or more after surgery, and / or within 72 hours, 48 ​​hours, 24 hours, 12 hours or less after said surgery.

85. A method according to any one of claims 1 to 84, wherein the sample is isolated post-operatively, within 12 hours, preferably within 6 hours, after surgery.

86. The method of any one of claims 1 to 85, wherein the sample is isolated one day after surgery.

87. The method of any one of claims 1 to 86, wherein the sample is isolated 2 days after surgery.

88. The method of any one of claims 1 to 87, wherein the sample is isolated 3 days after surgery.

89. 89. The method of any one of claims 1 to 88, wherein the first sample is isolated pre-operatively and / or peri-operatively and the second sample is isolated post-operatively.

90. 90. The method of any one of claims 1 to 89, wherein the first sample is isolated pre-operatively and the second sample is isolated peri-operatively and / or post-operatively.

91. The method of any one of claims 1 to 90, wherein the sample is selected from the group consisting of a blood sample, such as a whole blood sample, a serum sample or a plasma sample, a saliva sample, and / or a urine sample.

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