Biomarkers in Trauma, Injury and Critical Care

Series Preface
Preface
Contents
About the Editors
Contributors
Part I: General Overviews: Circulating and Body Fluid Biomarkers in Organ Injury and Trauma
	1 A Synopsis of Routine Blood Biomarkers in Trauma, Injury Critical Care and Recovery: General Overview
		Introduction
		Characteristics of Biomarkers in Trauma, Injury Critical Care, and Recovery
		Various Definitions of Biomarkers
		Significance of Medical Biomarkers in Trauma, Injury Critical Care, and Recovery
		Biomarkers in Critical Care
		Established Blood Biomarkers in Orthopedic Trauma
		Biomarkers for Mild Traumatic Brain Injury: Unresolved Issues
		Established Blood Biomarkers in Acute Cardiac Disease
		Established Blood Biomarkers in Acute Lung Injury
		Established Blood Biomarkers in Acute Kidney Injury
		Established Blood Biomarkers in Acute Medical Condition of Gastrointestinal Track and/or Liver
		Conclusion
		Mini-Dictionary of Terms
		Key Facts of Biomarkers in Trauma, Injury Critical Care, and Recovery
		Summary Points
		References
	2 A Synopsis of Emerging Blood Biomarkers in Trauma, Injury Critical Care, and Recovery: General Overview
		Introduction
		Different Types of Emerging Biomarkers in Trauma, Injury Critical Care, and Recovery
		Classification of Emerging Biomarkers According to Their Main Clinical Application in Trauma, Injury Critical Care, and Recove...
		Role of Biomedicine and Emerging Biomarkers in Modern Medicine´s Trauma, Injury Critical Care, and Recovery
		Modern Medical Diagnostics in Trauma, Injury Critical Care, and Recovery
		An Overview on Emerging Biomarkers in Cardiovascular Events in Trauma, Injury Critical Care, and Recovery
		Emerging Biomarkers in COVID-19 Critical Care and Recovery
		Emerging Biomarkers of Infection in the Critical Care
		Clinical Outcomes and Emerging Biomarkers: Overlaps and Differences
		Conclusion
		Limitations of Biomarkers
		Mini-Dictionary of Terms
		Key Facts on Emerging Blood Biomarkers in Trauma, Injury Critical Care, and Recovery
		Summary Points
		References
	3 Biomarkers in Neurological Injury: Fibrinogen, Fibrinogen/Fibrin Degradation Products (FDPs), and D-dimer
		Introduction
		Fibrinogen
		The Fibrinogen and Coagulation Cascade (Fig. 1)
		Fibrinogen and Inflammation
		Fibrinogen and the CNS
		FDP and D-dimer
		FDP, D-dimer and Fibrinolysis Cascades (Fig. 2)
		FDP, D-dimer, and the CNS
		Fibrinolytic Biomarker and Treatment
		Applications to Prognosis, Other Diseases, and Conditions
		Key Facts About Fibrinogen
		Key Facts About D-dimer
		Mini-Dictionary of Terms
		Summary Points
		Cross-References
		References
	4 Nerve Injury and Biomarkers
		Introduction
		Psychological and Cognitive and Behavioral Testing
		Peripheral Neurography of Nerve Fiber Integrity
		Central Markers of Nerve Fiber Integrity
		Use of Molecular Genetics to Understand Nerve Injury
			Artificial Intelligence
				Remaining Questions
		Conclusions
		References
	5 Blunt Abdomen Trauma and Biomarkers
		Introduction
		Biomarkers for Liver Injury
		Biomarkers for Kidney Injury
		Unsolved Mysteries
		Summary
		References
	6 Therapeutic Strategies in Patients with Postoperative Elevation of Cardiac Biomarkers
		Introduction
		Association Between Postoperative Elevation of Biomarkers and Outcome
			Pathophysiologic Background of Myocardial Injury and Infarction
			Evidence-Based Therapeutic Strategies in Nonoperative Myocardial Injury and Infarction
			Derivation of Therapeutic Strategies in Perioperative Myocardial Injury and Infarction
			Proposed Algorithm for Therapeutic Strategies of Perioperative Myocardial Injury and Infarction (Fig. 1)
		Basic and Advanced Risk Stratifications and Strategies to Prevent Postoperative Myocardial Injury and Infarction
			Perioperative Optimization Strategies
			Advanced Strategies for Biomarker-Based Perioperative Risk Stratification
			Other Biomarkers Under Investigation
		Conclusion and Perspectives
		Applications to Perioperative Myocardial Infarction/Injury
		Mini-Dictionary of Terms
		Key Facts of Perioperative Myocardial Injury/Infarction
		Summary Points
		Cross-References
		References
	7 Prognostic Biomarkers to Predict Outcomes in Trauma
		Introduction
			Prognostic Markers in Traumatic Brain Injury
			Putative Biomarker Molecules in Trauma
			IL-6
			CRP
			MCP-1
			Correlative Cytokines
			Single Nucleotide Polymorphisms
			Transcriptomics
			Syndecan-1
			Syndecan-1 and Thrombomodulin in Relation to Acute Kidney Injury Following Trauma
			Angiopoietin-2
			High-Mobility Group Box 1 (HMGB1)
			Mitochondrial DNA (mtDNA)
			Heat Shock Protein 70 (HSP70)
			Histones
		Multi-Omics: Emerging Technologies with Predictive Capability
		Conclusions
		Applications to Other Diseases or Conditions
		Mini-Dictionary of Terms
		Summary Points
		References
Part II: Biomarkers in Critical Care and Illness
	8 The Role of C-Reactive Protein and Implications to the Neonatal Intensive Care Unit
		Introduction
		Neonatal Sepsis
		Rational Antibiotic Use
		Blood Cultures
		CRP Kinetics and Clinical Utility
		Factors Affecting CRP Measurement
		Clinical Applications of C-Reactive Protein in Sepsis
		Disease Severity and Outcome Prediction
		CRP Response to Guide Antibiotic Therapy
		CRP Combined with Other Biomarkers
		Conclusion
		Applications to Other Diseases or Conditions
		Mini-Dictionary of Terms
			Acute Phase Reactant
			Antimicrobial Stewardship
			Biomarker
			Immunoassay
			Immunoturbidimetry
			Microbiome
			Nephelometry
			Negative Predictive Value
			Point-of-Care Test
			Positive Predictive Value
			Sensitivity
			Specificity
			Vertical Transmission
			Hospital-Acquired Infection
		Key Facts of Neonatal Sepsis
		Summary Points
		References
	9 Cell Cycle Arrest Biomarkers in the Intensive Care Unit
		Introduction
		Cell Cycle and Cell Cycle Arrest
			Cell Cycle
			Cell Cycle Arrest
		Cell Cycle Arrest in AKI
		AKI in ICU
		Application of Cell Cycle Arrest Biomarkers in Predicting AKI
			[TIMP-2] x [IGFBP7] Findings
			[TIMP-2] x [IGFBP7] to Predict Different Types of AKI
			Applications to Prognosis
			[TIMP-2] x [IGFBP7] Disadvantage in Predicting AKI
		Conclusion
		Mini-Dictionary of Terms
		Key Facts of AKI
		Key Facts of Cell Cycle Arrest
		Summary Points
		References
	10 Plasma Markers of Cholestasis in Critical Illness
		Introduction
		Etiology and Pathophysiological Mechanisms
			Normal Hepatobiliary Transport
			Hepatobiliary Transport During Critical Illness
		Diagnosis of Critical Illness-Induced Cholestasis
			Plasma Markers of Cholestasis
				Bilirubin and Bile Acids
				Alkaline Phosphatase and Gamma-Glutamyl Transpeptidase
			Other Diagnostic Tools
				Indocyanine Green Clearance
				Abdominal Sonography
				Other Laboratory Markers
		Epidemiology of Cholestasis in Critical Illness
			Pathologies Affecting Liver Function
			Interventions Affecting Liver Function
		Association of Critical Illness-Induced Cholestasis with Outcome
		Management of Critical Illness-Induced Cholestasis
			Current Management Strategies
		Future Research
		Mini-Dictionary of Terms
		Key Facts of Plasma Markers of Cholestasis in Critical Illness
		Summary Points
		Cross-References
		References
	11 Biomarkers of Oxidative Stress in Neonatal Hypoxic-Ischemic Encephalopathy
		Introduction
			Oxidative Stress
			Neonatal Hypoxic-Ischemic Encephalopathy: A Clinical Overview
			The Role of Oxidative Stress in Neonatal HIE
		Biomarkers of Oxidative Stress in Neonatal HIE
			Lipid Peroxidation Markers
				Malondialdehyde
			4-Hydroxynonenal (HNE)
				Prostaglandin-like Peroxidation Products (PPPs)
			Protein Oxidation Markers
			DNA Peroxidation Markers
			Antioxidant Enzymes
			Uric Acid
			Nonprotein-Bound Iron
			Nitric Oxide
			Bilirubin
			Galectin-3 and Quinolinic Acid
		Diagnostic and Prognostic Applications of Oxidative Biomarkers in Neonatal HIE
		Mini-Dictionary of Terms
		Key Facts of Oxidative Biomarkers in Neonatal HIE
		Summary Points
		References
	12 Measures of Classical and Alternative Complement Function in Serum as Markers in Critical Care
		Introduction
		Review of Classical, Lectin, and Alternative Pathways of Complement Activation
		Key Principles of Complement Pathway Regulation
		Evaluation of Complement Pathway Function
		Complement Pathway Biomarkers During Critical Illness
			Sepsis and Other Infections
			Acute Respiratory Failure
			Trauma
		Applications to Prognosis
		Conclusion
		Mini-Dictionary of Terms
		Key Facts of ``Measures of Classical and Alternative Complement Function in Serum as Markers in Critical Care´´
		Summary Points
		References
	13 Serum Aromatic Microbial Metabolites as Biological Markers in Intensive Care
		Summary Points
		Introduction
		In Search for Promising Metabolites
		Metabolites of Aromatic Amino Acids
		The Origin of Aromatic Metabolites in Human Blood
		Bacteria Producing AMM
		Why AMMs Are Biomarkers in Intensive  Care?
		Association of AMM with Mortality
		AMM and Septic Shock
		Applications to Prognosis
		Application to Meningitis
		Short About Methods
		Conclusion
		References
Part III: Biomarkers in Trauma
	14 Viscoelastic Hemostatic Tests and Fibrinogen Concentrations in Trauma
		Introduction
		Viscoelastic Hemostatic Tests
		Fibrinogen
		Principles of TEG and ROTEM FF Tests
		Comparison of TEG and ROTEM FF Tests
		New Viscoelastic Hemostatic Testing Systems
		Applications to Diagnosis of TIC and Hypofibrinogenemia
		Assessment of the FF Level and Hemostatic Effect of Fibrinogen Replacement
		TEG/ROTEM-Guided Fibrinogen Replacement
		Mini-Dictionary of Terms
		Key Facts of Trauma
		Summary Points
		References
	15 Radiotracers, Positron Emission Tomography Imaging and Traumatic Brain Injury
		Introduction
		Defining Traumatic Brain Injury
		Epidemiology of Traumatic Brain Injury
		Acute Consequences of mTBI: Primary and Secondary Injury
		Acute Consequences of mTBI: Neuroinflammatory Responses
		Repeat mTBI
		Repeat mTBI: Neurodegenerative Disorders
		Chronic Traumatic Encephalopathy
		Chronic Traumatic Encephalopathy: Theories
		Positron Emission Tomography Imaging
		Inflammatory Neuroimaging
		Metabolic Imaging
		Tau Imaging
		Amyloid Imaging
		Conclusions
		Mini-Dictionary of Terms
		Key Facts of Traumatic Brain Injury
		Summary Points
		References
	16 Circulating Polyunsaturated Fatty Acids (PUFAs) as Biological Indicators in Trauma
		Introduction
		PUFA Biosynthesis and Metabolism
		The Role of PUFAs in Trauma-Induced Inflammation and Coagulation
		Specialized Pro-Resolving Lipid Mediators (SPMs)
		Effects of Dietary Supplementation with PUFAs in Trauma Populations
			Traumatic Brain Injury (TBI) and Concussions
			Acute Respiratory Distress Syndrome (ARDS)
			Orthopedic Trauma and Arthritis
		Genetic and Epigenetic Determinants of PUFA Biosynthesis and Metabolism
		Future Directions
		Applications to Prognosis, Other Diseases, and Conditions
		Glossary: Mini-Dictionary
		Key Facts of PUFAs
		Summary Points
		References
Part IV: Biomarkers in Specific Conditions
	17 Blood Count Profiles as Biomarkers in Burns: Red Cells, Platelets, and Beyond
		Usefulness of CBC-Derived Biomarkers in Different Clinical Situations
			Sepsis and Septic Shock
			ARDS
			Cancer
			COVID-19
			COPD
			Cardiovascular Diseases
			Inflammation and Biomarkers in Burn Injury
			Procalcitonin (PCT)
			C-Reactive Protein (CRP)
			Cytokines
			IL-6
			IL-8
			Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Acute Kidney Injury (AKI)
			Blood Count Profiles in Burns
			Red Blood Cells
			Platelets
			White Blood Cells
			Complete Blood Count-Derived Parameters
		Summary Points
		References
	18 The Opportunity of Surfactant Protein D as a Potential Biomarker for Detecting Acute Lung Injury
		Definitions of Words and Terms
		Key Facts
			Key Facts for Acute Lung Injury
			Key Facts for Surfactant Protein D
		Introduction
		Biomarker Combination
		What Is Surfactant Protein  D?
		Respiratory Epithelium Markers
		The Advantage and Disadvantage of Using Circulating SP-D
		The Rationalization of Using Circulating SP-D as Biomarker Diagnostic for Acute Lung Injury Based on Literature Study
		Summary
		References
	19 Troponin as a Biomarker: Use in Non-cardiac Surgery
		Introduction
		Myocardial Infarction or Injury?
		Cardiac Troponin Assays
		Pathophysiology
		Prognosis and Predictors
		Future Perspectives
		Applications to Prognosis in General Population and Other Diseases
		Mini-dictionary of Terms
		Key Facts of Troponin as a Biomarker in Non-cardiac Surgery
		Summary Points
		References
	20 Glucose Variability Measures in Critical Care
		Introduction
		Blood Glucose Variability Measures
		Blood Glucose Variability in the Surgical Intensive Care Unit
			Post-Surgical and Trauma ICU
			Cardiac and Vascular Surgery
		Blood Glucose Variability in the Medical Intensive Care Unit
			Sepsis
			Post-Cardiac Arrest
		Blood Glucose in Neurocritical Care Unit
			Traumatic Brain Injury
			Stroke
			Subarachnoid Hemorrhage (SAH)
		Applications to Prognosis, Other Diseases, or Conditions
		Conclusion
		Mini-Dictionary of Terms
		Key Facts of Glucose Variability Measures in Critical Care
		References
	21 Fluid Biomarkers in Sports-Related Mild Traumatic Brain Injuries: Current Status and Novel Trends
		Introduction
		Mild TBI: Prevalence and Risk Factors
		Acute Pathophysiology of mTBI and Associated Symptoms
			Excitotoxicity
			Axonal Injury
			Neuroinflammation
			Connection to Clinical Symptoms
		Transition from Acute to Chronic Pathophysiology
		Challenges with Diagnosis of mTBI
		Blood Biomarkers for mTBI
			Neuronal Damage Biomarkers
			Glial Activation Markers
			Inflammatory Markers
		Extracellular Vesicle Biomarkers
		Exosomal Biomarkers in mTBI
		Conclusion and Future Directions
		Applications to Prognosis, Other Diseases or Conditions
		Mini-Dictionary of Terms
		Key Facts of mTBI
		Summary Points
		References
	22 Biomarkers in Hypoxic Brain Injury: Methods, Discoveries, and Applications
		Introduction
		Discovery
		Pathophysiology
		Methodology
		Other Biomarkers in Hypoxic Brain Injury
		Method
		Application to Other Diseases
		Key Facts
		Summary
		References
	23 D-Dimer Levels, Stroke, and Critical Care
		Introduction
		Ideal Criteria of Biomarkers for brain disorders
		Use of a Panel of Serum Protein Markers
		Serum Biomarkers for Stroke Diagnosis
		Biomarkers for the Diagnosis of Ischemic Stroke
		Biomarkers of Ischemic Stroke Etiology
		Biomarkers of Final Infarct Volume and Outcome
		Biomarkers of Hemorrhagic Transformation
		Biomarkers of Arterial Recanalization
		D-Dimer and Ischemic Stroke
			D-Dimer Formation
				Coagulation
				Fibrinolysis
		D-Dimer Test Collection and Panels
		Medical Conditions Affecting D-Dimer (DD) Levels
		The Clinical Implications of D-Dimer Measurement
			Relation Between D-Dimer and Different Phases and Subtypes of IS
		D-Dimers in Critically Ill COVID-19 Patients
		Importance of D-Dimer in Different Diseases
			D-Dimer and Venous Thromboembolism
			Pulmonary Embolism and D-Dimer (PE)
			D-Dimer Significance in Critically Ill Patients
		Stroke Biomarkers´ Limitations
		Terms in Mini-Dictionary
		Key Facts of D-Dimers
		Summary of D-Dimer
		References
	24 Intraoperative Management and Its Influence on Postoperative Biomarker Release
		Introduction
		The Importance of Perioperative Organ Injury Following Noncardiac Surgery
			Organ Injury Versus Biomarker Release
			Perioperative Organ Injury Is Common
			Perioperative Organ Injury Is Clinically Relevant
		The Link Between Intraoperative Management and Perioperative Organ Injury Following Noncardiac Surgery
			Physiologic Primer
				Oxygen Supply/Demand Mismatch as an Initiator of Organ Injury
				The Importance of Pressure and Flow
				Myocardial Oxygen Demand in the Perioperative Setting
			Risk Factors for Postoperative Organ Injury
				Major Bleeding
				Hemodynamic Derangements
					Arterial Hypotension as the Common Denominator of Intraoperative Circulatory Insufficiency
					Prognostic Importance of Intraoperative Hypotension.
					Myocardial Injury: Other Relevant Hemodynamic Disturbances.
				Severe Hypoxemia
		Perioperative Strategies to Avoid Postoperative Organ Injury Following Noncardiac Surgery
			Risk Stratification
			Major Bleeding
			Intraoperative Hemodynamic Derangements
				Blood Pressure Goals
				Etiologies of Intraoperative Hemodynamic Derangements
				Treatment of Intraoperative Hemodynamic Derangements
					Fluid Therapy
					Vasopressors
					Inotropes
					Avoidance of Venous Congestion
		Future Directions
			Research Priorities in Perioperative Medicine
			Understanding Perioperative Organ Injury: Moving from Populations to Individuals
				Biomarkers Poised to Transform Perioperative Medicine
				Preventing Perioperative Organ Injury: Leveraging Not Fearing Heterogeneity Through Individualization
		Conclusion
		Applications to Prognosis
		Mini-Dictionary of Terms
		Key Facts of Perioperative Organ Injury
		Summary Points
		References
	25 Biomarkers in Neonatal Brain Injury: Interpreting Research into Clinical Practice
		Introduction
		S100B
			S100B in Neonatal Brain Injury
			S100B in CSF
			S100B in Cord Blood
			S100B in Serum
			S100B in Urine
			S100B in Saliva
			S100B in Amniotic Fluid
			Applications to Prognosis
		NSE
			NSE in Cord Blood
			NSE in Serum
			NSE in CSF
			Applications to Prognosis
		Conclusion
		Mini-Dictionary of Terms
		Key Facts of Neonatal Brain Injury
		Summary Points
		Cross-References
		References
	26 Biomarkers in Patients with Chronic Obstructive Pulmonary Disease (COPD) in Emergency Medicine and the Intensive Care Unit:...
		Introduction
		Blood Biomarkers
			C-Reactive Peptide
			Fibrinogen
			Procalcitonin
			B-Natriuretic Peptide (BNP)
			Neopterin
			SP-d
			sRAGE (Serum Levels of Soluble Receptor for Advanced Glycation End Products)
			Biomarker Panels
		Exhaled Biomarkers
			Fractional Excretion of Nitric Oxide (Fe No)
			Exhaled Carbon Monoxide
			Exhaled Breath Condensate (EBC)
		Sputum Biomarkers
		Biomarkers in BAL and Bronchial Biopsies
		Imaging Biomarkers
			MRI
			CT Scan
		Conclusion
		Mini-Dictionary of Terms (5-15 Terms)
		Key Facts of Biomarkers in Patients with Chronic Obstructive Pulmonary Disease (COPD) in Intensive care unit and Emergency med...
			Key Facts of COPD
			Key Facts of Ideal Biomarkers
		Summary Points
		References
Part V: Specific Components
	27 Procalcitonin As a Biomarker and Mediator of Sepsis: Implications for Critical Care
		Introduction
			Pathophysiology of PCT Secretion
			Diagnostic Accuracy
			Procalcitonin-Guided Antibiotic Stewardship
			COVID-19 and PCT
		Experimental Data on a Potential Mediator Role of PCT
			PCT Mediates Cytokine Release and Immune Cell Migration
			Neutralization of PCT Is Associated with Reduced Mortality and Morbidity in Experimental Sepsis
		Applications to Prognosis
		Applications to Other Diseases or Conditions
		Mini-Dictionary of Terms
		Key Facts of Procalcitonin As a Biomarker and Mediator of Sepsis: Implications for Critical Care
			Key Facts of PCT As Prognostic Marker of Sepsis
			Key Facts of PCT in COVID-19
			Key Facts of PCT in Experimental Sepsis
			Summary Points (5-15)
		References
	28 Serum Interleukin-6 Levels as a Biomarker in Trauma
		The Effect of Trauma on the Organism
		SIRS Caused by Trauma
			Pathophysiology
			Interleukin-6
			The Other Biomarkers of the SIRS
			Conclusion
			Applications to Prognosis, Other Diseases, or Conditions
			Mini-Dictionary of Terms
		Key Facts of Serum IL-6 Levels
		Summary Points
		References
	29 The Role of Vitamin D As a Biomarker in Trauma
		Introduction
		Production and Absorption
		Immune Function
		Traumatic Brain Injury
		Burns
		Musculoskeletal Injury
		Lung Injury and Acute Respiratory Distress Syndrome
		Critical Illness
		Acute Kidney Injury
		Anemia of Critical Illness
		Mortality
		Applications to Prognosis
		Mini-Dictionary of Terms
		Key Facts About Vitamin D
		Summary Points
		References
	30 Selenium Concentrations and Multiple Trauma/Trace Elements in Trauma: A Focus on Selenium
		Introduction
			Physiological Changes in Patients after Trauma
			Physiological Function of Trace Elements
			Selenium Deficiency and Supplementation in Critically ill Patients
			Selenium in Trauma Patients
			Selenium Supplementation in Trauma Patients
		Applications to Prognosis, Other Diseases or Conditions
			Applications to Prognosis
			Applications to Other Diseases or Conditions
		Mini-Dictionary of Terms
		Key Facts of Selenium in Trauma
		Summary Points
		References
	31 Presepsin: Methods of Measure, Features and Biomarker Potential in Sepsis and Critical Care
		Introduction
		Presepsin: A Biomarker of Early Immune Response
		Presepsin in Sepsis Diagnosis and Prognosis
			Presepsin and Renal Function
		Pediatric Sepsis
			Diagnosis of Sepsis in Emergency Department
			Application in Perioperative Medicine
			Presepsin in Orthopedic Surgery
		Application in Viral Infections
			Methods of Measure
		Mini-Dictionary of Terms
		Key Facts of ``Presepsin: Methods of Measure, Features and Biomarker Potential in Sepsis and Critical Care.´´
			Key Facts of Sepsis
			Key Facts of Severe COVID-19
		Key Facts of Perioperative Medicine
		Summary Points
		References
	32 Review of our Current Understanding of ADAMTS13 and Von Willebrand Factor in Sepsis and Other Critical Illnesses
		VWF and ADAMTS13 in Hemostasis
		Known Associations Between VWF and ADAMTS13 in Disease
		ADAMTS13 and VWF in Critically Ill Patients with Sepsis
		Mechanistic Insights on the Dysfunction of ADAMTS13 and VWF in Sepsis
		Role of ADAMTS13 and VWF in Driving ICU Mortality
		Potential Therapies
		Conclusions
		Dictionary of Terms
		Key Facts of Review of our Current Understanding of ADAMTS13 and Von Willebrand Factor in Sepsis and Other Critical Illnesses
		Summary
		References
	33 Circulating TGF-β1 Levels: Linking Muscle and Trauma
		Introduction
		Disease States with Altered Circulating TGF-β Levels
			Cardiovascular Diseases
			Fibrosis and Wound Healing
			Infection and Cancer
			Trauma
		Effects of TGF-β1 on Different Cell Types During Muscle Regeneration
			Inflammatory Cells
			Myogenic Cells
			Connective Tissue Cells
		Circulating TGF-β1 Levels: Linking Muscle and Trauma
			Source of Circulating TGF-β1
			Factors Affecting Circulating TGF-β1 Levels Following Trauma
			Circulating Versus Muscle TGF-β1
			Function of Circulating TGF-β1 in Muscle
		Conclusion and Future Direction
		Applications to Prognosis, Other Diseases or Conditions.
		Mini-Dictionary of Terms
		Key Facts of TGF-β1
		Summary Points
		References
	34 Neurofilament Light Chain in the Blood As Biochemical Markers in the Critically Ill
		Introduction
		Biochemical and Biological Characteristics of Neurofilament Light Chain
		Potential Confounders and Interferences with Serum Neurofilament Light Chain Concentrations
			Volume of Distribution
			Increasing Age
			Neurological Comorbidities
			Renal Insufficiency
			Non-Neurological Comorbidities
			Treatment-Related Influences on Serum Neurofilament Levels
			Advantage of Neurofilament Light Chains in Contrast to Neuron-Specific Enolase with Hemolysis
		Temporal Profile
		CSF/Serum Correlation and Blood-Brain Barrier
		Evidence Regarding Neurofilament Light Chain in Specific Critical Illnesses
			Cerebrovascular Accidents
			Nontraumatic Subarachnoid Hemorrhage (SAH)
			Traumatic Brain Injury (TBI)
			Hypoxic-Ischemic Brain Injury After Cardiac Arrest (CA)
			Epilepsy
			Neuroinflammatory Conditions of the CNS
			Guillain-Barré Syndrome (GBS)
			Delirium, Anesthesia, and Surgery
			Infectious Disease and Sepsis
			Coronavirus Infectious Disease (COVID)-19
		Applications to Prognosis
		Conclusions
		Mini-Dictionary of Terms
		Key Facts of Serum Neurofilament Light Chain Levels
		Summary Points
		References
	35 S100B As a Biomarker in Traumatic Brain Injury
		Introduction
		Biomarkers
		S100B
		Predicting Positive CT Findings in Mild TBI
		Predicting Outcome
		Predict Secondary Injury Development and Treatment Efficacy
		Other Biomarkers
		Conclusion
		Applications to Prognosis, Other Diseases, or Conditions
		Key Facts
		Mini Dictionary of Terms
		Summary Points
		References
	36 Biomarkers of Sepsis and a Focus on PCSK9
		Introduction
		Biomarkers in Sepsis: An Overview
		PCSK9: What About This Molecule? Could PCSK9 Be a Useful New Sepsis Biomarker?
		PCSK9 Inhibitors
		PCSK9 Inhibitors and COVID-19
		Future Perspectives
		Applications to Prognosis, Other Disease or Conditions
		Mini-Dictionary of Term (5-15)
		Key Fact of Sepsis
		Summary Points
		References
	37 Urinary Potassium Excretion as a Biomarker in Critically Ill for the Identification of AKI: A Review
		Introduction
			Physiology of Potassium Homeostasis
				Renal Handling of Potassium
				Potassium Handling in Pediatric Age Group
				Potassium Handling during Pregnancy
				High Dietary Intake
				Enteric Sensors of K
				Potassium Physiology During Exercise
				Circadian Rhythm of K Secretion
			Potassium Handling During Pathological States
				Effect of Plasma Tonicity and Acid-Base Disorders
				Effect of Volume Status
				Hypertension
				Chronic Kidney Disease (CKD)
			Acute Kidney Injury
				Urine Output
				Serum Creatinine
			Urinary Biochemistry as Biomarkers in the Assessment of AKI
				Urinary Microscopy
				Fractional Excretion of Urea (FeUr)
				Fractional Excretion of Sodium (FeNa)
				Spot Urine Na and Urine Na/ Urine K Ratio
				Fractional Excretion of Potassium (FeK)
		Conclusion
		References
	38 Blood Cortisol as a Biomarker in Intensive Care Unit
		Introduction: Blood Cortisol as a Biomarker in Intensive Care Unit
		Blood Cortisol and Delirium
		Blood Cortisol and Trauma
		Blood Cortisol and Sepsis-Septic Shock
		Applications to Prognosis, Other Diseases, or Conditions
		Mini-Dictionary of Terms
		Key Facts of Blood Cortisol as a Biomarker in Intensive Care Unit
		Summary Points
		References
	39 Citrullinated Histone H3 as a Biomarker in Sepsis and Critical Care
		Introduction
		Sepsis and Cit-H3
		Comparison of Cit-H3 and Other Sepsis Biomarkers
		Cit-H3 in Urosepsis
		Cit-H3 in Critical Care Patients
		Cit-H3 in ARDS
		Cit-H3 in Pediatric Sepsis
		Cit-H3 and Liver Dysfunction
		Cit-H3 and Cardiopulmonary Resuscitation
		Cit-H3 and Patient Follow-Up
		Applications to Prognosis
		Applications to Other Diseases or Conditions
		Mini-Dictionary of Terms
			Key Facts of Cit-H3 in Sepsis and Critical Care
		Summary Points
		References
	40 Tumor Necrosis Factor-Alpha (TNF-Alpha) as a Biomarker in Trauma and Critical Care
		Introduction
			TNF-α
			History of TNF
			The Structure of TNF-α
			The Role of TNF-α in Trauma
			The Role of TNF-α in Sepsis
			The Role of TNF-α in Traumatic Brain Injury (TBI)
			The Role of TNF-α in Lung Injury/ARDS
		Applications to Prognosis, Other Diseases or Conditions
			Applications to Prognosis
			Applications to Other Diseases or Conditions
		Mini-Dictionary of Terms
		Key Facts of TNF-Alpha
		Summary Points
		References
	41 ADAM10 as a Biological Marker in Traumatic Brain Injury
		Introduction
		Pathophysiology of TBI
		Recent Advances in Imaging Diagnostics
		Need for TBI Biomarkers
		A Disintegrin and Metalloproteinase 10 (ADAM10)
		ADAM10 and Traumatic Brain Injury
		Mini-Dictionary of Terms
		References
Part VI: Biomarkers in COVID-19
	42 Laboratory Markers of COVID-19 in the Emergency Room
		Introduction
		Disease Progression and Laboratory Markers in Emergency Room
		Disease Progression
			Viral Entry and Replication
			Immune Response and Inflammation
			The Coagulative Cascade and Growing Inflammation
		Laboratory Markers in Emergency Room
			Blood Gas-Analyses (BGA): Partial Pressure of Oxygen and Oxygen Saturation
		Hematological Biomarkers
			Hemoglobin Quantification
				WBC-Related Numbers: Absolute Lymphocyte Count (Cells/μL) and Neutrophil to Lymphocyte Ratio
				Platelet Count (Cells/μL)
		Inflammatory Biomarkers
			C-Reactive Protein (CRP)
				Procalcitonin (PCT)
				Creatine Kinase (CK)
		Comprehensive Metabolic Panel Biomarkers
			Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)
			Creatinine
			High-Sensitivity Troponin (hs-Tn) and Natriuretic Peptides Type B (BNP)
			Other Biomarkers
				D-Dimer
				Lactate Dehydrogenase (LDH)
		Biomarkers: From Bench to Patient
		Applications to Prognosis
		Mini-Dictionary of Terms
		Key Facts of COVID-19 Biomarkers
		Summary Points
		References
	43 Serum Angiotensin II as a Biomarker in COVID-19
		Introduction
		Renin-Angiotensin System (RAS)
		Angiotensin II
		The Role of Angiotensin II in the Classical Renin-Angiotensin System (First Axis)
		The Role of Angiotensin II in the Non-classical Renin-Angiotensin System (Second Axis)
		The Role of Angiotensin II in the Tissue Renin-Angiotensin System
		The Effects of Angiotensin II
		The Role of Angiotensin II in COVID-19
		Serum Angiotensin II Levels in COVID-19
		Applications to Prognosis, Other Diseases, or Conditions
			Applications to Prognosis
			Applications to Other Diseases or Conditions
		Mini-Dictionary of Terms
		Key Facts of Angiotensin II
		Summary Points
		References
	44 Polyunsaturated Fatty Acid-Derived Lipid Mediators as Biomarkers in Critical Care
		Introduction
			Discovery of Resolution as the Flip Side of Inflammation
			Inflammation Contains the Seeds of Resolution
			The Role of Dysregulated Inflammation in the Pathogenesis of COVID-19
		Pathologic Implications of Dysregulated Inflammation
			Sepsis
			Acute Respiratory Distress Syndrome
			Influenza
		Pro-inflammatory Cascade and Inflammation Resolution in COVID-19
			Pathogenesis of Severe COVID-19
			PUFAs in COVID-19
			Beyond PUFAs: Lipidomics and SPMs in COVID-19
		Therapeutic Targets and Future Directions for Specialized Pro-resolving Mediators
		Applications to Prognosis, Other Diseases, or Conditions
		Conclusions
		Mini-Dictionary of Terms
			Specialized Pro-resolving Mediator
		Key Facts
			Key Facts of Inflammation Resolution
			Key Facts of Sepsis
			Key Facts of Acute Respiratory Distress Syndrome
			Key Facts of N-3/N-6 PUFA Ratio
		Summary Points
		References
Part VII: Physical Platforms and Physiology
	45 Optic Nerve Sheath Diameter as a Biological Marker and Its Radiological Evaluation in Brain Injury
		Introduction
		Intracranial Pressure in Traumatic Brain Injury
		Pathophysiology
		Clinical Findings
		ICP Monitoring
		Invasive Methods
		Non-invasive Methods
		Optical Nerve Sheath Diameter
		ONSD Measurement Methods
			Ultrasonography
			Computed Tomography
			Magnetic Resonance Imaging
		Applications to Prognosis
		Conclusion
		Mini-Dictionary of Terms
		Key Facts of ONSD
		Summary Points
		References
	46 Neural Activity and Oscillations as Biological Markers in Traumatic Brain Injury
		Introduction
		Signs, Symptoms, and Sequelae of mTBI
		The Biomechanical Forces and Neurochemical Consequence Serving mTBI
		Invisible Fingerprinting of the Brain: Magnetoencephalography
		Revealing the ``Spectral Fingerprints´´ of mTBI with MEG
			Resting-State Studies
			Task-Based Studies
		Differentiating ``Invisible Injuries´´: Disentangling mTBI from PTSD
		Future Directions and Applications
		Conclusion
		Applications to Prognosis and Conditions
		Mini-Dictionary of Terms
			Mild Traumatic Brain Injury/Concussion
			Neural Oscillations/Brain Waves/Brain Rhythms
			Magnetoencephalography
		Key Facts of Neural Activity and Oscillations as Biological Markers in Traumatic Brain Injury
			Mild Traumatic Brain Injury
		Summary Points
		References
	47 Viscoelastic Hemostatic Assays in the Management of the Trauma Patient
		Introduction
		Trauma-Induced Coagulopathy
			Impaired Clot Formation, Dysregulated Fibrinolysis, and Platelet Dysfunction
			Acidosis, Hypothermia, and Hypocalcemia
		How Viscoelastic Monitoring Assays Work
		Understanding VMA Results as They Reflect the Clotting Process
		VEM-Guided Trauma Resuscitation
		Limitations
		Predicting Hypercoagulability
		Future Directions
		Applications to Other Diseases or Conditions
		Mini-dictionary of Terms
		Key Facts of Trauma-Induced Coagulopathy (TIC)
		Key Facts of Viscoelastic Hemostatic Assays
		Summary Points
		References
	48 Biomarkers of Cardiac Stretch in Critical Illness: A Narrative Review
		Introduction
		Biomarkers of Cardiac Stretch
		Natriuretic Peptides in Diagnosis and Prognosis of Heart Failure
		Natriuretic Peptides in Multisystem Critical Illness
			Sepsis
			Major Trauma
		Natriuretic Peptides in Cardiac Critical Illness
			Cardiac Surgery
			Cardiac Arrest and Cardiogenic Shock
		Natriuretic Peptides in Respiratory Critical Illness
			SARI, ARDS, and Mechanical Ventilation
			Pulmonary Vascular Disease
			Airways Disease
		Natriuretic Peptides in Non-cardiorespiratory Illness
		Mini Dictionary of Terms
		Key Facts of Natriuretic Peptides
		Summary Points
		References
	49 Cerebrospinal Fluid as a Platform for Biomarker Identification in Traumatic Brain Injury
		Introduction
		Current State of Proteomic Biomarker Research Following Traumatic Brain Injury
		Biological and Methodological Aspects of Cerebrospinal Fluid
			Cerebrospinal Fluid Physiology
			Specific Methodological Considerations in Cerebrospinal Fluid Proteomics
		Proteomic Methods for Biomarker Discovery in CSF
		Cerebrospinal Fluid Protein Biomarkers Show Promise Across Traumatic Brain Injury Studies
		Discussion and Conclusions
		Applications to Prognosis, Other Diseases, or Conditions
		Mini-Dictionary of Terms
		Key Facts
		Summary Points
		Cross-References
		References
Part VIII: Scoring Systems, Models, and Indirect Measures
	50 The APACHE II Scoring Systems and the ICU
		Introduction
		Characteristics of an Ideal Scoring System
		Why Do We Need Scoring Systems in ICU?
		Evolution of the APACHE Scores
		Pitfalls While Calculating APACHE II Score
		Uses of APACHE II Score in the ICU
		APACHE III and APACHE IV
		Other Scoring Systems Used in ICU
		Evaluating a Scoring System
		Conclusion
		Applications to Prognosis, Other Diseases, or Conditions
		Mini-Dictionary of Terms
		Key Facts of APACHE II Score Calculation
		Summary Points
		References
	51 The Score for Trauma Triage in Geriatric and Middle-Age (STTGMA): Utilizing Macroscopic Clinical Biomarkers to Guide Patien...
		Introduction
		Origin of STTGMA
		How STTGMA Was Created
		Evolution of STTGMA
			Frailty Factor
			COVID-19 Factor
			ASA Score
		STTGMA Has Wide Applicability
		STTGMA Application for Various Fracture Patterns
			Fracture Locations
		STTGMA Application for Inpatient Admission
			Delays to Surgery
			Effective Timing of Blood Transfusions in Hip Fracture Patients
		STTGMA Application after Discharge
			Discharge Location
			Post-Discharge Fall Risk
			Loss of Ambulatory Level and ADLs at 1 Year
		Conclusion
		Additional Applications
			Applications to a Healthcare Landscape Increasing in Cost
			Applications to Other Diseases or Conditions
			Application to Orthopedic Biomarkers
		Mini-Dictionary of Terms
		Key Facts of Hip Fractures
		Key Facts of Osteoporosis
		Key Facts of Abbreviated Injury Scale and Charlson Comorbidity Scale
		Summary Points
		References
	52 Body Mass as a Biomarker and Femoral Fracture
		Introduction
		Body Mass and Its Components
			Five Level Model
			Change in Body Composition Through Aging
		Body Mass as a Risk Factor of Hip Fracture
		Body Mass and Mortality
		Body Mass and Functional Status
		Body Mass and Complication and Secondary Fracture
		Conclusion
		Mini-Dictionary of Terms
			ADL
			AWGS
			BI
			BIA
			DXA
			FIM
			HHS
			Mini Mental State Examination
			Mini Nutritional Assessment-Short Form
			Muscle Fiber
			PMS
			Sarcopenia
			SMI
			TUG Test
			YAM
		Applications to Other Diseases or Conditions
		Key Facts of Body Mass as a Biomarker and Femoral Fracture
		Summary Points
		References
	53 Scoring for Hemorrhage Severity in Traumatic Injury
		Introduction
		Severity Scores As Biomarkers
		Patient Stratification
			ML for Patient Stratification in Trauma
			Artificial Intelligence (AI) for Predictive Analytics in Trauma
		Challenges and Opportunities
		Mini-Dictionary of Terms
		Key Facts of Scoring for Hemorrhage Severity in Traumatic Injury
		Summary Points
		Cross-References
		References
	54 Modeling Orthopedic Injury and Its Impact: Biological Measures of Hypercoagulability and their Applications
		Introduction
		Hypercoagulability, Fibrinolysis, and Viscoelastic Testing in Trauma
		The Impact of Orthopedic Injury on Coagulation
		Current Orthopedic Trauma Animal Models Including Coagulation Assays
			Benefits of Using Animal Models
			Overview
			Nonhuman Primates
			Swine
			Sheep
			Rabbits
			Rats
			Mice
		Summary of Coagulation Profiles in Animal Model Species
			Large Animals
			Small Animals
			Considerations and Limitations of Specific Models for Future Studies
		Conclusion
		References
Part IX: Resources
	55 Recommended Resources for Biomarkers in Disease: Trauma, Injury, and Critical Care
		Introduction
		Resources
		Other Resources
		Summary Points
		References
Index