|Year : 2022 | Volume
| Issue : 1 | Page : 14
Early Clinical Management of Sepsis: Past, Present, and Future
Jerome C Anyalebechi, Craig M Coopersmith
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA
|Date of Submission||13-May-2022|
|Date of Acceptance||28-Jun-2022|
|Date of Web Publication||12-Aug-2022|
Dr. Craig M Coopersmith
101 Woodruff Circle, Suite WMB 5105, Atlanta 30322, Georgia
Source of Support: None, Conflict of Interest: None
Sepsis is a syndrome initiated by an infection in which an aberrant host response to the initiating microbe leads to organ dysfunction, and, all too frequently, mortality. An enormous increase in our understanding of sepsis has occurred over the past 25 years. Unfortunately, this increase has not been matched by successful new therapies, and sepsis treatment continues to be centered on timely antibiotics and supportive care. The Surviving Sepsis Campaign has focused practitioners on bundles for quality improvement and guidelines for bedside management. Adhering to standardized care has been associated with improvements in patient outcome. The mainstays of sepsis management, including diagnosis, fluid resuscitation, antimicrobial management, and vasopressors, are critical to successfully treating patients with sepsis and septic shock and play a major role in determining outcome from sepsis. At the same time, there is increasing recognition that a “one size fits all” model cannot always be the best approach to patient management because of the inherent heterogeneity associated with sepsis, both in terms of initiating microbe and the host response. Further, identifying new targets for therapy may allow for improved outcomes. This review study serves to highlight the past and present facets of early clinical management of septic patients and then illustrate future directions that will hopefully improve outcomes in this common and lethal syndrome.
Keywords: Sepsis, clinical management, intensive care unit, SOFA, qSOFA, vasopressors, antibiotics, fluids, critical care, intensive care
|How to cite this article:|
Anyalebechi JC, Coopersmith CM. Early Clinical Management of Sepsis: Past, Present, and Future. J Transl Crit Care Med 2022;4:14
| Introduction|| |
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The global burden is massive with an estimated 48.9 million cases of sepsis recorded worldwide prior to the onset of the COVID-19 pandemic, accounting for 19.7% of all global deaths. Based upon the significant morbidity and mortality associated with the syndrome, the World Health Organization recently released a resolution on sepsis with the aim to improve its prevention, diagnosis, and clinical management. One of the most impactful efforts toward decreasing mortality from sepsis has been the Surviving Sepsis Campaign. The Campaign has multiple arms. Perhaps the two best known are its bundles, intended for quality improvement purposes, and guidelines, intended to drive clinical practice at the bedside. Each of these has been revised multiple times as available evidence is released.,,,, Data suggests that these guidelines have likely decreased mortality from sepsis.,,
The vast majority of septic patients are admitted through the emergency department. However, sepsis can present not only in the community but also in long-term facilities, on the hospital wards or in the intensive care unit, so familiarity with both diagnosis and management is of paramount importance for all clinicians. Further, while the lay public often has a strong knowledge of many common medical conditions (i.e., chest pain radiating down the left arm is highly concerning for a myocardial infarction), many have never heard of sepsis or are entirely unaware of its symptoms that should result in rapidly seeking medical care.
| Recognizing and Defining Sepsis|| |
While effective therapies to treat sepsis are relatively new, the concept of sepsis has been around for millennia., It was mentioned in scriptures in ancient Greece, coming from the Greek word “sepo” which means “I rot.” It was first used in a medical context in Homer's poems and mentioned in the writing of Hippocrates 2500 years ago. The decay in sepsis was believed to occur in the colon, which released substances that caused “auto-intoxication.” In 129–199, Galen, a Roman physician and philosopher theorized about sepsis and developed theories of wound healing and pus that lasted for 1500 years. In the 1800s, the golden age of germ theory, Semmelweiss, Lister, Pasteur, and Koch furthered our understanding of microbiology and infectious disease. Slightly more than 100 years ago, Schottmuller wrote that “sepsis is present if a focus has developed from which pathogenic bacteria, constantly or periodically, invade the bloodstream in such a way that this causes subjective and objective symptoms.”
The first systematic attempt to define sepsis came in 1991, in a consensus conference now known as Sepsis-1. Sepsis was initially defined as the systemic inflammatory response (SIRS) in response to infection. SIRS (and thus clinical recognition of sepsis) was defined by abnormalities in heart rate, respiratory rate or PaCO2, temperature, and white blood cell count, in the setting of suspected infection. Severe sepsis was defined as sepsis complicated by organ dysfunction and septic shock was defined as hypotension persisting despite adequate fluid resuscitation. Characterizing and defining sepsis was unprecedented at the time, and Sepsis-1 has earned a rightful place in history as a large step forward for the medical community. Given the limitations of Sepsis-1, a second task force in 2001 sought to improve the definition. Ultimately, Sepsis-2 concluded that other than expanding a list of signs and symptoms related to sepsis to better reflect clinical bedside experience no evidence existed for altering the definition. In a forward thinking manner that would predict a future of precision medicine approaches toward the syndrome, Sepsis-2 introduced the concept of predisposition, insult/infection, response and organ dysfunction (PIRO), a hypothesis-generating staging system for sepsis.
Sepsis-1 (and Sepsis-2) was a seminal advance in diagnosis, which has implications for management, clinical trials, epidemiology, and bench research. At the same time, numerous limitations were identified. SIRS was remarkably nonspecific since half of patients in a hospital will have SIRS sometime during their stay. Further, one in eight septic patients had zero or one SIRS criteria, and the need for two SIRS criteria excluded similar patients with infection, organ failure, and significant mortality. A definition that could both encompass a huge number of nonseptic patients and simultaneously miss a significant portion of septic patients was problematic. Next, there was a concern about the term “severe sepsis” since this implies that there might be a “nonsevere” form of sepsis. For a syndrome that has a remarkably high mortality, this potentially sent the wrong message to practitioners. Finally, the Sepsis-1 definition was not actually a definition. The word “definition” means the essential nature of what something is, and assuredly the SIRS criteria are not the essential nature of what sepsis is.
As such, the Sepsis-3 definition was published in 2016. Sepsis-3 made a distinction between definition and clinical criteria. The definitions of sepsis and septic shock were intellectual in nature and tried to give the best understanding of what sepsis is. Sepsis was defined as life-threatening organ dysfunction secondary to a dysregulated host response to infection, while septic shock was defined as a subset of sepsis in which cellular and metabolic abnormalities are profound enough to substantially increase mortality.
While these were intellectual advances, they are not useful to the bedside clinician. Sepsis-3 therefore included criteria to be used at the bedside to identify sepsis. Organ dysfunction was identified as a sequential-related organ failure assessment (SOFA) score >2 (or an increase of 2 if baseline was not 0). The SOFA score, which predated the Sepsis-3 definition, was developed as a tool for objectively describing the degree of organ dysfunction within a patient. It is composed of PaO2/FiO2, platelets, bilirubin, mean arterial pressure or vasopressor dose, Glasgow Coma Scale, creatinine, and urine output in an attempt to objectively quantitate dysfunction in respiratory, hematologic, gastrointestinal, cardiovascular, neurologic, and renal systems, respectively. As such, sepsis is now diagnosed at the bedside by a combination of clinical suspicion of infection combined with a SOFA score >2. Notably, this still has significant imprecision as suspicion of infection is based upon clinical findings (fever, leukocytosis, etc.) that may be seen in noninfectious conditions, and infection cannot be confirmed until cultures come back positive, often 2–3 days after initial patient presentation. In addition, septic shock clinical criteria included a combination of (a) hypotension, (b) pressor requirement, and (c) a lactate level of >2 mmol/L.
Notably, Sepsis-3 was not simply a consensus conference but also used a big data approach from millions of patient charts to define the clinical criteria for septic shock. In addition, given the fact that the first two words of the sepsis definition are “life-threatening,” the term severe sepsis was deemed superfluous and was eliminated from the definition, as were the SIRS criteria. Of note, while the SIRS criteria have relatively limited utility in defining organ dysfunction in sepsis, they retain significant usefulness in identifying infection (especially fever and white blood cell count). In an attempt to identify patients at risk of either death or prolonged intensive care units (ICU) stay, a big data approach was also used to identify the “quick SOFA” (qSOFA) score. There are three elements in the qSOFA criteria: respiratory rate ≥22/min, altered mental status, and systolic blood pressure ≤100 mmHg [Table 1], and fulfilling two or more criteria indicates a higher likelihood of a patient having a poor outcome from sepsis. There has been considerable confusion related to the qSOFA score. Despite its name, it is not a subset of the SOFA score as it contains different criteria (i.e., respiratory rate is not part of SOFA) and was identified and validated using entirely different methods. In addition, it is critical to understand that qSOFA is not intended to be part of the definition of sepsis but a screen for septic patients who have a higher likelihood of a bad outcome. Notably, while qSOFA performs well outside the ICU, its performance is worse within the ICU, and it should not be used in that setting. Despite ongoing controversy regarding qSOFA, multiple validation studies show that it is effective in what it was designed to do., However, qSOFA is not the definition of sepsis and should not be used as such nor should one wait to treat a patient until the qSOFA sore is two.
One final element of Sepsis-3 that has received little attention but is of significant importance is the statement that a clinician must have a high index of suspicion for sepsis should any unexplained organ dysfunction be present in patients. While it is seemingly evident that clinicians should always maintain an open mind and never come to a single diagnosis too quickly, this is often not followed, and a key take home of Sepsis-3 is that if a patient has infection, look for organ dysfunction while if a patient has organ dysfunction, look for infection.
| Sepsis Management|| |
As evidenced by the length of the Surviving Sepsis Guidelines, a summary of evidence-based sepsis management is a massive undertaking and is outside the scope of this review. However, we believe that it is important to highlight a few key points that are particularly important or controversial in the early management of sepsis.
| Timing of Treatment|| |
The term “golden hour” was initially coined in the trauma literature and refers to the concept that prompt definitive treatment after traumatic injury has the highest likelihood to improve outcomes. This has since been extrapolated to other medical fields such as cardiology and neurology for accelerating treatment for myocardial infarction and stroke.,, While the concept of timely intervention has been applied to those fields since the 1980s and 1990s, it was not until 2001 that timely intervention was widely recognized as critical in the treatment of sepsis. This recognition followed a single-center randomized controlled trial examining early goal directed therapy in which a protocolized approach for 6 h in the emergency department significantly improved mortality in patients presenting with sepsis or septic shock. Three subsequent large multicenter randomized control trials and a meta-analysis failed to find clinical benefit of this protocolized approach.,,, However, it would be a misinterpretation of the data to suggest that early therapy is not beneficial. In fact, the original trial was actually so influential that the control arms of “usual care” in the subsequent trials all looked like the experimental arm in the initial trial. Hence while some of the elements of the original protocol do not improve outcome (continuous ScVO2 monitoring, mandatory blood transfusion), the concept that septic patients require rapid resuscitation remains a hallmark of sepsis therapy.
The urgency of treatment for sepsis is highlighted in the recent “hour-1 bundle” from the Surviving Sepsis Campaign, which combines elements of previous 3 hour and 6 hour bundles. The “hour-1 bundle” has five elements including (a) obtaining blood cultures, (b) rapid administration of antimicrobial therapy, (c) bolusing 30 mL/kg of crystalloid, (d) measuring lactate, and (e) starting vasopressors if the patient remains hypotensive despite fluid resuscitation. There has been significant controversy related to the hour-1 bundle. It is therefore important to emphasize that the bundle highlights the need to begin resuscitation and management immediately, as the hour-1 timeframe refers to initiation of treatment. Notably, multiple trials have shown that treatment delays in multiple components of sepsis bundles are associated with higher mortality after the onset of sepsis.,,,
| Fluid Resuscitation|| |
Septic patients are typically hypovolemic, due to a combination of fluid losses (diarrhea, emesis), poor oral intake, and insensible losses due to capillary leak. This has made fluid resuscitation a hallmark of sepsis treatment. Understanding that each patient is an individual with unique needs, the Surviving Sepsis Campaign guidelines suggest fluid resuscitation begin with a 30 mL/kg crystalloid bolus. Notably, this weak recommendation is downgraded from a prior strong recommendation due to low quality of evidence. We acknowledge that this recommendation continues to be controversial with some experts stating no guidance can be given as all resuscitation needs to be individualized to patient-specific endpoints, while others advocate for lower amounts of resuscitation with consideration of earlier vasopressor usage. This is based on data that suggest multiple intravenous fluid boluses lead to a net positive fluid status for patients, which may impair organ function and worsen overall mortality. Two ongoing multicenter randomized control trials, the CLOVERS trial (NCT03434028) and the CLASSIC trial (NCT03668236), are attempting to answer the question of at what point does fluid become detrimental by comparing liberal fluid administration to restrictive administration with vasopressor use. We believe that an initial crystalloid bolus of 30 mL/kg remains appropriate for the majority of patients, but clinicians must carefully assess if an individual patient should be treated differently than guidelines suggest as guidelines should never take the place of clinical judgment.
The most appropriate crystalloid used for initial resuscitation has been extensively studied. Historically, normal saline has been the most commonly used crystalloid fluid., Normal saline is an isotonic solution that is “unbalanced” because it has a chloride concentration approximately 50% greater than the chloride concentration of extracellular fluid and contains no organic anion to act as an acid-base buffer. In contrast, lactated Ringer's solution, Plasma-Lyte (either Plasma-Lyte A or Plasma-Lyte 148), and Hartmann's solution are “balanced” crystalloid solutions as they contain a chloride concentration similar to physiologic levels and contain an organic anion (e.g., lactate or gluconate), resulting in a more neutral pH. Multiple preclinical and smaller studies have suggested some benefit in using balanced crystalloid solutions as normal saline use has been associated with increased frequency of acute kidney injury,, metabolic acidosis,,, and possible increased risk of death., These preliminary data eventually led to the SMART trial, a pragmatic cluster-randomized, multiple crossover trial comparing normal saline to balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A) in 15,802 critically ill adult patients in a single academic medical center. This trial found a statistically significant reduction in the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction at 30 days. These findings, however, have not been replicated in three randomized controlled trials comparing normal saline to balanced crystalloids. The SPLIT trial randomized 2,278 patients to receive either buffered crystalloid or normal saline in a cluster randomized double-crossover trial in 4 ICUs in New Zealand and found no difference in acute kidney injury in patients treated with balanced solution. The BASICS trial randomized 10,520 patients to receive either normal saline or balanced solution and found no difference in 90 day mortality or in the composite endpoint seen in the SMART trial. Finally, the PLUS trial randomized 5,037 patients to receive either normal saline or Plasma-Lyte 148 in 53 ICUs in Australia and New Zealand and found no difference in either death or kidney injury at 90 days. It should be noted that the mean amount of fluid given in each of these studies was modest. Taking the totality of the evidence, there is no clear data signal to support giving either normal saline or balanced crystalloids for initial resuscitation for septic patients. There remains a theoretical reason to potentially favor balanced crystalloids in patients who require large volume resuscitation or who have significant hyperchloremia at baseline; however, we emphasize that any benefit, if one exists, is currently unproven.
Following initial crystalloid resuscitation, albumin can be used for further intravascular volume especially in patients who may require substantial amounts of crystalloid fluids. The use of albumin continues to be controversial. Albumin is significantly more expensive than crystalloid, and a more expensive drug or intervention should only be used if there is a clear benefit compared to a cheaper one. There have been multiple trials examining albumin in sepsis and septic shock. These have generally been negative in terms of demonstrating differences in mortality despite post hoc analyses often finding benefit in some subgroups. The overall lack of a survival benefit with albumin has been demonstrated in large meta-analyses examining its usage in critically ill patients., However, it should be noted that a recent retrospective cohort study of patients receiving large volume resuscitation of >60 mL/kg showed decreased mortality and adverse kidney events at 30, 90, and 365 days in patients who received 5% albumin. In addition, patients who receive albumin have higher blood pressure, higher static filling pressures, and lower net fluid balance, which are important outcomes even if the choice of fluid has not been consistently shown to change mortality.,,
| Antimicrobial Therapy and Source Control|| |
Per definition, the inciting event of sepsis is infection. This makes administration of appropriate antimicrobial therapy and treating the source of infection key to outcomes from sepsis. The importance of rapid antimicrobial administration is clear, as even small delays in administering antibiotics results in increased mortality in patients with septic shock.,,,
Understanding that immediate administration of antibiotics in septic shock is life-saving, antibiotic initiation in the absence of shock is more nuanced. A balanced approach seeks to take into account (a) the certainty of diagnosis, (b) evidence related to timing of antimicrobial administration, and (c) potential side effects of antibiotics. There is no question that antibiotics, when used appropriately, are enormously effective in preventing morbidity and mortality. However, antibiotics also have side effects that must be taken into account when the decision is made to initiate antimicrobial therapy. Side effects can be seen on an individual basis such as development of Clostridium difficile colitis, acute kidney injury, allergic reaction, etc. In addition, antibiotic usage plays a key role in the development of antibiotic resistance, which has implications both for individual patients and for society as a whole. As such, while the risk/benefit ratio for initiating antimicrobial therapy is clear for septic shock, for patients without shock, the decision is more complex. This is first due to the fact that a diagnosis is often unclear. If a patient truly has sepsis, appropriate antimicrobial therapy is beneficial. However, starting antibiotics in patients with an alternative diagnosis can induce patient harm without any benefit since antimicrobial agents have zero utility in noninfectious disease and yet have potential risk.,, In addition, while long delays in initiation of antimicrobial therapy are harmful, the data are not convincing that starting antibiotics immediately (as opposed to following a small delay) leads to improved outcome in sepsis without shock. As such, the Surviving Sepsis Campaign revised its guidelines to take these competing priorities into account by recommending antibiotic use immediately in all patients with possible or probable septic shock and in patients with sepsis where there is a high degree of confidence in the diagnosis from the bedside clinician. However, for patients with possible sepsis without shock in which confidence in the diagnosis is lower, the guidelines recommend a short period of assessment to determine if the cause of disease is infectious or noninfections and to administer antibiotics within 3 h if concern for infection persists. Ideally, antibiotics should not be initiated until cultures are obtained since even a single dose of an antimicrobial agent substantially decreases the chance of a positive culture. However, logistical challenges in obtaining cultures are common in many hospitals and antibiotics should not be withheld when waiting for cultures if doing so will result in a substantial delay of treatment.
Initial therapy should include one or more broad-spectrum antimicrobials that will cover all likely pathogens. This is crucially important since administering inappropriate antimicrobials as empiric therapy or even giving incorrect doses to patients with sepsis and septic shock is associated with a significant increase in mortality.,, The choice of antimicrobials relates to the patient's clinical history, the potential source(s) of sepsis, and the chance that infecting organism(s) will be multidrug resistant, including but not limited to location at time of infection (hospital, community), recent antibiotic usage, local microbial flora, etc., While initial therapy should be individualized as much as is practicable, generally, initial therapy will be empiric, and clinicians should use local and hospital-specific antibiograms as this will increase the likelihood of a patient receiving adequate initial therapy. Biomarkers (including procalcitonin) do not have proven utility in the decision to start antibiotics, and therefore should not be used.
Antibiotics should only be narrowed after the inciting pathogen has been identified with sensitivities or clinical improvement has been noted. While duration of antibiotic therapy is a complex topic outside the scope of this review, we wish to emphasize that there should be a daily assessment for antimicrobial de-escalation or discontinuation as the patient's clinical status changes, and that procalcitonin may be a useful tool in assisting in the decision to discontinue antibiotics.,
Source control should ideally be obtained as soon as medically and logistically practical after the diagnosis has been made. Depending on the clinical scenario, this may require surgical intervention, percutaneous drainage, or removal of intravascular access devices that are possible sources of sepsis or septic shock after establishing another form of vascular access. Since sepsis is a time-sensitive disease, time is of the essence as significant delays in obtaining definitive source control has been shown to have deleterious effects on mortality.,, The type of source control intervention depends on the disease process, patient's status, the probability of the procedure's success, and logistical factors at the institution.
| Vasopressors|| |
Hypotension in septic patients is often multifactorial and multiple causes can be addressed simultaneously or nearly simultaneously. The specific treatment for vasodilation resulting in distributive shock is vasopressor therapy. The goal of pressors is to optimize tissue perfusion, rather than simply raising blood pressure.
Vasopressors have been in use since the 1940s. Vasopressors mechanistically work by targeting different physiologic elements involved in blood pressure regulation. Norepinephrine is the first line agent that should be used in septic shock based upon a combination of its efficacy and side effect profile. When norepinephrine fails to adequately raise the mean arterial pressure or in the setting of escalating doses, vasopressin can then be added followed by epinephrine. After an extended time without the any new vasopressors, angiotensin II recently became available for the treatment of vasodilatory shock. Although data are less robust for angiotensin II and its place in the treatment of sepsis is still to be determined, this can be effective for treatment of patients with vasodilatory shock that does not respond to high-dose vasopressors.,
Vasopressors are optimally given through a central venous catheter. However, a central venous catheter may not immediately be placed depending on logistical constraints or patient-specific anatomical issues. Further, for patients in whom the treating clinician questions whether vasopressors will be needed on more than a short-term basis, it may be appropriate to delay placing a central venous catheter. In any of these scenarios, it is generally considered to be safe to administer vasopressors through a larger bore, more proximally placed peripheral intravenous catheter for up to 24 h.
For patients with septic shock and an ongoing need for vasopressor therapy, the preponderance of the evidence suggests a benefit of intravenous corticosteroids, typically hydrocortisone, as an adjunctive therapy. While the effect of steroids on mortality have been mixed in randomized controlled trials, the majority of studies demonstrate that patients are weaned off of vasopressors earlier if started on steroids.,,,,, Additional benefits may include more rapid weaning of mechanical ventilation (potentially related to less requirement for vasopressors), while side effects include hyperglycemia and neuromuscular weakness.
| Future Direction for Therapy and Research|| |
Despite significant advances in improving survival from sepsis since the advent of the Surviving Sepsis Campaign, outside of antimicrobial therapy, most sepsis management is nonspecific, with a focus on supportive care. Thus, many opportunities exist for research into improving outcomes. One obvious challenge in patient care is that many clinicians treat patients the same, despite clear differences in initiating microbe, patient age, gender, comorbidities, environment, and genetics. We have all seen the scenario where two nearly identical patients receive nearly identical care, yet their outcomes are strikingly different. A key reason behind this is that although the patients may appear to grossly be nearly identical, their host response may be entirely distinct and therapies that might benefit one patient might have no impact (or even be harmful) in the other. The recent explosion of research aimed at precision medicine through identification of clinical sepsis phenotypes,,,,,,, genomic sequencing and classification,,,, biomarker-based strategies and multiplatform omics will hopefully move us from a “one size fits all” world into one where care can be individualized much more precisely than is possible today. In addition, unbiased assessment of the host response holds promise for both predicting decompensation before it is visible to the clinician,, and for the development of novel therapeutics. Notably, the concept of what constitutes the host response continues to evolve as potential targets can be widely differing with complementary processes of human origin (immune system, endothelial, gut, brain, etc.) and microbial origin in the microbiome. There also continues to be a significant role for implementation science as unfortunately, there are frequently large gaps between evidence-based best practice and clinical behavior at the bedside. Of note, to help guide future research priorities for sepsis, the Surviving Sepsis Campaign Research Committee identified a top six clinical and top four basic science questions that need answers in order to bridge the fundamental knowledge gaps that remain in the understanding and treatment of sepsis [Table 2] and [Table 3].,,,,
|Table 3: Surviving sepsis campaign top basic science research priorities*|
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| Conclusions|| |
While sepsis has been discussed in various manners for thousands of years, the modern age of early sepsis management is only a few decades old. Improvements in the sepsis mortality rate are due to multifactorial reasons including improved mechanistic understanding, targeted antimicrobial therapy, and evidence-based guidelines intended to assist bedside clinicians with treatment. We believe the future of sepsis will be as distinct from current management as the ICUs of today are from the ICUs of 50 years ago. More robust definitions of sepsis (i.e., Sepsis-4) will result from a more complete understanding of the syndrome. Pathogen identification will occur in real time at point of care rather than waiting two or more days for cultures to result. Instead of treating all patients the same, sepsis care will be individualized using new technologies that will allow for a precision medicine approach, whereby therapy can be targeted on an individualized basis. Finally, new therapeutics that manipulate the host response as well as the microbiome will result in improved survival, and improved long-term quality of life, compared to current strategies.
Financial support and sponsorship
The study was financially supported by the National Institutes of Health (GM095442, GM072808, GM104323, AA027396).
Conflicts of interest
Dr. Coopersmith is an Associate Editor-In-Chief of the journal. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and his research groups.
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[Table 1], [Table 2], [Table 3]