Sepsis is one of the common severe complications in critically ill patients with trauma, burns, shock, and infections. It remains a significant threat to human health, characterized by high incidence, high mortality, and high treatment costs. Millions of people are diagnosed with sepsis globally each year, with a mortality rate ranging from 16.7% to 33.3%. Sepsis-induced cardiomyopathy (SIC), also known as sepsis-induced myocardial dysfunction (SIMD), is one of the most severe complications and a major cause of death in sepsis, directly affecting the prognosis of sepsis patients. Studies have shown that the mortality rate of septic patients with cardiac dysfunction can be as high as 70%, while it is only 20% for those without cardiac dysfunction. Effective cardiac protection can improve the prognosis of sepsis patients and reduce their mortality rate. Therefore, the prevention and early treatment of sepsis-induced cardiomyopathy are of great significance for improving patient survival rates. International medical experts and organizations have been researching and summarizing sepsis, but there is still a lack of systematic summaries regarding sepsis-induced cardiomyopathy. The Critical Care Medicine Professional Committee of the Chinese Association of Integrative Medicine organized relevant experts to discuss and formulate this consensus.
1. Background of the Consensus
Currently, the expert consensus or guidelines related to sepsis in traditional Chinese medicine (TCM) or integrative medicine mainly include: the “Expert Consensus on the Integrated Diagnosis and Treatment of Sepsis” published by the Emergency Medicine Professional Committee of the Chinese Association of Integrative Medicine in 2013, the “Expert Consensus on the Integrated Diagnosis and Treatment of Septic Shock” published in 2019, and the TCM section of the “Guidelines for the Treatment of Severe Sepsis / Septic Shock” published by the Chinese Medical Association in 2015. SIC is a common but under-recognized issue that cannot be ignored. According to literature search results, there has been a significant increase in literature related to SIC in recent years, including reviews, meta-analyses, systematic evaluations, basic experimental studies, and clinical research, but no guidelines or expert consensus on SIC have been published domestically or internationally.
In recent years, research progress on SIC mainly includes pathogenesis, diagnostic methods, Western medical treatment measures, and TCM. The pathogenesis of SIC is not fully understood, but it is currently believed to be multifactorial, involving the production of inflammatory factors and cascade effects, endothelial injury and microcirculation disorders, mitochondrial dysfunction, and dysregulation of apoptosis and autophagy. Diagnosis mainly relies on clinical manifestations combined with laboratory results of elevated myocardial injury/cardiac function markers and echocardiographic findings. Under active anti-infection, appropriate fluid resuscitation, and effective organ function support, treatment measures include the use of vasopressor drugs, positive inotropic agents (such as dobutamine, milrinone, and levosimendan), frequency control (beta-blockers, ivabradine), statins, immunotherapy, and mechanical circulatory support (such as intra-aortic balloon pump (IABP) and extracorporeal membrane oxygenation (ECMO)). The TCM treatment of SIC is based on the “Three Syndromes and Three Methods” for syndrome differentiation, namely, heat toxin syndrome with heat-clearing and detoxifying methods, blood stasis syndrome with blood-activating and stasis-resolving methods, and acute deficiency syndrome with methods to support the righteous qi and consolidate the foundation. The blood-activating and stasis-resolving method is an important treatment approach, using detoxifying and blood-activating, warming yang and blood-activating, and qi-tonifying and blood-activating herbs. TCM injections include Shenfu injection, Xuebijing injection, and Xinmailong injection.
The above is the recent theoretical progress in integrative medicine and the background for writing the “Expert Consensus on the Integrated Diagnosis and Treatment of Sepsis-Induced Cardiomyopathy”. SIC is a pathological stage of severe illness during the progression of sepsis, and current sepsis guidelines or expert consensus do not systematically elaborate on SIC. It is necessary to compile a separate expert consensus on SIC to provide evidence support for clinical diagnosis and treatment. For the treatment of SIC, Western medicine mainly adopts measures including early anti-infection treatment, fluid resuscitation, the use of vasoactive drugs, and organ support. Since sepsis patients often experience dysfunction across various systems and organ failures, simple Western medical treatment may not achieve satisfactory results, making it necessary to combine effective TCM treatment measures and adopt an integrative approach to treat SIC.
This consensus gathers domestic experts in integrative critical care medicine, referencing domestic and international sepsis diagnosis and treatment guidelines and recent related research, following the requirements for formulating clinical guidelines in TCM and integrative medicine, and based on their academic and clinical experience, drafted the current stage of the “Expert Consensus on the Integrated Diagnosis and Treatment of Sepsis-Induced Cardiomyopathy” in China, hereinafter referred to as the “Consensus”, aiming to assist clinical physicians, especially critical care physicians, in early identification, early diagnosis, and early treatment of such patients, thereby reducing mortality.
2. Diagnostic Criteria for SIC
Currently, there is no specific “gold standard” for the diagnosis of SIC. Clinically, SIC is diagnosed through the presence of cardiac dysfunction or hemodynamic abnormalities in septic patients, combined with abnormal echocardiographic findings and elevated myocardial injury markers (cardiac troponin (cTnT/cTnI)) and/or cardiac function markers (brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP)).
2.1 Diagnosis of Sepsis is a Prerequisite. Currently, Sepsis 3.0 is used as the diagnostic basis for sepsis and septic shock, and other causes of heart failure, such as acute coronary syndrome (ACS), must be excluded.
2.2 Clinical Manifestations: Acute onset, with global cardiac function involvement as the main manifestation, and decreased sensitivity to fluid resuscitation and catecholamine drugs. It is reversible, generally recovering to normal within 7-10 days, without leaving clear cardiac sequelae.
2.3 Electrocardiogram: The electrocardiogram lacks specific diagnostic criteria for SIC, with the most common arrhythmias being sinus tachycardia and atrial fibrillation.
2.4 Echocardiography: Echocardiography is currently the main diagnostic basis for SIC, and patients with hemodynamic instability should undergo echocardiography. It is necessary to distinguish between systolic and diastolic dysfunction, with diastolic dysfunction often being overlooked and requiring enhanced assessment. The main findings on cardiac color Doppler ultrasound include cardiac dilation and reduced ejection fraction (EF), which generally can fully recover within 7-10 days, without the presence of scar tissue similar to that after myocardial infarction. Increasingly, studies support the use of speckle tracking echocardiography to study SIC. Attention should be paid to differentiating it from pericardial effusion, ACS, and left ventricular outflow tract (LVOT) obstruction.
2.5 Hemodynamic Monitoring: Pulmonary artery catheter (PAC) and pulse indicator continuous cardiac output monitoring (PiCCO) can supplement echocardiography to understand the patient’s pre- and post-load and changes in cardiac function, while also guiding the use of vasoactive and positive inotropic drugs.
2.6 Cardiac Markers cTnI and BNP (or NT-proBNP): Elevated biomarkers are very common in septic patients, with cTnI and NT-proBNP being commonly used in clinical practice and having high sensitivity. Elevated cardiac biomarkers are clear indicators of the severity of illness and prognosis in septic patients.
2.6.1 cTnI: Elevated cTnI during sepsis may reflect changes in myocardial cell permeability or necrosis rather than atherosclerotic disease. Its concentration generally increases with the severity of the disease, and cTnI levels in patients who die within a short period are often higher than those in survivors.
2.6.2 BNP or pro-brain natriuretic peptide (Pro-BNP): BNP is mainly synthesized and secreted by ventricular myocytes, and changes in ventricular load and wall tension are the main conditions that stimulate BNP secretion. Elevated plasma concentrations reflect impaired cardiac function and indicate poor prognosis. BNP also promotes natriuresis and diuresis, has a strong vasodilatory effect, and is released under pressure, reflecting myocardial load and indirectly reflecting cardiac function.
3. TCM Etiology and Pathogenesis of SIC
Ancient literature does not have direct records of disease names related to SIC, but based on its clinical manifestations, it falls under the categories of “palpitations,” “chest obstruction,” and “dyspnea” in TCM. Septic shock and multiple organ dysfunction belong to “collapse syndrome” and “exhaustion syndrome,” which are discussed in major works focusing on infectious diseases such as “Treatise on Febrile Diseases” and “Differentiation of Warm Diseases.” After thousands of years of clinical practice, TCM has accumulated rich experience in the prevention and treatment of sepsis and organ injury. TCM has its advantages in preventing and treating sepsis, and contemporary practitioners have enriched the discussion on the etiology and pathogenesis of SIC based on previous discussions. Current understanding of the pathogenesis of sepsis mainly includes toxic heat accumulation, blood stasis obstructing channels, deficiency of righteous qi, and obstruction of the bowels. Sepsis is often seen in elderly patients with weak constitutions or after major surgeries, where righteous qi is deficient, the defensive qi fails to secure the exterior, and pathogenic factors prevail, leading to the invasion of toxic pathogens into the lung and the consumption of righteous qi, with the pathogens entering the blood and affecting the pericardium. “Heart yang is the sun among yangs”; after the invasion of pathogenic factors, heart yang is damaged, and deficiency of yang leads to an inability to circulate blood; the kidney is the source of yin and yang, and insufficient kidney yang fails to warm the heart yang, resulting in further deficiency of heart yang and an inability to transform water and qi into urine, leading to edema. The occurrence of cardiac dysfunction in sepsis is due to the deficiency of righteous qi and the predominance of pathogenic factors, thus the etiology of cardiac dysfunction in sepsis is based on the deficiency of righteous qi, characterized by deficiency at the root and excess at the branch.
4. Western Medical Prevention and Treatment Strategies for SIC
4.1 Prevention: Once a patient is diagnosed with sepsis, active treatment measures should be taken to prevent its progression to SIC, including infection control and correcting the dysregulated response caused by infection. These measures should continue even after the diagnosis of SIC.
4.1.1 Infection Control: Within 1 hour of diagnosing sepsis, empirical broad-spectrum antibiotic therapy should be initiated while controlling the source of infection to maximally suppress potential pathogens, and blood cultures for aerobic and anaerobic bacteria should be performed simultaneously without delaying antibiotic treatment to further guide antibiotic therapy.
4.1.2 Fluid Management: Fluid resuscitation is a necessary measure for the prevention and treatment of SIC. When the ventricular preload is low, the pressure-volume curve during diastole is relatively flat, and the initial amount of fluid resuscitation has the greatest impact on cardiac function. The “International Guidelines for the Treatment of Sepsis and Septic Shock” recommend that at least 30 mL/kg of crystalloid fluid should be infused within the first 3 hours of fluid resuscitation. Over-resuscitation is associated with an increased risk of death, and fluid resuscitation should be guided dynamically by comprehensive assessments including passive leg raise tests, rapid fluid challenges, central venous pressure (CVP), urine output, oxygen saturation (SO2), and lactate levels.
4.1.3 Blood Lactate Monitoring: Studies indicate that a lactate level >4.0 mmol/L upon initial admission to the intensive care unit (ICU) is an independent risk factor for the occurrence of SIC. Therefore, monitoring blood lactate levels and improving lactate clearance may effectively reduce the incidence of SIC.
4.2 Pharmacological Treatment
4.2.1 Vasoactive Drugs: Norepinephrine (NE) is recommended as the first-line drug for septic shock, with the addition of epinephrine or vasopressin as a second drug. NE is an alpha receptor agonist that constricts small arteries and veins, used for hypotension or paralysis in sepsis. Research has shown that it is more effective than dopamine in septic patients. The recommended dosage is 0.1-0.3 μg·kg-1·min-1, and caution should be taken as extravasation can lead to local tissue necrosis, so it is advisable to use it via deep veins.
4.2.2 Positive Inotropic Agents: The use of positive inotropic agents in SIC patients helps to increase cardiac output (CO), but there is no significant improvement in prognosis. In the state of sepsis, CO needs to reach physiological levels, and studies have shown that targeting a cardiac index (CI) above normal does not improve survival rates.
4.2.2.1 Dobutamine is the most commonly used positive inotropic agent, which can increase CI when used alone but also increases oxygen consumption. The combination of dopamine and dobutamine carries a high risk of arrhythmias. It should be considered for use when there is clear evidence of decreased CO, and preload has reached optimal levels, particularly in patients with low CO and bradycardia.
4.2.2.2 Milrinone has limited research in SIC. In a pediatric trial, milrinone improved cardiovascular function in “non-hyperdynamic” septic shock patients without adverse outcomes. The combination of milrinone and metoprolol can improve CI, reduce heart rate, and increase stroke volume index, potentially alleviating adverse reactions from inotropic agents. Currently, milrinone is not recommended for routine use in SIC treatment, but may be considered when low CO is confirmed and dobutamine is ineffective.
4.2.2.3 Levosimendan is a calcium sensitizer that enhances myocardial contraction without relying on catecholamine pathways, reducing oxygen demand, arrhythmias, and catecholamine resistance during sepsis. Studies have shown that compared to dobutamine, levosimendan effectively improves hemodynamics and increases gastric mucosal blood flow, creatinine clearance, urine output, and lactate clearance. However, current clinical studies show inconsistent results regarding the impact of levosimendan on the prognosis of SIC patients, and it is not recommended for routine use.
4.2.3 Recombinant Human Brain Natriuretic Peptide (rh-BNP): rh-BNP has effects in reducing inflammatory responses, diuresis, alleviating tissue edema, and lowering pulmonary capillary wedge pressure. Studies indicate that rh-BNP can lower NT-proBNP and cTnI in septic patients through neuroendocrine regulation, and to some extent improve left ventricular ejection fraction (LVEF), with good safety. However, whether it can improve SIC still requires further large-scale clinical studies for confirmation.
4.2.4 Negative Frequency Drugs
4.2.4.1 Esmolol, as a selective beta-blocker, has pharmacological effects in regulating inflammatory responses and immune responses, inhibiting myocardial oxidative stress, reducing the hyperadrenergic drive of sepsis, improving beta-adrenergic receptor sensitivity, protecting mitochondria, and inhibiting myocardial apoptosis, which can help reduce myocardial oxygen demand and increase diastolic filling. Studies have shown that esmolol treatment for SIC is generally effective, and under sufficient fluid resuscitation, it protects the myocardium, improves cardiac function, and enhances prognosis by reducing sympathetic nervous tension, stabilizing heart rate, and improving hemodynamics. However, the timing and dosage of its use still require extensive research for further clarification, and it should be applied under strict hemodynamic monitoring.
4.2.4.2 Ivabradine can improve sinus tachycardia without the negative inotropic effects associated with beta-blockers. Trials have shown that the use of ivabradine can improve heart rate, diastolic volume index, and venous blood oxygen saturation (SvO2), while reducing lactate levels and decreasing NE dosage. However, this study included both cardiogenic and septic shock patients, leading to confounding factors, and it is currently not recommended as routine treatment for SIC.
4.2.4.3 Other treatments with potential efficacy include statins, dexmedetomidine, hydrocortisone, alpha-2 receptor antagonists, erythropoietin, vitamin C, and sulfur dioxide.
4.3 Non-Pharmacological Treatments such as Auxiliary Circulation (IABP, ECMO):
Extracorporeal support therapy is widely used in cardiogenic shock caused by congestive heart failure, and its application in SIC is based on this experience. Currently, there are few clinical trials regarding IABP and ECMO. Before deciding on the appropriate support device, the patient’s hemodynamics, such as the degree of left, right, or biventricular failure and systolic and diastolic dysfunction, need to be considered. The drawback is that these are all supportive treatments and do not directly treat SIC, and the associated costs and risks are high, so they should be used cautiously in well-equipped medical centers.
5. TCM Treatment for SIC
5.1 Specific Application of the “Four Syndromes and Four Methods” Differentiation: Professor Wang Jinda and others proposed the “Three Syndromes and Three Methods” for treating sepsis based on the differentiation of the six meridians and the differentiation of defensive qi, nutritive qi, and blood, categorizing sepsis into heat syndrome, stasis syndrome, and deficiency syndrome, with corresponding treatment methods being heat-clearing and detoxifying, blood-activating and stasis-resolving, and qi-tonifying and consolidating. Through extensive basic and clinical research, it has been confirmed that the developed “Four Syndromes and Four Methods” (which adds the solid bowel syndrome and the method of unblocking the bowels) has a good therapeutic effect on myocardial depression in sepsis, reducing the mortality rate of sepsis to some extent.
5.1.1 Heat-Clearing and Detoxifying Method: The levels of pro-inflammatory and anti-inflammatory cytokines in sepsis are closely related to the severity of the condition and prognosis. TCM believes that heat injures the blood vessels and causes blood stasis. The heat-clearing and detoxifying herbal compound represented by Xuebijing injection has the effects of cooling blood, promoting qi and blood circulation, and detoxifying, which has a certain antagonistic effect on myocardial depression and also plays a role in bidirectional immune regulation. Huanglian Jiedu Decoction (composed of 9 g of Gardenia, 9 g of Coptis, 6 g of Scutellaria, and 6 g of Phellodendron) is indicated for the syndrome of excessive fire toxin in the three burners. Clinical studies have proven that when combined with Western medicine, Huanglian Jiedu Decoction can effectively treat SIC and significantly reduce myocardial injury, possibly related to the reduction of inflammatory responses.
5.1.2 Blood-Activating and Stasis-Resolving Method: Microcirculation disorders during sepsis are well recognized, causing endothelial cell swelling and deposition of fibrin in blood vessels, promoting the migration of neutrophils to the myocardial interstitium, leading to cardiac edema. Changes in microcirculation cause mitochondrial dysfunction in myocardial cells and complex metabolic changes, ultimately leading to the development of myocardial depression. The inflammatory response promotes the activation of coagulation mechanisms, which exacerbates the inflammatory response, and coagulation abnormalities induce myocardial depression. Therefore, controlling both pro-inflammatory responses and coagulation responses is essential in the treatment of myocardial depression in sepsis. The coagulation dysfunction in sepsis patients is due to the obstruction of toxic pathogens and the accumulation of pathogenic toxins, leading to obstruction of qi and blood flow, resulting in myocardial obstruction. Blood-activating herbs can effectively improve microcirculation. For example, Qishen Huoxue Granules (composed of Astragalus, Salvia, Red Peony, Chuanxiong, Safflower, and Angelica) primarily promote blood circulation and resolve stasis. Research has confirmed that it can improve mitochondrial metabolic disorders in myocardial cells, block the vicious cycle of oxidative stress, and reduce inflammatory responses, thereby alleviating myocardial injury. Clinical studies show that it can improve myocardial injury in septic patients without affecting the duration of mechanical ventilation, the use of vasoactive drugs, or prognosis. It is recommended to take Qishen Huoxue Granules (10 g) orally or via nasogastric tube three times a day in addition to Western medicine treatment. Research shows that Tongguan Capsules (composed of Astragalus, Salvia, and Leech) can lower plasma inflammatory mediator levels and reduce myocardial injury markers cTnI and BUN levels in septic patients, while also improving myocardial diastolic function. It is recommended to take Tongguan Capsules (3 capsules) orally or via nasogastric tube three times a day in addition to Western medicine treatment.
5.1.3 Unblocking the Bowels and Attacking Downward Method: In the pathogenesis of sepsis, the lungs and intestines are both susceptible to attacks by toxic pathogens and are also places where toxic pathogens accumulate. Dysbiosis of the intestinal flora and the translocation of endotoxins can trigger excessive inflammatory responses and organ dysfunction. Therefore, for patients with heat accumulation in the intestines, using methods to unblock the bowels, clear heat, and preserve yin can effectively reduce inflammatory mediator levels and alleviate myocardial injury. Research has shown that Jinhong Decoction (composed of 9 g of Rhubarb, 15 g of Red Vine, and 30 g of Dandelion) can effectively protect against early myocardial injury in sepsis and improve cardiac function. It is recommended to take Jinhong Decoction (200 mL) orally or via nasogastric tube, prepared by boiling 1 dose daily, divided into 2 doses.
5.1.4 Supporting Righteous Qi and Consolidating the Foundation Method: In the later stages of sepsis, there is a significant depletion of qi and yin, leading to dryness of body fluids and an inability to nourish various organs, resulting in weak pulse, exhaustion of qi and yin, collapse of yang qi, organ failure, and deficiency of both yin and yang. Treatment should focus on restoring pulse, nourishing yin, tonifying qi, rescuing yang, and supplementing both yin and yang. The theory of acute deficiency syndrome plays a very important role in the treatment of sepsis. Acute deficiency syndrome refers to the overwhelming pathogenic qi that exceeds the body’s ability to resist disease, leading to rapid depletion and exhaustion of qi, blood, body fluids, yin, and yang, resulting in a temporary deficiency of righteous qi. This is the most common and severe pathological form of the struggle between righteous and pathogenic qi in critical conditions, holding significant importance in emergency rescue. Since most SIC patients exhibit deficiency of heart qi or heart yang, leading to decreased systolic and/or diastolic function and even hemodynamic instability, applying the theory of acute deficiency syndrome throughout the treatment helps to nourish the righteous qi, tonify heart qi (yang), improve cardiac function, stabilize hemodynamic parameters, and enhance the prognosis of SIC patients. Research indicates that the use of Dushen Decoction as an adjunctive treatment for sepsis can increase CO, improve hemodynamics and organ perfusion status, reduce inflammatory responses, increase platelet counts, and prevent the progression to disseminated intravascular coagulation (DIC). It is recommended to take Dushen Decoction (30 g of fresh ginseng, boiled with water to a concentration of 100 mL) every 12 hours in addition to Western medicine treatment.
5.2 Application of TCM Injections: In recent decades, the TCM community has strengthened research and exploration of TCM formulations, and the treatment of this condition has evolved from traditional oral decoctions and powders to injections, greatly improving the efficacy of TCM in treating septic shock, while being convenient, safe, and reliable.
5.2.1 Guidelines for the Use of TCM Injections: ① Once diagnosed with SIC, TCM injections can be used based on syndrome differentiation. ② When hemodynamics stabilize and there is a need to withdraw medications, it is recommended to withdraw vasoactive drugs before TCM injections.
5.2.2 Currently, commonly studied TCM injections for treating SIC include: Xuebijing injection: suitable for heat toxin and blood stasis syndrome, recommended dosage: 100 mL, diluted and infused intravenously twice daily. Shenfu injection: suitable for heart yang deficiency and collapse of yang qi, commonly used in emergencies, 20 mL of Shenfu injection can be pushed intravenously over 15 minutes, and can be used continuously 2-3 times, then changed to 100 mL diluted and infused intravenously 2-3 times daily. Shengmai injection: suitable for qi and yin deficiency, weak pulse, and impending collapse, recommended dosage: 50 mL, diluted and infused intravenously twice daily. Shenmai injection: suitable for qi and yin deficiency syndrome, recommended dosage: 50 mL, diluted and infused intravenously twice daily. Astragalus injection: suitable for heart qi deficiency and blood stasis, recommended dosage: 60 mL, diluted and infused intravenously once daily. Xinmailong injection: suitable for yang deficiency and blood stasis syndrome, recommended dosage: 5 mg/kg based on body weight, diluted and infused intravenously twice daily.
6. Outlook
SIC clearly affects the prognosis of sepsis patients, and its importance is increasingly recognized. Early identification, diagnosis, and intervention are particularly critical. Existing evidence indicates that echocardiography is the most important diagnostic basis and assessment tool, and a standardized diagnostic process should be established as soon as possible. New biomarkers may assist in the early rapid identification of potential SIC patients. Close hemodynamic monitoring will provide directional guidance for SIC treatment, with pharmacological treatment primarily involving vasoactive and positive inotropic drugs, and mechanical circulation used when necessary, which is expected to become a major component of the SIC treatment system. The dialectical use of TCM injections should become a research focus in the next stage of TCM treatment for SIC.
Author: He Jianzhu (Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Postdoctoral Workstation of Shanghai University of Traditional Chinese Medicine) Expert Group Leader: Guo Liheng (Second Affiliated Hospital of Guangzhou University of Chinese Medicine), Zhang Minzhou (Second Affiliated Hospital of Guangzhou University of Chinese Medicine) Expert Group Members (sorted by surname stroke order): Ma Mingyuan, Ma Chunlin, Ma Li, Fang Bangjiang, Kong Li, Wu Minsheng, Liu Ming, Liu Baoshe, Liu Wanyan, Liu Jingyuan, Jiang Ronglin, Shou Songtao, Li Lan, Li Zhijun, Li Wei, Li Yinping, Yang Guang, Yang Zhixu, Yang Bo, He Jianzhu, Zhang Minzhou, Chen Zili, Chen Yan, Chen Yi, Chen Jian, Lin Xinfeng, Zhou Jiang, Fang Li, Hu Mahong, Duan Meili, Chai Yanfen, Qian Yiming, Gao Peiyang, Guo Liheng, Guo Yingjun, Guo Liuxue, Liang Qun, Zeng Hongke, Wen Miaoyun, Dai Feiyue
Conflict of Interest: All authors declare no conflict of interest.
References (omitted)
