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RESEARCH ARTICLE
Asia Pac J Clin Trials Nerv Syst Dis 2018,  3:18

Clinical treatment outcomes of acute ischemic stroke: protocol for a registry ambispective cohort study


First Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China

Date of Web Publication15-May-2018

Correspondence Address:
Juan Feng
First Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3932.232077

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  Abstract 

Background and objectives: Many types of neuroprotective agents and traditional Chinese medicines are commonly used for the clinical treatment of ischemic stroke in China. However, there is no high-quality randomized controlled trial assessing efficacy and safety, and these medicines have not been recommended in the guidelines. Therefore, in this study, we will analyze the treatment outcomes of acute ischemic stroke in the clinic.
Design: This is a registry, single-center, ambispective cohort study.
Methods: The study will be conducted at the Shengjing Hospital of China Medical University, China. Data for 600 cases of acute ischemic stroke from October 2016 to November 2017 were retrospectively collected for trend analysis in January 2018. Furthermore, data for 1400 cases of acute ischemic stroke have been prospectively collected since February 2018. Stroke patients will be visited five times: on admission (baseline assessment, visit 1), during medication and treatment in the hospital (visit 2), at discharge (visit 3), 90 ± 14 days after treatment (outpatient clinic or telephone follow-up, visit 4), and 360 ± 28 days after treatment (telephone follow-up, visit 5).
Outcome measures: Outcome measures will include vital signs, electrocardiogram, laboratory findings and imaging findings, Glasgow Coma Scale, Essen Stroke Risk Score, National Institutes of Health Stroke Scale, modified Rankin Scale, and adverse events. National Institutes of Health Stroke Scale score at discharge (visit 3) will be the primary outcome measure; the remainder will be secondary outcome measures.
Discussion: This study of the clinical treatment and outcomes of acute ischemic stroke should help in optimizing clinical diagnosis and treatment.
Ethics and dissemination: This trial was designed in October 2017. This trial has been approved by the Ethics Committee of Shengjing Hospital of China Medical University of China in December 2017 (approval number: 2017PS40K). This trial was registered in December 2017. Subjects with acute ischemic stroke from October 2016 to November 2017 were retrospectively recruited for trend analysis in January 2018. Other subjects began to be prospectively recruited from February 2018, and prospective collection will be finished within 36 months. Each subject will be followed up for 360 days. The follow-up will be completed in November 2021. Data analysis will be finished in November 2022. The results of the trial will be disseminated in a peer-reviewed journal.
Trial registration: This trial had been registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-OOC-17013773). Protocol version (1.0).

Keywords: registry, single-center, ambispective cohort study; acute ischemic stroke; optimization of clinical diagnosis and treatment; Glasgow Coma Scale; Essen Stroke Risk Score; National Institutes of Health Stroke Scale; modified Rankin Scale


How to cite this article:
Han D, Liu S, Qiao XY, Gao Y, Liu J, Feng J. Clinical treatment outcomes of acute ischemic stroke: protocol for a registry ambispective cohort study. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:18-26

How to cite this URL:
Han D, Liu S, Qiao XY, Gao Y, Liu J, Feng J. Clinical treatment outcomes of acute ischemic stroke: protocol for a registry ambispective cohort study. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2018 Jul 21];3:18-26. Available from: http://www.actnjournal.com/text.asp?2018/3/2/18/232077


  Introduction Top


Research background

Stroke is a major health problem in China, with high morbidity, high disability and high recurrence rate. Acute ischemic stroke is the most common type, accounting for 60-80% of all strokes (Group of guidelines for the diagnosis and treatment of Acute Ischemic Stroke in the Cerebrovascular Disease Section of the Neurology Branch of the Chinese Medical Association, 2010). Patients frequently suffer from impaired neurological functioning, as well as psychiatric and behavioral dysfunctions, which severely affect their quality of life and impart a heavy emotional and financial burden on families and society. Population monitoring data released by the Statistics Center of the Ministry of Health of China reveal that approximately 2 million strokes occur every year in China, and that approximately 1.5 million people die of cerebrovascular disease every year. Furthermore, of the 5–6 million people that survive, approximately 75% have varying degrees of disability and approximately 40% have severe disabilities (The Ministry of Health Disease Control Bureau and Neurology Branch, Chinese Medical Association, 2017). Therefore, prevention and rapid and effective treatment of stroke are urgently needed.

To date, only ultra-early thrombolysis and antiplatelet therapy have been supported by evidence-based medicine in the treatment of ischemic stroke. Intravenous thrombolysis with recombinant tissue plasminogen activator within 3 hours of onset substantially reduces the risk of death and severe disability in patients (Li et al., 2013). The European Cooperative Acute Stroke Study III suggests that intravenous recombinant tissue plasminogen activator administered within 3–4.5 hours of stroke is safe and effective, improving prognosis (Hacke et al., 2008). The largest clinical trial of urokinase thrombolysis was conducted in China. A total of 465 acute ischemic stroke patients were enrolled from 51 centers. The study showed that thrombolysis with urokinase was safe and effective within 6 hours of onset (Cooperaring Group for National 95's Project, 2002). Therefore, because of the type I evidence, thrombolysis is currently recommended treatment in national guidelines worldwide. However, the proportion of patients given thrombolytic treatment remains very low. The rate of thrombolysis for stroke in the United States does not exceed 3.5% (Xydas et al., 2012). The rate of intravenous thrombolysis in China for patients with ischemic stroke is approximately 1–3% (Jin et al., 2012). Thus, most patients are not given the potential benefit of thrombolysis. Furthermore, there is still a lack of evidence-based medicine for non-thrombolytic patients.

At present, there are more than 100 drugs used clinically for ischemic stroke. The Chinese Quality Evaluation of Stroke Care and Treatment (2009) analyzed current treatments for acute ischemic stroke in China. The study showed that 75.9% (3632/4783) of patients with ischemic stroke received intravenous edaravone, ganglioside, cattle encephalon glycoside and ignotin injection, cinepazide maleate injection, and citicoline. In addition, 83.1% of stroke patients were treated with intravenous or oral Chinese medicines. Over 100 traditional Chinese medicines are used in China, including Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong, puerarin, and Angong Niuhuang injection. Furthermore, antiplatelet drugs such as aspirin can be used 24 hours after thrombolysis (Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke of the Cerebrovascular Disease Section of the Neurology Branch of the Chinese Medical Association, 2010). Studies on the treatment of ischemic stroke are listed in [Table 1].
Table 1: Previous studies on ischemic stroke published from 2016 to 2018 in China

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Novelty and main objective of this study

Neuroprotective agents and traditional Chinese medicines are commonly used in the clinic. Nevertheless, because of the lack of high-quality randomized controlled trials to assess their efficacy and safety, these medicines have not been recommended in the guidelines. The study therefore aims to analyze the current treatment status of acute ischemic stroke in clinical practice. This registry, single-center, ambispective cohort study comprises statistical analysis of clinical treatment plans, treatment outcomes and follow-up results, with the objective of helping to optimize the clinical diagnosis and treatment of ischemic stroke.


  Methods/Design Top


Study design

This registry, single-center, ambispective cohort study will be conducted in Shengjing Hospital of China Medical University, China. Data for 600 cases of acute ischemic stroke from October 2016 to November 2017 were retrospectively collected for trend analysis in January 2018. Data for 1400 cases of acute ischemic stroke have been prospectively collected since February 2018. Treatment options, treatment outcomes, and follow-up results in patients with acute ischemic stroke will be recorded in the clinic.



Stroke patients will be visited five times, as follows: on admission (baseline assessment, visit 1), during medication and treatment in hospital (visit 2), at discharge (visit 3), 90 ± 14 days after treatment (outpatient clinic or telephone follow-up, visit 4) and 360 ± 28 days after treatment (telephone follow-up, visit 5). A detailed description of the assessment items is given in [Table 2].
Table 2: Description of the assessments during the five visits of patients with acute ischemic stroke

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Recruitment

Data for acute ischemic stroke patients from October 2016 to November 2017 were retrospectively collected in January 2018. Acute ischemic stroke patients in the outpatient clinic and Inpatient Department of the Department of Neurology have been recruited since February 2018. Patients who are interested in participating in the study can contact the project leader by telephone, email and WeChat.

Participant selection

Patients with acute ischemic stroke will be recruited.

Inclusion criteria

Patients who meet all of the following criteria will be considered for study inclusion:

  • Accordance with Chinese Guidelines and Consensus on Diagnosis and Treatment of Cerebrovascular Disease (2016 version) (Neurology Branch, Chinese Medical Association, 2016). This includes sudden onset of behavioral signs or disturbance of consciousness confirmed by imaging examination
  • Age ≥ 18, irrespective of sex
  • Provision of informed consent from patients or legal guardians for prospective collection of data


Exclusion criteria

Patients who meet one or more of the following conditions will be excluded from the study:

  • Cranial computed tomography (CT)/magnetic resonance imaging (MRI) images showing cerebral hemorrhage
  • Severe systemic disease; life expectancy less than 3 months.
  • Physicians participating in disease registration are of the opinion that the patient is unlikely to provide continuous follow-up information
  • History of cranial surgery
  • Pregnancy
  • Participation in other clinical studies or trials


Treatment programs

Doctors will choose specific treatment plans for stroke based on the patient's clinical history and symptoms (Neurology Branch, Chinese Medical Association, 2016). The choice, dosage and course of treatment will not be limited.

Specific treatment of acute ischemic stroke refers to the intervention of a specific link in the pathophysiological mechanism of ischemic injury. These treatments include the following: (i) intravenous thrombolytic drugs, such as recombinant tissue plasminogen activator and urokinase; (ii) antiplatelet drugs, such as aspirin and clopidogrel; (iii) anticoagulants, such as unfractionated heparin, low molecular weight heparin, heparinoids, oral anticoagulants and thrombin inhibitors; (iv) plasma volume expanders, such as hydroxyethyl starch and low molecular weight dextran; (v) neuroprotective agents, such as edaravone, citicoline and gangliosides; (vi) drugs for improving cerebral blood flow, such as butylphthalide and urinary kallidinogenase; (vii) traditional Chinese medicines, such as Shuxuetong injection and Danhong injection.

When patients enter the study (visit 1), all accompanying diseases and combined medication will be recorded in detail. During visit at discharge, the changes in any combined medication will be recorded in detail. Combined medication refers to any other drugs except that for acute ischemic stroke given during hospitalization. Nonspecific drugs include dehydrating agents, antihypertensive drugs, lipid-lowering drugs, hypoglycemic agents and anti-infective agents. For each drug, the following information will be collected: general name, dosage, start date, stop date or continuous use, and indications.

Outcome measures

Stroke patients will be visited five times, as follows: on admission (baseline assessment, visit 1), during medication and treatment in hospital (visit 2), at discharge (visit 3), 90 ± 14 days after treatment (outpatient clinic or telephone follow-up, visit 4) and 360 ± 28 days after treatment (telephone follow-up, visit 5). All indicators will be evaluated at the various visits.

Primary outcome measure

National Institutes of Health Stroke Scale (NIHSS) score at discharge (visit 3) will be the main outcome measure. A higher score indicates greater impairment.

Secondary outcome measures

  • NIHSS scores at visits 1 and 2.
  • Modified Rankin Scale (mRS) score at visits 1, 3, 4 and 5 will be used to assess the recovery of neurological function in stroke patients. The higher the score, the worse the neurological function (Wilson et al., 2002).
  • Essen Stroke Risk Score at visit 2. The score is a risk prediction scale for stroke recurrence. The higher the score, the higher the risk of stroke and vascular events (Weimar et al., 2009).
  • Glasgow Coma Scale score at visits 1 and 3 will be used to assess the degree of coma. A lower score indicates a more severe disturbance of consciousness, brain death or poor prognosis (Teasdale and Jennett, 1974).
  • Mini-Mental State Examination at visit 4, only for patients who have been followed up in the hospital. The results can effectively reflect mental state and the degree of cognitive impairment. The lower the score, the worse the mental state and cognitive function (Pangman et al., 2000).
  • Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification at visit 3. TOAST divides ischemic stroke into five types based on clinical features, imaging and laboratory examination, as follows: large-artery atherosclerosis, cardioembolism, small-artery occlusion (lacunar infarct), acute stroke of other determined etiology, and stroke of undetermined etiology (Dziadkowiak et al., 2016).
  • The degree of stenosis and the change in infarct size analyzed using cranial CT/MRI images at visits 1 and 2.
  • Proportion of patients with adverse reactions and death.


Safety evaluation

  • Vital signs, including body temperature, pulse, respiration and blood pressure, will be evaluated at visits 1–3. Changes in body temperature will be measured on the first day of onset at visit 1.
  • Laboratory examination, including conventional blood tests, blood glucose, blood lipids, liver and kidney functions, myocardial enzymes, blood electrolytes and coagulation function at visits 1–3
  • Electrocardiography at visits 1 and 3
  • Incidence of symptomatic intracranial hemorrhage during hospitalization


Adverse events

In accordance with Good Clinical Practice (Bureau No. 3) (China Food and Drug Administration, 2003), Drug Adverse Reaction Reporting and Monitoring Management Measures (Ministry of Health of China No. 81) (Ministry of Health, 2011) and Drug Registration Regulations (Bureau No. 28) (China Food and Drug Administration, 2007), investigators will carry out their relevant duties, and handle, record and report adverse events/serious adverse events.

An adverse event refers to any adverse medical event that occurs after a patient or clinical study subject takes a drug. This event does not necessarily have a causal relationship with the treatment. To minimize the risk to the patients and meet regulatory requirements, the investigator will evaluate the relevance of adverse events and treatment, and determine the classification criteria for the relationship between adverse events and test drugs (definitely related, possibly related, possibly unrelated, definitely unrelated, or undetermined).

Regardless of the type of treatment the subject received, appropriate treatment will be taken immediately for any adverse events. The investigators or authorized personnel will report adverse events to Liaoning Food and Drug Administration and Ethics Committee within 24 hours.

Trial procedure

[Figure 1] shows the flow chart of the study protocol.
Figure 1: Trial flow chart.

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Outcome assessments

The schedule of outcome assessments is shown in [Table 3].
Table 3: Schedule of outcome assessments

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Sample size

To comprehensively collect patient information for different drug combinations and treatments, the patients will be consistently monitored long-term. Data for 600 patients hospitalized in the Department of Neurology of Shengjing Hospital of China Medical University of China from October 2016 to November 2017 were retrospectively collected in January 2018. In addition, data for 1400 cases have been prospectively collected since February 2018, and data collection will continue until February 2021. The study will therefore initially include a total of 2000 cases, although the final number of cases might be less.

Statistical considerations

All data will be analyzed using descriptive statistics. Measurement data will be expressed as the mean, median, standard deviation, the lower quartile (q1), upper quartile (q3), minimum and maximum. The 95% confidence interval of the mean will be calculated. Enumeration data will be expressed as the frequency and relative number. The 95% confidence interval of the rate will be calculated. If necessary, missing information for the visit will be filled in using the Last Observation Carried Forward method.

Included subjects will be assigned to the full analysis set. According to the intention-to-treat principle, this will be the data set of patients who receive at least one treatment regimen and have at least one post-baseline efficacy assessment.

Changes in NIHSS score at visit 3 compared with baseline data. An analysis of variance will be performed if the difference between the scores before and after treatment satisfies normality and variance homogeneity. If this analysis reveals a statistically significant difference, the Bonferroni test will be used for pairwise comparison. Otherwise, the Kruskal-Wallis test will be carried out. If this test indicates statistical significance, the Wilcoxon rank-sum test will be used, and the Bonferroni method will be used to calibrate the P-values for pairwise comparison.

The proportion of patients with good prognosis (mRS score = 0–2), poor prognosis (mRS score = 3–5) and who die (mRS score = 6) at visit 4 will be analyzed using descriptive statistics. Their numbers and proportions will be calculated. Intergroup differences will be compared using the chi-square test or Fisher's exact test. If the difference between groups is statistically significant, the Bonferroni test will be used to adjust the α-value for further pairwise comparison. Safety will mainly be analyzed using descriptive statistics. Incidence of symptomatic intracranial hemorrhagic transformation during hospitalization will be compared using the chi-square test or Fisher's exact test.

The incidence of serious adverse events to products related to the sponsor will be described according to relevant national laws and regulations. Vital signs and laboratory measurements will be statistically described and compared with the baseline using paired t-test or signed rank test. Changes in laboratory and electrocardiogram results before and after treatment will be assessed by cross tabulation.

For the recurrence rate of stroke and incidence of post-stroke dementia, the number and proportion of cases will be described and compared with the chi-square test or Fisher's exact test. If the difference between groups is statistically significant, the Bonferroni test will be used to adjust the α-value for further pairwise comparison. The effects of specific treatments on the different TOAST subtypes of stroke, and the effect of various risk factors and the combined application of different drugs on prognosis will be described by tabular comparison.

After entering the study, a proportion of patients will be analyzed using interim analysis. When the data are collected and loaded into the database, the first interim analysis will be carried out to check whether the core data allows for preliminary and meaningful data analysis. Subsequent interim analysis will be planned and performed as the study progresses, with the objective of analyzing the contents of the entire database.

The data collected in this study may be combined with data from other regions for analysis. In accordance with applicable laws and regulations, the subject's information will be kept confidential.

Data collection and management

The investigator will complete the subject registration form in a consistent and systematic manner so that the subject can be easily identified during and after the study. The subject's identity registration form is a confidential document, and investigators will keep it at the research center. To ensure confidentiality, this registration form will not be duplicated. All research-related reports and letters will use the subject's initials and numerical identifiers to describe the subject.

According to the requirements of the study, we will design the case report form to optimize data collection. The timeline will be used to systematically collect and arrange the clinical data. As the study progresses, we may use an electronic data capture system for data collection. If there is any change, we will apply for ethics review.

After the last visit of the last subject is completed, the full data set will be collected, and the investigator will inform the hospital ethics committee and the relevant person in charge that this study is finished.

This is a case collection study initiated by the hospital department itself. The subject information collected will be mainly used for statistical analyses and eventual publication as a clinical research study. If appropriate, we might also combine our data with those of other hospitals for analysis and publication. In this case, we will indicate the source of the data. Moreover, participating investigators will be acknowledged as authors when the work is published. For the data collected, the subjects’ information will be kept confidential and will be managed in accordance with the laws and regulations. Data will be statistically analyzed by professional statisticians. Anonymized data will be available indefinitely at www.figshare.com.

Data monitoring

Before the start of the study, we will train the relevant personnel involved in the study. We will carefully fill in the relevant information to ensure that the data are reliable. Moreover, to ensure the accuracy of the data, investigators will be required to periodically check the data by bidirectional verification until the end of the study.

Ethics and dissemination

The writing and editing of the study report will be performed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Additional file 1 [Additional file 1]). This study has been approved by the Ethics Committee of Shengjing Hospital of China Medical University of China (approval number: 2017PS40K) (Additional file 2 [Additional file 2]).

This is a non-intervention case collection study. During retrospective collection, because the patients have been discharged, it will not be possible to obtain informed consent. We guarantee not to collect content involving personal privacy, including personal identity. Personal contact information and the real name will not be leaked. If we are able to contact the patient during the telephone follow-up, we will request patient consent. The patient data will not be collected if the patient refuses consent.

During prospective collection, we will obtain informed consent before collecting patient data. Because this is a non-intervention case collection study, we will inform the patients that their treatment will not be affected by their participation. Before a potential subject is selected, the investigator or his authorized staff will explain the purpose, methods, possible benefits, potential risks and any possible discomfort. The investigator will inform the participants that participation in the study is voluntary and that they can withdraw at any time. If subjects refuse to participate in this study, they can still choose other treatments, and this rejection will not affect their future treatment. Finally, the subject will understand that the investigator will maintain his record for long-term follow-up, and their records may be viewed by the officers and sponsors of the drug administration department within the limits of relevant laws and regulations. Subject's privacy will be protected.

This study will only collect and process data that are indispensable for the study of the efficacy, safety, quality and application of the drug. The collection and use of these data will maintain full patient confidentiality and will comply with the relevant laws and regulations that protect the subject's privacy.

Subjects have the right to obtain personal information from the investigator and may request changes to wrong or incomplete data. Appropriate replies will be given to such requests, taking into account their content and purpose, the status of the study, and the relevant laws.

Appropriate technical steps and management measures will be taken to prevent the subjects’ personal information from being obtained and disclosed by unauthorized persons, and from being subjected to accidental or illegal destruction, loss or alteration. Throughout the study period, the relevant personnel who have the right to view the subjects’ personal data will keep them confidential.


  Discussion Top


Contributions and problems of previous studies in this field

At present, intravenous recombinant tissue plasminogen activator is the first choice for the clinical treatment of acute ischemic stroke worldwide. However, the proportion of patients given thrombolysis for ischemic stroke is low in China (Jin et al., 2012). Intravenous thrombolysis, antiplatelet therapy, anticoagulants, blood volume expansion, neuroprotective agents, medications to improve cerebral blood flow, and traditional Chinese medicines are clinically used in China (Chen, 2016; Liu and Yu, 2016; Zeng and Zhao, 2016; Chen et al., 2017; Gao et al., 2017; Huang, 2017; Jiang et al., 2017; Li et al., 2017; Li, 2017; Liu et al., 2017; Xu et al., 2017; Yu and Ma, 2017; Yuan, 2017; Yang et al., 2018).

Characteristics of this study protocol

The China QUEST registry study, evaluating ischemic stroke care and treatment in China, was published only about 10 years ago (Group of the China Quality Evaluation of Stroke Care and Treatment, 2009). In recent years, neuroprotective agents and traditional Chinese medicines have been used clinically to treat acute ischemic stroke. However, there are no guidelines for treatment. Therefore, this study is the first comprehensive analysis of treatment programs, treatment outcomes and follow-up results for acute ischemic stroke.

Limitations of this study

This is a registry cohort study that includes retrospective analysis. Large-sample randomized controlled trials are needed to evaluate and optimize treatment for acute ischemic stroke.

Significance of this study

Our results will provide a foundation for optimizing clinical diagnosis and treatment strategies for acute ischemic stroke.


  Trial Status Top


This study was designed in October 2017 and was approved by the Ethics Committee of Shengjing Hospital of China Medical University of China in December 2017 (approval number: 2017PS40K). This study was registered in December 2017. Subjects with acute ischemic stroke from October 2016 to November 2017 were retrospectively recruited for trend analysis in January 2018. Other subjects began to be prospectively recruited from February 2018, and prospective collection will be finished within 36 months. Each subject will be followed up for 360 days. The follow-up will be completed in November 2021. Data analysis will be finished in November 2022. Recruitment for the prospective analysis is ongoing.

Additional files

Additional file 1: SPIRIT checklist.

Additional file 2: Ethical approval document.

Author contributions

Study design and guidance: JF. Study design and implementation: DH. Data collection and bidirectional verification: SL, XYQ, YG and JL.

Conflicts of interest

The authors declare that the research is conducted in the absence of any commercial or financial relationships that can be construed as a potential conflict of interest.

Financial support

None.

Institutional review board statement

This study has been approved by the Ethics Committee of Shengjing Hospital of China Medical University of China (approval number: 2017PS40K) and follows the Declaration of Helsinki and relevant ethical principles.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms. In the form, the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This study follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of the Shengjing Hospital of China Medical University, China.

Copyright transfer agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data after deidentification (text, tables, figures, and appendices) will be in particular shared. The study protocol and clinical study report will be made public within 6 months after completion of the trial. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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