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. Author manuscript; available in PMC: 2024 Jan 31.
Published in final edited form as: Acad Emerg Med. 2023 Aug 28;30(11):1101–1109. doi: 10.1111/acem.14787

Delayed first medical contact to reperfusion time increases mortality in rural emergency medical services patients with ST-elevation myocardial infarction

Jason P Stopyra 1, Anna C Snavely 1,2, Nicklaus P Ashburn 1,3, Michael W Supples 1, Chadwick D Miller 1, Simon A Mahler 1,4,5
PMCID: PMC10830062  NIHMSID: NIHMS1957190  PMID: 37567785

Abstract

Background:

ST-elevation myocardial infarction (STEMI) guidelines recommend an emergency medical services (EMS) first medical contact (FMC) to percutaneous coronary intervention (PCI) time of ≤90 min. The primary objective of this study was to evaluate the association between FMC to PCI time and mortality in rural STEMI patients.

Methods:

We conducted a cohort study of patients ≥18 years old with STEMI activations from January 2016 to March 2020. Data were obtained from a rural North Carolina Regional STEMI Data Registry, which included eight rural EMS agencies and three PCI centers, the National Cardiovascular Data Registry, and the EMS electronic health record. Prehospital and in-hospital time intervals were digitally abstracted. The outcome of index hospitalization mortality was compared between patients who did and did not meet FMC to PCI time goal using Fisher’s exact tests. Negative predictive value (NPV) for index hospitalization death was calculated with 95% confidence intervals (CIs). A receiver operating characteristic curve was constructed and an optimal FMC to PCI time goal was identified by maximizing NPV to prevent index hospitalization death.

Results:

Among 365 rural EMS STEMI patients, 30.1% (110/365) were female with a mean ± SD age of 62.5 ± 12.7 years. PCI was performed within the 90-min time goal in 60.5% (221/365) of patients. Among these patients, 3% (11/365) died during initial STEMI hospitalization, with 1.4% (3/221) mortality in the group that met the 90-minute time goal compared to 5.6% (8/144) in patients exceeding the time goal (p = 0.03). Meeting the 90-min time goal yielded a 98.6% (95% CI 96.1%–99.7%) NPV for index death. A 78-min FMC to PCI time was the optimal cut point, yielding a NPV for index mortality of 99.3% (95% CI 96.1%–100%).

Conclusions:

Death among rural patients with STEMI was four times more likely when they did not receive PCI within 90 min.

Keywords: disparity, EMS, mortality, prehospital, rural, STEMI

INTRODUCTION

Each year nearly 175,000 patients experience an ST-elevation myocardial infarction (STEMI) in the United States.1 For patients with STEMI, reducing total ischemic time via prompt reperfusion therapy is the principal determinant of improved outcomes.2–4 Preventing delays in STEMI care is associated with decreased mortality, recurrent myocardial infarction (MI), and other morbidities, such as congestive heart failure.5–8 Thus, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend a first medical contact (FMC) to percutaneous coronary intervention (PCI) time of 90 min or less.2 The Mission: Lifeline program provides further guidance for prehospital providers, including rapidly moving from FMC to 12-lead electrocardiogram (ECG) acquisition, limiting scene time, and providing early activation of the PCI center.9 Emergency medical services (EMS) STEMI protocols that include direct transportation to a PCI-capable hospital and prehospital PCI center activation have improved patient outcomes.10–14 Furthermore, when FMC to PCI time is anticipated to be >120 min, the guidelines recommend reperfusion by thrombolysis rather than PCI.2

Many rural EMS agencies fail to consistently achieve the recommended 90-min FMC to PCI time goal.10,11,15–17 Rural Americans are much less likely to receive timely definitive STEMI treatment than their urban counterparts and are therefore exposed to excess morbidity and mortality.18,19 The ACC/AHA endorse the need for prehospital strategies to reduce total ischemic time, particularly in rural settings.20–24 The Centers for Disease Control and Prevention has made achieving health equity and improving cardiovascular health for rural Americans one of the Healthy People 2020 goals because rural Americans are more likely to be unhealthy, older, living in poverty, uninsured, and medically underserved.25,26

Meeting the ACC/AHA 90-min FMC to PCI goal is dependent on care processes at both EMS agencies and receiving hospitals.27–30 Unsuccessful ECG transmission and delayed PCI center activation may negatively affect overall PCI time metrics,5,30–33 but it remains unclear how individual time intervals, such as FMC to ECG and scene time, are associated with mortality in patients cared for by rural EMS agencies. The primary objective of this study was to evaluate the association between FMC to PCI time and index hospitalization mortality in rural STEMI patients. In addition, secondary objectives included evaluating the association between component time intervals and mortality and evaluating the association between component EMS time intervals and to door to PCI time to assess the relationship between prehospital time intervals and any downstream delays in care once at the receiving PCI center.

METHODS

Study design

We conducted a retrospective cohort study of STEMI patients cared for by eight rural North Carolina (NC) county EMS agencies from January 2016 to March 2020. Demographic, medical history, assessment, and time data were abstracted from each EMS agency electronic health record (EHR) and entered into a Research Electronic Data Capture (REDCap) database by study staff. These data were then linked to National Cardiovascular Data Registry (NCDR) data to create a 2016–2020 Rural NC Regional STEMI Data Registry. This study was approved by the Wake Forest University Institutional Review Board and granted a waiver of informed consent. The STROBE guidelines helped direct the research and article development processes.34 A data registry flow diagram is presented in Figure S1. This study was registered at ClinicalTrials.gov (NCT04381260).

Setting and patient population

Patients ≥18 years old who were transported to one of the three registry tertiary care hospitals by a rural EMS agency and received primary PCI for STEMI were included. Interfacility transports and patients with prehospital cardiac arrest were excluded. EMS agencies were selected for participation based on being in a rural county (as defined by the 2014 U.S. Census Bureau American Community Survey) that transports patients to one of three tertiary medical centers with 24/7 PCI capability in the central region of NC (one large academic hospital, two smaller community hospitals). Each agency is continually operated at the paramedic level and receives medical direction from a board-certified emergency physician. All agencies have the authority to activate the catheterization lab, but this activation can be canceled by either the emergency physician or the cardiologist upon review of the transmitted ECG. The chest pain protocol for each agency is largely uniform as it is strongly based on the NC Chest Pain Protocol (Figure S2). All are encouraged to follow the 2013 ACC/AHA guidelines that recommend prehospital identification and activation of cardiac catheterization laboratory.2 Table S1 describes the participating EMS agencies.

Outcomes and measures

The primary outcome was all-cause index hospitalization mortality as determined from the 2016–2020 Rural NC Regional STEMI Data Registry. The primary exposure of interest was the proportion of patients that achieved the 90-min FMC to PCI goal, where FMC to PCI was defined as patient contact time (recorded by EMS personnel after arrival on scene) to first PCI device deployment (angioplasty or stent) time in minutes. A secondary exposure was the proportion of patients meeting the 120-min threshold for thrombolytic administration. In addition, we evaluated FMC to PCI as a continuous time and component time intervals, such as dispatch time, EMS response time, time to first ECG, PCI center activation time, scene time, transport time, total EMS time, and door to PCI time. Dispatch time was the period from when the 911 call was received to when EMS was dispatched. EMS response time was the period from when EMS was dispatched to arrival on scene. Time to first ECG was the period from EMS arrival to first 12-lead ECG being performed. Activation time was the time from first 12-lead ECG acquisition to when the PCI center team was activated. Scene time was the period from EMS arrival on scene to departure from scene. Transport time was the period from EMS scene departure to hospital arrival. Total EMS time was the time from EMS arrival on scene to arrival at the hospital. Door to PCI time was defined as the time of EMS arrival at destination to first PCI device deployment. The 2016–2020 Rural NC Regional STEMI Data Registry was queried to determine patient demographic variables including age, sex, and race and ethnicity, as well as their cardiac risk factors, past medical history, and initial vital signs (systolic blood pressure, heart rate, and oxygen saturation).

Statistical analysis

Descriptive statistics including counts, percentages, means, and standard deviations (SDs) were used to describe the study population. Fisher’s exact tests were used to compare the outcome of index encounter deaths between patients who did and did not meet the 90-min FMC to PCI time goal (primary) and the 120-min thrombolytic threshold (secondary). Ninety-five confidence intervals (95% CI) were also calculated for the difference in index death rates between patients who did and did not meet time goals using a Wald approximation. A receiver operating characteristic curve was constructed and an optimal FMC to PCI time goal was identified by maximizing negative predictive value (NPV) to prevent index encounter death. The goal was to achieve a NPV for the outcome of index death of at least 99% while maintaining an operationally feasible time goal. For each time goal, test characteristics (sensitivity, specificity, NPV, and positive predictive value) were estimated and reported with exact 95% CIs. Negative likelihood ratios and positive likelihood ratios were also estimated and reported along with 95% CIs calculated using the method of Simel et al.35

Continuous times were described using medians, interquartile ranges (IQR), and boxplots and compared between patients with and without index encounter deaths using Wilcoxon rank-sum tests. Hodges–Lehmann estimators were also calculated for the shift in location of the distribution of times for patients with mortality compared to those without mortality. Linear mixed models were used to evaluate the association between component EMS time intervals and door to PCI time to assess the relationship between prehospital time intervals and any downstream delays in care once at the receiving PCI center. Linear mixed models were used to account for clustering of times within agencies. This was not necessary for the mortality outcome as no correlation within agency was observed.

RESULTS

During the study period, 365 rural patients with STEMI were included. The cohort was 30.1% (110/365) female and 6.3% (23/365) non-White, with a mean ± SD age of 62.5 ± 12.7 years. PCI was performed within the 90-min time goal in 60.5% (221/365) of patients and within 120 min in 88.8% 324/365, meaning that 11.2% (41/365) would have been thrombolytics candidates. Mortality during index hospitalization occurred in 3.0% (11/365) of patients. Patient demographics and risk factors are summarized in Table 1.

TABLE 1.

Rural STEMI patient characteristics.

Patient characteristic Total (N = 365) Patients without index mortality (n = 354) Patients with index mortality (n = 11)
Age (years) 62.5 ±12.7 62.2 ±12.6 72.7 ± 13.1
Sex (female) 110 (30.1) 105 (29.7) 5 (45.5)
Race
 White 342 (93.7) 332 (93.8) 10 (90.9)
 Black 18 (4.9) 17 (4.8) 1 (9.1)
 Asian 6 (1.6) 6 (1.7) 0 (0)
 Ethnicity (Hispanic) 1 (0.3) 1 (0.3) 0 (0)
Risk factors
 Current smoking 168 (46.0) 163 (46.0) 5 (45.5)
 Hypertension 250 (68.5) 239 (67.5) 11 (100)
 Hypercholesterolemia 223 (61.1) 215 (60.7) 8 (72.7)
 Diabetes 106 (29.0) 101 (28.5) 5 (45.5)
 BMI (lb./in.2) 29.4 ±5.9 29.5 ±6.0 29.3±5.0
 Prior MI 80 (21.9) 76 (21.5) 4 (36.4)
 Prior PCI 79 (21.6) 74 (20.9) 5 (45.5)
 Prior CABG 21 (5.8) 19 (5.4) 2 (18.2)
 Current dialysis 3(0.8) 3 (0.8) 0 (0)
 Cancer 41 (11.2) 41 (11.6) 0 (0)
 Prior CHF 32 (8.8) 31 (9.0) 0 (0)
 Prior Afib 14 (3.8) 14 (4.0) 0 (0)
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Note: Data are reported as mean ± SD or n (%).

Abbreviations: Afib, atrial fibrillation; BMI, body mass index; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CHF, congestive heart failure; PVD, peripheral vascular disease; MI, myocardial infarction; PCI, percutaneous coronary intervention.

Among patients who met the 90-min FMC to PCI goal the index hospitalization mortality rate was 1.4% (3/221) compared to 5.6% (8/144) in patients who did not meet the 90-min goal (p = 0.03, 95% CI for difference 0.3%–8.8%). Meeting the 90-min time goal yielded a 98.6% (95% CI 96.1%–99.7%) NPV for index death. Patients with FMC to PCI times >120 min had a mortality rate of 14.6% (6/41) versus 1.5% (5/324) in patients with PCI in ≤120 min (p < 0.001, 95% CI for difference 3.0%–28.1%). Meeting the 120-min threshold yielded a 98.5% (95% CI 96.4%–99.5%) NPV for index death. A 78-m in FMC to PCI time was the optimal cut point for rural STEMI patients, yielding a NPV of 99.3% (95% CI 96.1%–100%) for index death. The performances of 78-, 90-, and 120-min FMC to PCI time goals for index encounter mortality are presented and compared in Table 2 and Figure 1.

TABLE 2.

Performance of different cut points for index hospitalization mortality.

Cut Point (min) Sensitivity (95%CI) Specificity (95% CI) PPV (95% CI) N PV (95% CI) +LR (95% CI) −LR (95% CI)
78 90.9% (58.7–99.8%) 39.0% (33.9–44.3%) 4.4% (2.1–8.0%) 99.3% (96.1–100%) 1.49 (1.21–1.83) 0.23 (0.04–1.52)
90 72.7% (39.0–94.0%) 61.6% (56.3–66.7%) 5.6% (2.4–10.7%) 98.6% (96.1–99.7%) 1.89 (1.29–2.78) 0.44 (0.17–1.17)
120 54.5% (23.4–83.3%) 90.1% (86.5–93.0%) 14.6% (5.6–29.2%) 98.5% (96.4–99.5%) 5.52 (2.95–10.30) 0.50 (0.26–0.96)
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Abbreviations: −LR, negative likelihood ratio; +LR, positive likelihood ratio; NPV, negative predictive value; PPV, positive predictive value.

FIGURE 1.

FIGURE 1

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Receiver operating characteristic curve for index hospitalization mortality. AUC, area under the receiver operating characteristics curve.

The median (IQR) FMC to PCI time was 122 (91–138.5) min for patients who had index death and 84 min (IQR 72–98) for those who survived to hospital discharge (p = 0.004). Similarly, for door to PCI time, the median (IQR) was 76 (55.5–97) min for patients who died compared to 42 (33–56) min for those who did not (p = 0.001). Only three of the 11 patients with index hospitalization mortality had a documented delay in PCI (need for intubation, emergent placement of left ventricular support device, “other”). While not statistically significant, there was a potentially clinically meaningful difference in activation time between patients with and without index mortality. The median (IQR) activation time was 28 (9–48) min for patients who died and 15 (8–23) min for those who did not (p= 0.10). Other individual prehospital time components were similar for patients with and without index mortality and are summarized in Table 3 and Figure 2. Time to first ECG acquisition (0.41, 95% CI 0.01–0.82), activation time (0.90, 95% CI 0.82–0.98), and scene time (1.15, 95% CI 0.55–1.75) were all associated with increased door to PCI time. The linear mixed model results are shown in Table 4.

TABLE 3.

Prehospital time intervals stratified by index hospitalization mortality.

Prehospital time interval (min) Total (n = 365)a Patients without mortality (n = 354)a Patients with mortality (n = 11)a Shift in locationb (95% CI) p-valuec
FMC to PCI (n = 365) (PCI time - at patient) 85 (73–99) 84 (72–98) 122 (91–138.5) −29.0 (−51.0 to −9.0) 0.004
Dispatch time (n = 365) (dispatch - call received) 1 (0–2) 1 (0–2) 1 (0–1.5) 0.0001 (−1.0 to 1.0) 0.84
Response time (n = 365) (on scene - dispatch) 9 (6–12) 9 (6–12) 10 (9–12.5) −1.0 (−4.0 to 2.0) 0.39
Time to first ECG (n = 361) (12-lead ECG - at patient) 4 (2–6) 4 (2–6) 4 (3.5–13) −1.0 (−4.0 to 2.0) 0.44
Activation time (n = 327) (cath lab activation - 12-lead ECG) 15 (8–23) 15 (8–23) 28 (9–48) −10.9 (−31.0 to 1.0) 0.10
Scene time (n = 365) (depart scene - on scene) 14 (12–18) 14 (12–17) 15 (13.5–22) −2.0 (−6.0 to 1.0) 0.16
Transport time (n = 365) (at destination - depart scene) 27 (22–33) 26.5 (22–33) 27 (19–30.5) 1.0 (−4.0 to 7.0) 0.67
Total EMS time (n = 365) (at destination - on scene) 41 (35–48) 41 (35–48) 42 (33–50) −2.0 (−9.0 to 6.0) 0.68
Door to PCI time (n = 365) (PCI time - at destination) 43 (33–57) 42 (33–56) 76 (55.5–97) −30.0 (−49.0 to −12.0) 0.001
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Abbreviations: FMC, first medical contact; IQR, interquartile range; PCI, percutaneous coronary intervention.

a

Data are reported as median (IQR).

b

Hodges-Lehmann estimator for the shift in location of the distribution of times for patients with mortality compared to those without mortality.

c

Wilcoxon rank-sum test.

FIGURE 2.

FIGURE 2

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Box plots for time intervals and index hospitalization mortality. FMC, first medical contact; PCI, percutaneous coronary intervention.

TABLE 4.

Associations with door to PCI time (linear mixed model).

Time (min) Estimate (95%CI) p-value
Dispatch time (n = 365) (dispatch - call received) −0.53 (−2.64 to 1.56) 0.63
Response time (n = 365) (on scene - dispatch) 0.37 (−0.22 to 0.93) 0.20
Time to first ECG (n = 361) (12-lead ECG - at patient) 0.41 (0.01 to 0.82) 0.046
Activation time (n = 327) (cath lab activation - 12-lead ECG) 0.90 (0.82 to 0.98) <0.001
Scene time (n = 365) (depart scene - on scene) 1.15 (0.55 to 1.75) <0.001
Transport time (n=365) (at destination - depart scene) −0.28 (−0.63 to 0.13) 0.13
Total EMS time (n = 365) (at destination - on scene) 0.09 (−0.18 to 0.39) 0.52
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Abbreviations: FMC, first medical contact; PCI, percutaneous coronary intervention.

DISCUSSION

This analysis identified that the guideline recommended 90-min FMC to PCI time goal is not achieved in almost 40% of rural STEMI encounters. Patients failing to meet this time goal had a significantly greater chance of index hospitalization death. Prior studies have shown that mortality decreases when system delays in reperfusion are prevented, but until now, this has never been studied specifically in a rural population.7,36,37 We also found that delays in time to ECG acquisition, time to PCI center activation, and scene time were associated with downstream delays in door to PCI time once the patient arrived to the PCI center. Thus, these EMS time intervals may be key modifiable determinants of door to PCI times and major drivers of FMC to PCI time.

Patients who died during the index hospital stay had longer door to PCI times than patients surviving to discharge. The door to PCI time is a critical element in mitigating STEMI-associated mortality. Recognizing this, Mission: Lifeline established the Prehospital Activation of Hospital Resources (PreAct). This approach to STEMI management attempts to standardize prehospital activation for STEMI and has also introduced strategies where prehospital STEMI patients go directly to the cardiac catheterization lab and bypass the emergency department altogether.38 Previous research strongly supports early and efficient PCI lab activation being associated with decreased mortality. While we found that early PCI lab activation is associated with decreased door to PCI time, we did not find a statistically significant mortality benefit associated with early PCI lab activation. However, this study was likely underpowered to detect this key difference, but a clinically meaningful difference of more than 10 min that was observed. Given the limited sample size of this study and the existing body of evidence, it is highly likely that early PCI lab activation decreases door to PCI time and improves mortality among rural EMS STEMI patients.

Rural EMS agencies may also be able to improve patient outcomes by minimizing time to ECG acquisition and by limiting scene time. In our analysis, we found that each of these steps in care are directly associated with door to PCI time. Additionally, previous research demonstrates that prolonged time to ECG acquisition and longer scene times are key rural STEMI care disparities.17 Compared to their urban counterparts, rural STEMI patients have an ECG obtained 1 min later in their prehospital care and spend approximately one additional minute on scene.17 Studnek et al.9 found that for every 1-min delay in calling 9–1-1 to PCI there was a 3% decreased chance of 1-year survival. Therefore, rural EMS agencies have the potential to drastically improve care by addressing these two modifiable parts of prehospital care and may benefit from additional guidance from the destination hospital.

Historically key STEMI time goals have been established by expert opinion driven by limited data (Level B AHA/ACC recommendations). The 90-min FMC to PCI goal and 120-min FMC to PCI threshold for thrombolytics have not been previously evaluated in a rural STEMI population. In our cohort, the optimal FMC to PCI time was 78 min. Patients meeting this time goal had <1% chance of index hospitalization death. However, given the long transport distances associated with rural patients, this 78-min goal may not always be feasible.

Our data suggest that when FMC to PCI times are severely prolonged (>120 min), agencies may need to consider thrombolytics as an alternative to PCI,2 as these patients have a greater odds of surviving when given thrombolytics rather than waiting for PCI.39 Additional research demonstrates that thrombolytics administered by EMS decreases mortality compared to hospital-based thrombolysis.40 In our study, the 11.2% of rural patients who did not receive PCI within 120 min may have benefitted from thrombolysis rather than transport for primary PCI. It is imperative that EMS agencies critically evaluate the decision to transport for PCI on a case-by-case basis because a “one size fits all” approach may result in some patients not meeting the established time benchmarks and being exposed to excess mortality. Rural EMS agencies may consider partnership with online emergency physician medical control to develop and implement a prehospital thrombolysis administration protocol as an alternative if they are frequently unable to achieve the established FMC to PCI benchmark.

LIMITATIONS

This study has limitations. The data set represents EMS agencies in the Piedmont of NC and may not be generalizable to STEMI patients in other rural EMS systems. Only 6.3% of the patient cohort was non-White, which limits generalizability. Additionally, one of the of the region’s four PCI centers did not share data for creating the registry. This may have introduced selection bias. These data are also observational so inferences of causality and ability to determine time between onset of symptoms and call for aide are limited. There were only 11 deaths in the data set, which limited our ability to further explain differences in prehospital care processes as it relates to index hospitalization mortality. Finally, we halted data collection for the registry in March 2020 owing to the COVID-19 pandemic.

CONCLUSIONS

Rural emergency medical services patients with ST-elevation myocardial infarction experience a critical disparity in cardiovascular care as many do not achieve the guideline-based 90-min first medical contact to percutaneous coronary intervention goal. Rural patients who do not meet this goal experience higher rates of index hospitalization mortality. We found that an first medical contact to percutaneous coronary intervention time of 78 min was optimal to prevent index hospitalization mortality in this sample of rural emergency medical services ST-elevation myocardial infarction patients. Rural emergency medical services agencies and their online medical control physicians should take an objective, multifaceted approach to improve their first medical contact to percutaneous coronary intervention times as well as consider alternative treatments for ST-elevation myocardial infarction, such as thrombolytics if a significant delay in percutaneous coronary intervention of >120 min) is anticipated.

Supplementary Material

Supplemental Figure 1
Supplemental Figure 2
Supplemental Table 1

ACKNOWLEDGMENTS

The authors thank David Herrington, MD; Doug Easterling, PhD; Ralph D’Agostino; E. Brooke Lerner, PhD; Scott Rhodes, PhD; Kathryn Weaver, PhD; David Miller, MD; Brennan E. Paradee, MS; Claudia Olivier, PhD; Indra Newman, PhD; and Tom Roth for their assistance with the manuscript.

FUNDING INFORMATION

Dr. Stopyra received research funding from HRSA (H2ARH39976-01-00), Roche Diagnostics, Abbott Laboratories, Pathfast, Genetesis, Cytovale, Forest Devices, Vifor Pharma, and Chiesi Farmaceutici. Dr. Ashburn received funding from NHLBI (T32HL076132). Dr. Snavely received funding from Abbott Laboratories and HRSA (1H2ARH399760100). Dr. Miller received research funding from Siemens, Abbott Point of Care, Creavo Medical Technologies, Grifols, and NHLBI (5U01HL123027); he has a U.S. Patent on cardiac biomarkers for coronary artery disease related to cholesterol esters. Dr. Mahler received funding/support from Roche Diagnostics, Abbott Laboratories, OrthoQuidel Clinical Diagnostics, Siemens, Grifols, Pathfast, Genetesis, Cytovale, Beckman Coulter, and HRSA (1H2ARH399760100); he is a consultant for Roche, Quidel, Genetesis, Inflammatix, Radiometer, and Amgen and the Chief Medical Officer for Impathiq Inc. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award KL2TR001421. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Figure 1
NIHMS1957190-supplement-Supplemental_Figure_1.pdf (124.7KB, pdf)
Supplemental Figure 2
NIHMS1957190-supplement-Supplemental_Figure_2.pdf (122KB, pdf)
Supplemental Table 1
NIHMS1957190-supplement-Supplemental_Table_1.docx (13.2KB, docx)

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