Clinical factors predicting return emergency department visits in chemotherapy-induced febrile neutropenia patients

a b s t r a c t

Background: Although chemotherapy-induced febrile neutropenia (FN) is the most common and life-threatening Oncologic emergency, the characteristics and outcomes associated with return visits to the emergency department (ED) in these patients are uncertain. Hence, we aimed to investigate the predictive factors and clinical outcomes of chemotherapy-induced FN patients returning to the ED.

Method: This single-center, retrospective observational study spanning 14 years included chemotherapy-induced FN patients who visited the ED and were discharged. The primary outcome was a return visit to the ED within five days. We conducted logistic regression analyses to evaluate the factors influencing ED return visit.

Results: This study included 1318 FN patients, 154 (12.1%) of whom revisited the ED within five days. Patients (53.3%) revisited the ED owing to persistent fever (56.5%), with no intensive care unit admission and only one mortality case who was discharged hopelessly. Multivariable analysis revealed that Shock Index >0.9 (odds ratio [OR]: 1.45, 95% confidence interval [CI], 1.01-2.10), thrombocytopenia (<100 x 103/uL) (OR: 1.64, 95% CI, 1.11-2.42), and lactic acid level > 2 mmol/L (OR: 1.51, 95% CI, 0.99-2.25) were associated with an increased risk of a return visit to the ED, whereas being transferred into the ED from other hospitals (OR: 0.08; 95% CI, 0.005-0.38) was associated with a decreased risk of a return visit to the ED.

Conclusion: High shock index, lactic acid, thrombocytopenia, and ED arrival type can predict return visits to the ED in chemotherapy-induced FN patients.

(C) 2023

  1. Introduction

Chemotherapy-induced febrile neutropenia (FN) is the most common and life-threatening oncologic emergency. FN patients present various morbidity and mortality risks regarding their baseline

Abbreviations: FN, Febrile neutropenia; ED, Emergency department; MASCC, Multinational Association for Supportive Care in Cancer; CISNE, Clinical Index of Stable Febrile Neutropenia.

* Corresponding author at: Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul 06351, Republic of Korea.

E-mail address: [email protected] (S.U. Lee).

characteristics, response to initial therapy, and the development of seri- ous adverse outcomes in the emergency department (ED) [1,2]. For screening low-risk FN, Risk-stratification tools such as the Multinational Association for Supportive Care in Cancer (MASCC) and Clinical Index of Stable Febrile Neutropenia (CISNE) scores have been developed [3-5].

The performance of CISNE and MASCC scores was validated in the ED [6,7]. However, guideline compliance of disposition for FN was poor [8,9]. Although low-risk patients can be discharged safely after ED treatment, emergency physicians tend to overtreat and unnecessarily hospitalize these patients [10-12].

During the COVID-19 pandemic, emergency physicians had to discharge more patients than in their usual ED practice owing to the shortage of Hospital resources [13,14]. In addition, they had to consider other clinical or systemic factors such as ED boarding time, overall


0735-6757/(C) 2023

assessment of patients, limitED capacity of Hospital beds, and MASCC or CISNE scores [15-20].

FN patients are recommended to avoid unnecessary Hospital visits because they are vulnerable to infection [21-23]. Hence, identifying the risk factors for the return visit to the ED in these patients is important. Therefore, we aimed to investigate the predictive factors and clinical outcomes of return visits to the ED in FN patients and provide clinicians a review of available resources, thereby enabling them to make informed Clinical decisions on ED disposition.

  1. Methods
    1. Study design and data source

The present study was a single-center retrospective observational study of FN patients discharged from an ED between January 2008 and December 2021. Data were extracted from the Clinical Data Warehouse of Samsung Medical Center (DARWIN-C), a tertiary academic hospital in South Korea with an average of 200 ED visits per day and approxi- mately 250,000 cancer patients visiting the outpatient department annu- ally. Additionally, we reviewed Electronic medical records to assess adverse outcomes and the burden of illness.

FN patients visiting the ED in our hospital underwent the following process. ED physicians initially assessed the patients and recom- mended consultation with a hematologist or oncologist if necessary. Subsequently, they decided to discharge patients based on the general condition, Clinical scores, expert opinions, and boarding time in the ED. This study was approved by our institution’s Institutional Review Board (IRB) (IRB No. 2022-01-007). Informed consent was waived owing to the observational nature of the study.

    1. Participants

We included all adult patients with chemotherapy-induced FN who visited the ED and were discharged. Patients with absolute Neutrophil counts of <1000 cells/mm3 and a history of undergoing chemotherapy within one month from the date of the visit to the ED were considered to have developed chemotherapy-induced neutropenia. We specified fever as any recorded temperature > 38.0?C. We excluded patients aged <19 and if the ED outcome was an admission, transfer out, or death. Additionally, patients who visited the ED to issue official docu- ments such as medical statements or diagnosis reports or who Left without being seen were also excluded.

    1. Data collection

An ED specialist studying data science extracted the data. Two ED specialists with work experience of >5 years reviewed the EMR charts separately in half and discussed unclear cases if necessary. We investi- gated the patients’ demographics, initial vital signs, initial mental status, cancer type (namely diagnosis) and cancer staging (based on TNM combinations), treatment setting (neoadjuvant, adjuvant, and advanced or palliative), route of ED visit (direct visit, referred from outpatient part, and transfer in from other hospitals) and initial laboratory test. The initial vital signs included systolic blood pressure (SBP), diastolic blood pressure , pulse rate (PR), respiratory rate (RR), body temperature (BT), and shock index. The shock index was defined as PR divided by SBP.

We collected additional information through EMRs on the adverse

clinical outcomes, cause of revisit, and ED outcomes in return visit patients. Moreover, we investigated the patients who were readmitted to the hospital after ED discharge through other means such as direct transfer from other urgent care facilities, other hospital wards or inten- sive care unit (ICU).

We reviewed the EMR chart and blood culture, urine, cerebrospinal

fluid, and radiological (chest radiograph, chest/abdomen/neck CT, e.g.)

test reports of patients who revisited the ED to identify the infection source. Patients with unclear diagnoses regarding the source of infec- tion were defined as having “fever of unknown infection source.”

We retrospectively calculated the MASCC and CISNE scores by reviewing the EMR chart. Patients described as “well appearing” or “no symptom or sign” were assigned “none or mild” for the burden of illness in the MASCC score; those with significant distress, symptoms, or signs were assigned “severe;” and those who did not belong to the abovementioned categories were assigned “moderate.” Patients with missing Eastern Cooperative Oncology Group (ECOG) categories and unclear or inaccessible information in their EMR charts were assigned the ECOG performance status of 0. For example, we assumed that a pa- tient did not have mucositis if the related finding was not documented in their EMR.

    1. Study outcomes

The primary outcome was a return visit to the ED within five days. We set the endpoint by considering previous research that defined a “favorable outcome” as fever resolution for five consecutive days with- out a serious medical complication [5]. The secondary outcome was the clinical presentations and adverse outcomes at ED revisit. We also selected the adverse outcomes based on complications of the MASCC risk index. The adverse outcomes included hypotension (systolic pres- sure < 90 mmHg or requiring inotropes), acute respiratory failure (SaO2 < 90% or PaO2 < 60 mmHg with room air or need for mechanical ventilation), acute kidney injury (increase in creatinine to >=1.5x base- line), acute heart failure (including new-onset or worsening peripheral edema, ascites, pulmonary edema, increased supplemental oxygen demand), arrhythmia, and major bleeding (requiring transfusion of two units of RBCs).

    1. Statistical analysis

All continuous and categorical variables were reported as medians (interquartile range [IQR]) after normality test and numbers (percent- ages), respectively. To test the differences in characteristics between non-revisit and revisit groups, a Mann-Whitney test was applied for continuous variables. Chi-square test or Fisher’s exact test, whichever appropriate, was used for comparing categorical variables. We conducted univariable and multivariable logistic regression analyses to evaluate the factors associated with the return visit to the ED. We selected age, sex, and variables with a P-value <0.1 in univariable anal- ysis to apply the multivariable logistic regression model. Variables with clinical and statistical multi-collinearity were excluded from the multivariable model. Previous literature was referred to predict adverse outcomes related to blood test cutoff values in FN patients visiting the ED [5,24]. The results were reported as odds ratio (OR) and a 95% confidence interval (CI). A two-sided P-value <0.05 was considered sta- tistically significant for all statistical analyses, which was performed using R Software (version 4.1.2, the R Foundation for Statistical Comput- ing, Vienna, Austria, https://www.R-project.org).

  1. Results
    1. Study population

Of the 5908 chemotherapy-induced FN patients who visited the ED between January 2008 and December 2021, 151 were aged <19, 4357 were admitted to the hospital, 54 were transferred to another hospital, and 21 died in the ED; 1325 were discharged from the ED. Subsequently, we excluded seven patients (five patients left without being seen and two patients only visited for a medical certificate). Of these patients, 154 (12.1%) revisited ED within 5 days; 1318 patients were included in the final analysis (Fig. 1).

Fig. 1. Patient selection diagram. ED: emergency department.

    1. Patient characteristics

Table 1 summarizes the baseline characteristics of the study popula- tion. The median (IQR) age was 55.0 (19.8) years, and 903 (68.5%) patients were female. Hematologic malignancies were present in 314 (19.4%) patients. Of the 1063 solid tumors, breast cancer (46.4%) was the most common, followed by Lung cancer (13.5%) and pancreatic cancer (3.8%), and 354 (38.6%) patients were in TNM stage IV. Of the 1325 patients who were discharged from the ED, 1190 (90.3%) were at MASCC low risk and 336 (25.5%) and 505 (38.3%) were at CISNE low and intermediate risk, respectively. Detailed information about the two groups is provided in the Supplementary Table 1.

    1. Characteristics and clinical outcomes of patients returning to the ED

Table 2 summarizes the clinical information of patients who returned to the ED. A total of 154 patients revisited the ED within 5 days. Median (IQR) age of these patients was 56.5 (27.0) years, and 102 (66.2%) patients were female. More than half (53.3%) of the patients who had returned to the ED revisited the ED owing to persistent fever, followed by those who revisited for coughing or sputum (20.1%), diarrhea (7.1%), abdominal pain (4.6%), dyspnea (4.6%), and general weakness (2.0%). Five patients (3.3%) revealed positive blood culture test results and were hence asked to return to the ED. Eighty-five (55.2%) patients were discharged after ED management, 67 (43.5%)

Table 1

Baseline characteristics of the patients.


Overall patients

Non-return visit patients

Return visit patients


(n = 1318)

(n = 1164)

(n = 154)

Age, median (IQR)

55.0 (19.8)

54.0 (19.0)

57.0 (20.0)


Female, n (%)

903 (68.5)

801 (68.8)

102 (66.2)


Tumors, n (%)



178 (13.5)

152 (13.1)

26 (16.9)


29 (2.2)

26 (2.2)

3 (2.0)


31 (2.4)

29 (2.5)

2 (1.3)


50 (3.8)

46 (4.0)

4 (2.6)


611 (46.4)

556 (47.8)

55 (35.7)

Other solid malignancya

144 (10.9)

125 (10.7)

19 (11.7)

leukemia and hematology malignancy

TNM stagingb, n (%)

314 (19.4)

269 (23.1)

45 (29.2)


Stage I-III

709 (53.8)

613 (52.7)

96 (62.3)

Stage IV

354 (26.9)

310 (26.6)

44 (28.6)

Treatment setting, n (%)



349 (26.5)

316 (27.2)

33 (21.4)


356 (27.0)

310 (26.6)

46 (29.9)

First-line treatment for advanced disease

163 (12.4)

138 (11.9)

25 (48.7)

Second (subsequent)-line treatment

379 (28.8)

340 (29.2)

39 (25.3)


71 (5.4)

60 (5.2)

11 (7.1)

MASCC score, n (%)


low risk

1190 (90.3)

1049 (90.1)

141 (94.6)

high risk

128 (9.7)

115 (9.9)

13 (8.4)

CISNE score, n (%)


low risk

336 (25.5)

304 (26.1)

32 (20.8)

intermediate risk

505 (38.3)

452 (38.8)

53 (34.4)

high risk

477 (36.2)

408 (35.1)

69 (44.8)

MASCC, Multinational Association for Supportive Care in Cancer.

CISNE, Clinical Index of Stable Febrile Neutropenia; BMT, bone marrow transplantation; IQR, interquartile range.

MASCC <21 was classified as high-risk group. CISNE score was categorized as follows: 0, low; 1-2, intermediate; and > 3, high risk.

a Sarcoma (53), Ovarian (30), Esophageal cancer (23), Bladder (17), Head and neck (13), Cholangiocarcinoma (5), Hepatocellular carcinoma (2), Prostate (1).

b Only for solid cancer.

Table 2 General characteristics and clinical outcomes of emergency department (ED) return visits (n = 154).

Variables N, %

Age, median (IQR) 56.5 (27.0)

Sex, n (%) 102 (66.2)

Initial vital sign, median (IQR)

Systolic blood pressure

108.7 (26.2)

Diastolic blood pressure

71.0 (13.5)

Pulse rate

106.5 (19.8)

Respiratory rate

19.0 (2.3)

Body temperature

37.6 (0.8)

Initial mental status


150 (97.4)


1 (0.7)


0 (0.00)


1 (0.7)


2 (1.3)

Chief complaints of ED revisit


82 (53.3)

Abdominal pain

7 (4.6)


11 (7.1)

Coughing or sputum

31 (20.1)


7 (4.6)

General weakness

3 (2.0)

Requested to return ED

5 (3.3)


8 (5.2)

Adverse clinical outcomes

14 (9.1)


6 (2.0)

Acute kidney failure

4 (2.6)

Acute heart failure/Arrhythmia

2 (1.3)

Acute respiratory failure

4 (2.6)

Major Bleeding

1 (0.7)


35 (22.7)

ED outcome


85 (55.2)


67 (43.5)


1 (0.7)


1 (0.7)

ED initial laboratory findings, median (IQR)

absolute neutrophil count, x103/uL

0.3 (0.4)

Hemoglobin, g/dL

9.5 (1.6)

Platelet, x103/uL

143.0 (110.0)

Total bilirubin, mg/dL

0.7 (0.8)

Total protein, g/dL

6.2 (0.4)

Albumin, g/dL

3.6 (0.3)

CRP, mg/dL

8.2 (8.6)

Creatinine, mg/dL

0.7 (0.4)

Lactic acid, mmol/L

1.9 (2.5)

Infection source

Urinary tract infection

9 (5.8)

Colitis or enteritis

11 (7.1)


18 (11.7)

Severe oral mucositis

4 (2.6)

Catheter related infection

3 (2.0)


9 (5.8)

Unknown origin

100 (64.9)

IQR, interquartile range.

a Dizziness, bleeding episode, headache, palpitations, skin rash, syncope, chest dis- comfort, nausea and vomiting.

b Cellulitis (2), peritonsillar abscess (2), sinusitis (2), anal abscess (1), epididymitis (1), meningitis (1).

* Hopeless discharge.

were admitted to the general ward, and none were admitted to the ICU. One patient who was discharged in a hopeless condition at the first ED visit had died at an ED return visit. One patient was transferred to another facility after a return visit and revealed a favorable condition at the outpatient department during a follow-up visit 10 days later.

Fourteen (9.1%) revisit patients presented with adverse clinical outcomes. Of these, six (2.0%) had hypotension, four (2.6%) had acute kidney failure, and four (2.6%) had acute respiratory failure. Two pa- tients presented with acute heart failure or arrhythmia, and only one (0.7%) patient had a major Vaginal bleeding event. Thirty-five (22.7%) patients were diagnosed with bacteremia (defined as having one or

more positive blood cultures). Pneumonia (11.7%) was the most common source of infection, followed by colitis or enteritis (7.1%) and urinary tract infection (5.8%); 100 (64.5%) patients were defined as having FUO.

    1. Predicting the ED return visit

The univariate logistic regression analysis indicated that the type of tumors, shock index (pulse rate [PR]/ systolic blood pressure [SBP]), the CISNE score, the type of ED arrival, platelet count, and lactic acid level of patients at the first ED visit were associated with a return visit to the ED (Table 3).

The multivariable analysis revealed that the shock index (PR/ SBP) > 0.9 (OR: 1.45, 95% CI, 1.01-2.10), platelet count <100,000/uL

(OR: 1.64, 95% CI, 1.11-2.42), and lactic acid level >= 2 mmol/L (OR: 1.51, 95% CI, 0.99-2.25) were associated with increased risk of a return visit to the ED, whereas being transferred into ED from other hospitals (OR: 0.08; 95% CI, 0.005-0.38) was associated with decreased risk of a return visit to ED.

  1. Discussion

To our knowledge, this is the first study predicting the return visit to the ED in chemotherapy-induced FN patients. Clinical outcomes of discharged FN patients have rarely been studied because they tend to be hospitalized more than that recommended by the guideline [8,9,12]. Therefore, we investigated the clinical outcomes and predictive factors of a return visit to the ED in a hospital with limited resources and overcrowded ED environments.

The MASCC and CISNE scores are calculated for risk stratification and FN disposition [3,25]. In contrast, we used these scores as candidate var- iables to predict return visits to the ED among discharged patients with various risk factors. Our study population included 128 (9.71%) and 477 (36.19%) high-risk MASCC and CISNE patients, respectively. Despite the high-risk scores, emergency physicians discharged patients by consid- ering their clinical factors, such as laboratory findings, reported symp- toms, response to ED treatment, or hospital resources. Only 1.1% of total discharged patients showed adverse outcomes, which was compa- rable to the risk of adverse outcomes in the CISNE low-risk group [4].

Although we could not evaluate the clinical outcomes of patients who did not return to the ED, no patient with FN was admitted owing to adverse outcomes within 7 days after ED discharge, as indicated by the EMR review. In addition, there was no direct transfer into ward/ ICU from other hospitals. Moreover, we investigated EMR charts of discharged patients and found that all patients visited the outpatient department or were admitted to the ward for scheduled chemotherapy within 30 days after ED discharge.

Patients with a high shock index, high lactic acid levels, and throm- bocytopenia were more likely to return to the ED. In contrast, patients transferred to the ED from other hospitals were less likely to revisit the ED. Shock index and lactic acid were related to dehydration and hy- povolemia [26,27]. In patients experiencing profound gastrointestinal side effects of chemotherapy, prolonged poor oral intake or diarrhea can induce dehydration [28-30]. The presence of lactic acid >=2 or a shock index >0.9 may indicate gastrointestinal side effects of a high grade and hence the need for IV hydration and observation for symptom recovery.

Shock index and lactic acid are also related to sepsis [31-33]. In addition to patients with sepsis or dehydration, lactic acid can be ele- vated in those with advanced or metastatic cancer, reflecting that a high tumor burden is associated with a hypermetabolic state [34-36]. Lactic acid elevation is a significant independent factor to predict an ED return visit. For patients with high shock index and lactic acid levels categorized as a low-risk group, longer ED treatment or short-term admission for supportive care was recommended.

Table 3

Logistic regression analysis of factors predicting emergency department (ED) return visits.

Univariable model

Multivariable model

Total (n = 1318)

Revisit (n = 154)

Odds ratio (95% CI)


Odds ratio (95% CI)


Age, median (IQR)

54.1 (13.1)

55.7 (13.0)

1.01 (1.00-1.02)


1.01 (1.00-1.02)


Sex, n (%)



102 (11.3)

0.89 (0.63-1.28)


1.22 (0.82-1.84)


Tumors, n (%)

Hematologic malignancies ?


45 (14.3)

1.37 (0.94-1.98)


1.03 (0.67-1.56)


Systolic blood pressure a

< 90


0 (0)

0.15 (0.001-1.04)


Diastolic blood pressure

< 60


14 (10.9)

0.91 (0.49-1.58)


Pulse rate

> 120


49 (14.5)

1.14 (0.79-1.62)


Respiratory rate

> 24


3 (16.7)

1.52 (0.35-4.68)


Body temperature

> 39


31 (12.7)

1.13 (0.73-1.69)


Shock index (PR/SBP)

> 0.9


102 (13.9)

1.48 (1.05-2.12)


1.45 (1.01-2.10)


Duration of neutropenia <1000, n (%)

> 7 days


13 (13.7)

1.22 (0.63-2.17)


Chemo cycle, n (%)

Not 1st


97 (11.5)

0.96 (0.68-1.37)


CISNE score, n (%)

intermediate risk


53 (10.5)

1.11 (0.71-1.78)


1.02 (0.64-1.64)


high risk


69 (14.5)

1.61 (1.04-2.53)


1.34 (0.84-2.16)


MASCC score

high risk


13 (10.2)

0.84 (0.44-1.48)


Route of ED visit

Outpatient part


9 (18.4)

1.62 (0.72-3.25)


1.33 (0.58-2.74)


Transfer in


1 (1.1)

0.08 (0.005-0.36)


0.08 (0.005-0.38)


Absolute Neutrophil Count, x103/uL

< 0.5 923 107 (11.6) 0.97 (0.68-1.41) 0.874

Hemoglobin, g/dLb

< 8.0


18 (17.5)

1.68 (0.95-2.82)


Platelet, x103/uL

< 100


67 (16.4)

1.85 (1.31-2.60)


1.64 (1.11-2.42)


Creatinine. mg/dL

>= 2


2 (15.4)

1.38 (0.21-5.20)


Total bilirubin, mg/dL

>= 2


6 (15.4)

1.39 (0.52-3.14)


Total protein, g/dL

< 6.4


69 (13.0)

1.23 (0.88-1.73)


Albumin, g/dL

< 3 23 3 (13.0) 1.14 (0.27-3.36) 0.838

CRP, mg/dL

>= 7 386 45 (11.7) 1.00 (0.68-1.43) 0.985

Lactic acid, mmol/L

>= 2 228 38 (16.7) 1.68 (1.12-2.48) 0.011 1.51 (0.99-2.25) 0.049

CI, confidence interval; IQR, interquartile range.

* Lymphoma, acute leukemia, chronic leukemia, myelodysplastic syndrome, multiple myeloma.

a The Firth method was applied in univariable analysis.

b Hemoglobin, g/dL was excluded from the multivariable model due to multi-collinearity with Platelet.

Thrombocytopenia is associated with the grade of bone marrow suppression [37,38]. Other laboratory findings, such as an atypical neu- trophil count, monocyte, and hemoglobin, also reflected bone marrow suppression. Of these, the platelet count was statistically significant in predicting a return visit to the ED. Similarly, thrombocytopenia is reportedly strongly associated with poor outcomes in cancer patients with FN [24].

The revisit rate was low when the route of ED visit involved being “transferred in from other hospitals” and for patients with confirmed discharge after ED treatment. We inferred that in our country, when FN patients visited a nearby ED, they were provided with Intravenous antibiotics and referred to tertiary hospitals, regardless of disease sever- ity, for further evaluation and a decision for hospitalization. Conse- quently, patients who were referred and had confirmed discharge had longer hospitalization time, and these factors would have led to the low ED revisit rate.

    1. Limitation

First, our study had the potential for misclassification bias because we measured the burden of illness as MASCC score by reviewing the pa- tients’ EMR charts. Additionally, we assumed values for missing data as a lower risk; hence, the risk underestimation for patients returning to the ED may affect the result. However, for most of the assumed vari- ables, abnormalities must be severe to significantly change CISNE or MASCC scores (e.g., ECOG or mucositis grade should be >=2). We believe that the degree of misclassification bias is less serious than it initially ap- pears. Second, our study design did not permit the direct assessment of data regarding visits to other hospital or death after ED discharge. How- ever, the follow-up visit records after ED discharge revealed no cases of mortality among the non-ED-revisit patients. Third, some of the ED return visits might have been due to concerning test results. Finally, the significant predictive factors can differ from other centers or

countries because of the single-center study design. However, the pre- dictive values, characteristics, and adverse outcomes of this large study population can help emergency physicians to make a decision on ED disposition.

  1. Conclusion

High shock index, high levels of lactic acid, thrombocytopenia, and ED arrival type can predict ED return visits in chemotherapy-induced FN.


Not Applicable.

CRediT authorship contribution statement

Sejin Heo: Writing – original draft, Investigation, Formal analysis, Data curation, Conceptualization. Kyeongman Jeon: Supervision. Boram Park: Formal analysis. Ryoung-Eun Ko: Methodology. Taerim Kim: Investigation. Sung Yeon Hwang: Investigation. Hee Yoon: Visu- alization. Tae Gun Shin: Methodology. Won Chul Cha: Resources. Se Uk Lee: Writing – original draft, Supervision, Project administration, Conceptualization.

Declaration of Competing Interest

The authors have no potential conflicts of interest to disclose.


We appreciate Ok Soon Jeong, Department of Data Service Team of Samsung Medical Center for assistance in extracting data from the CDW and advising data management.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2023.02.012.


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