Hellenic Journal of Cardiology xxx (xxxx) xxx

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Hellenic Journal of Cardiology

journal homepage: http://www.journals.elsevier.com/
hellenic-journal-of-cardiology/

Original Article

Clinical phenotypes according to diuretic combination in acute heart

failure
Raquel Lo
pez-Vilella 1, 2, *, Pablo Jover Pastor 2, Víctor Donoso Trenado 1, 2,

nchez-La
Ignacio Sa
zaro 1, 2, 3, Luis Martínez Dolz 2, 3, Luis Almenar Bonet 1, 2, 3
1
Heart Failure and Transplantation Unit, Hospital Universitari i Polit
ecnic La Fe, Valencia, Spain
2
Cardiology Department, Hospital Universitari i Polit
ecnic La Fe, Valencia, Spain
3
n Biom

Centro de Investigacio edica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Background: The treatment of congestion in heart failure (HF) is a challenge despite the therapeutic
Received 18 December 2022 arsenal available. The aim of this study was to analyze different combinations of diuretics used to resolve
Received in revised form congestion in patients admitted for decompensated HF and to define clinical profiles according to these
28 March 2023
treatments.
Accepted 31 March 2023
Available online xxx
Methods: Single-center study of 1,559 patients admitted for decompensated HF was done between 2016 and
2020. Patients were grouped according to the diuretic combination that led to clinical stabilization and
discharge from the hospital: (1) Loop diuretic. (2) Loop diuretic þ distal tubule (antialdosterone ± thiazides).
Keywords:
heart failure
(3) Loop diuretic þ distal þ proximal tubule (acetazolamide ± SGLT2 inhibitor). (4) Loop diuretic þ distal
congestion tubule þ collecting duct (tolvaptan). (5) Loop diuretic þ distal þ proximal þ collecting duct. Based on these
diuretics diuretic combinations, profiles with clinical, analytical, and echocardiographic differences were established.
clinical profiles Results: There were more previous hospitalizations in groups 4 and 5 (p ¼ 0.001) with a predominance of
treatment pulmonary congestion in profiles 1 and 2 and systemic congestion in 3, 4, and 5. Creatinine and CA125 were
higher in profiles 4 and 5 (p ¼ 0.01 and p ¼ 0.0001), with no differences in NT-proBNP. Profiles 4 and 5 had a
higher proportion of dilatation and depression of right ventricular (p ¼ 0.0001) and left ventricular
(p ¼ 0.003) function. Diuretic therapy-defined groups showed difference in clinical characteristics.
Conclusions: The diuretic treatment used identifies five clinical profiles according to the degree of
congestion, renal function, CA125, and right ventricular functionality. These profiles would guide the best
diuretic treatment on admission.
© 2023 Hellenic Society of Cardiology. Publishing services by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction producing a diuretic effect of varying intensity. The indication for

Heart failure (HF) is a clinical syndrome that invariably causes
congestion and leads to clinical decompensation, often requiring
hospitalization for stabilization. These symptoms of congestion
manifest themselves mainly at pulmonary, systemic, or mixed
levels. Currently, a large number of drugs are available for the
treatment of congestion that acts on different areas of the nephron
Abbreviations: AF, Atrial fibrillation; HF, Heart failure; iSGLT2, Sodium-glucose
cotransporter 2 inhibitors; LV, Left ventricle; RAASi, Renin-angiotensin-aldosterone
system inhibitors; RV, Right ventricle; TAPSE, Tricuspid annular systolic excursion.
* Corresponding author. Heart Failure and Transplantation Unit, La Fe University
and Polytechnic Hospital, 106, Fernando Abril Martorell Av, PC 46026, Valencia,
Spain.
E-mail address: lopez_raqvil@gva.es (R. Lo
pez-Vilella).
Peer review under responsibility of Hellenic Society of Cardiology.
one or the other does seem to depend exclusively not only on the
location of the congestion but also on other clinical characteristics
of the patient. This study aims to analyze whether, in patients with
decompensated HF, the different types and combinations of
diuretic drugs used to resolve congestive conditions are related to
the clinical profile of the patients.
2. Methods
This is a retrospective single-center study, conducted on an
initial cohort of 3,688 patients admitted consecutively with a
diagnosis of acute HF from January 2016 to December 2020. All
patients from the emergency department whose admission diag-
nosis was related to cardiac decompensation (pulmonary conges-
tion, acute pulmonary edema, decompensated HF, congestive HF,

https://doi.org/10.1016/j.hjc.2023.03.009
1109-9666/© 2023 Hellenic Society of Cardiology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).

pez-Vilella, P. Jover Pastor, V. Donoso Trenado et al., Clinical phenotypes according to diuretic combination in acute
Please cite this article as: R. Lo
heart failure, Hellenic Journal of Cardiology, https://doi.org/10.1016/j.hjc.2023.03.009

pez-Vilella, P. Jover Pastor, V. Donoso Trenado et al.
R. Lo Hellenic Journal of Cardiology xxx (xxxx) xxx

and low output) were included. The database was completed pro-
spectively, as patients were admitted. Patients admitted on a
scheduled basis or transferred from other centers for diagnostic-
therapeutic or drug tolerance studies were excluded. Patients
who died during admission were also excluded, as well as those
with infrequent diuretic combinations that did not allow their
analysis. The exclusion of deceased patients was done because the
intention was to analyze the diuretic combination with which the
patients had stabilized and allowed hospital discharge, to know the
treatment administered that had been beneficial in each clinical
profile (if the patient dies during admission, it is not possible to
know how the evolution during admission would have been).
Finally, the total number of patients analyzed was 1,559 (Fig. 1).
Patients were grouped into the five diuretic combinations most
frequently used for clinical stabilization. These were: 1) Loop di-
uretics (only furosemide was included as a loop diuretic, as it is the Figure 2. Profiles according to diuretic treatment administered during hospitalization.
one used in the center). 2) Loop diuretics plus distal convoluted Abbreviations: CD: collecting duct; D. loop: loop diuretics; DCT: distal convoluted
tubule (mineralocorticoid receptor antagonists and/or thiazides). 3) tubule; PCT: proximal convoluted tubule.
Loop diuretic þ distal convoluted tubule plus proximal convoluted
tubule (acetazolamide and/or sodium-glucose cotransporter 2 in- assessing both clinical signs (weight, diuresis, assessment of jugular
hibitors - iSGLT2-). 4) Loop diuretic þ distal convoluted tubule plus ingurgitation, pulmonary auscultation) and signs on complemen-
collecting duct (tolvaptan). 5) Loop diuretic þ distal convoluted tary examinations (pulmonary X-ray, echocardiographic assess-
tubule þ proximal convoluted tubule þ collecting duct (Fig. 2). ment of the inferior vena cava). No cut-off point was defined in
Clinical variables, HF etiology, history of cardiovascular risk, the terms of analytical biomarkers to decide on discharge of patients.
predominant type of congestion, associated drugs during treat- The study was approved by the Biomedical Research Ethics
ment, analytical parameters of renal function and biomarkers of Committee of the Center. In addition, the ethical principles for
myocardial stress and congestion, days of hospital stay, and medical research in human subjects as defined by the Declaration
biventricular echocardiographic assessment were analyzed. Echo- of Helsinki were followed.
cardiographic values to determine right ventricular dimension and
function were the standard values according to guidelines (baseline 2.1. Statistical analysis
diameter, tricuspid annular systolic excursion (TAPSE), S0 wave
velocity, and shortening fraction)1. Right ventricular dysfunction Continuous variables are summarized as a median and inter-
was defined as TAPSE <17 mm, S'wave <9.5 cm/sec, or right ven- quartile range because all of them did not show a normal distri-
tricular fractional area change <35%1. Patients were classified in the bution (Kolmogorov-Smirnov test with p < 0.05). Categorical
“low cardiac output” group when they required inotropic and/or variables are summarized as frequency (percentage). Comparison
vasopressor support. The analytical and echocardiographic data between groups was performed using the Kruskal-Wallis test for
were referred to as the first data obtained when the patient is continuous variables and Fisher's exact test or the Chi-square test
admitted to the hospital. This was usually for a blood test at the for categorical variables. All tests were two-tailed, establishing
time of admission and for echocardiography within 24-48 hours. statistical significance for a p-value <0.05. The statistical programs
Patients were discharged when the objective clinician had used were IBM SPSS Statistics Version 27® and Stata® Statistics/
improved both the patient's symptoms and signs of congestion, Data analysis version 16.1.

Figure 1. Patient selection flow chart. Abbreviations: CD: Collecting duct; Loop D.: Loop diuretics; HF: Heart failure; DCT: Distal convoluted tubule; PCT: Proximal convoluted
tubule.

2

pez-Vilella, P. Jover Pastor, V. Donoso Trenado et al.
R. Lo
3. Results
3.1. Clinical characteristics and treatment of the study population
Significant differences were found between the study variables
according to the clinical profile (Table 1). Thus, age was different
between groups, being higher in profile 1 and lower in profile 5
(p ¼ 0.0001). There were no differences in sex and underlying heart
disease leading to HF. No differences were found between various
cardiovascular risk factors or comorbidities except for the presence
of atrial fibrillation (AF), which was more frequent in groups 1 and
2 (p ¼ 0.0001). No differences were found between groups in terms
of days of hospital stay (p ¼ 0.2), but differences were found con-
cerning the presence of previous hospital admissions, which were
more frequent in groups 4 and 5 (p ¼ 0.001).
Differences were also observed in the pattern of patient
congestion (p ¼ 0.0001), with pulmonary congestion predominat-
ing in profiles 1 and 2, while systemic or mixed congestion pre-
dominated in profiles 3, 4, and 5.
Differences in concomitant medical treatment for HF were
found, with renin-angiotensin-aldosterone system inhibitors
-RAASi- (p ¼ 0.05), beta-blockers, ivabradine, and digoxin
(p ¼ 0.0001) being more frequently used in profiles 1, 2 and 3. Thus,
patients in profiles 4 and 5 had significant systemic congestion,
worse renal function, and a higher prevalence of right ventricular
dysfunction. In these patients, hypotension and renal failure
probably result in a lower percentage of patients treated with
standard medical therapy for heart failure. The dose of diuretics in
each group is shown in Table S1 (Supplementary Material).
3.2. Analytical and echocardiographic values
In profiles 4 and 5, hemoglobin (p ¼ 0.03) and hematocrit
(p ¼ 0.01) levels were significantly lower but creatinine (p ¼ 0.01)
3
Hellenic Journal of Cardiology xxx (xxxx) xxx
and CA125 (p ¼ 0.0001) levels were significantly higher. No sta-
tistically significant differences were found in potassium
(p ¼ 0.091) and NT-proBNP (p ¼ 0.1) levels.
At the echocardiographic level, significant differences were also
observed, with patients in profiles 4 and 5 showing greater
right ventricular dilatation (p ¼ 0.0001) and worse systolic
function of both right (p ¼ 0.0001) and left ventricle (p ¼ 0.003).
Detailed echocardiographic parameters are shown in Table S2
(Supplementary Material).
3.3. Profiles found
Diuretic therapy-defined groups identify five clinical profiles
according to the degree of congestion, renal function, CA125, and
right ventricular functionality (Fig. 3 and Central Illustration).
Profile 1: Pulmonary congestion, preserved renal function,
CA125 < 100 U/ml, and preserved right ventricular (RV) diameters
and function.
Profile 2: Pulmonary congestion, preserved renal function,
CA125 100-150 U/ml, and preserved RV diameters and function.
Profile 3: Systemic congestion, preserved renal function, CA125
100-150 U/ml, preserved RV size, and reduced RV systolic function.
Profile 4: Systemic congestion, reduced renal function, CA125
150-200 U/ml, preserved RV size, and reduced RV systolic function.
Profile 5: Systemic congestion, reduced renal function,
CA125 > 200 U/ml, increased RV size, and reduced RV systolic
function.
4. Discussion
Fortunately, a large number of diuretic drugs are available that
can reduce congestion in patients admitted for decompensated HF.
However, the combination of these drugs to improve the patient's
clinical status and allow discharge from the hospital is not defined,

pez-Vilella, P. Jover Pastor, V. Donoso Trenado et al.
R. Lo Hellenic Journal of Cardiology xxx (xxxx) xxx

Table 1
Clinical characteristics of the different study profiles.

n:1559 1 2 3 4 5 p
n:623 n:763 n:78 n:63 n:32

Age (years)# 79 (14) 72 (19) 71 (10) 73 (8) 68 (20) 0.0001

Male (n,%) 336 (54) 481 (63) 41 (53) 35 (56) 20 (63) 0.14
Heart disease (n, %) 0.09
Ischemic 162 (26) 206 (27) 20 (26) 23 (37) 16 (50)
Non-ischemic 63 (10) 99 (13) 11 (14) 8 (13) 4 (13)
Valvular 174 (28) 160 (21) 23 (29) 19 (30) 8 (25)
Other 224 (36) 298 (39) 24 (31) 13 (20) 4 (12)
Background (n, %)
Hypertension 492 (79) 595 (78) 74 (95) 51 (81) 24 (75) 0.67
Kidney dysfunction 181 (29) 142 (19) 14 (18) 16 (25) 8 (25) 0.17
Previous admission 100 (16) 153 (20) 20 (26) 24 (38) 16 (50) 0.001
Diabetes 274 (44) 289 (38) 38 (49) 23 (37) 16 (50) 0.6
Dyslipidemia 361 (58) 427 (56) 34 (44) 25 (40) 12 (38) 0.4
COPD 100 (16) 107 (14) 20 (26) 12 (19) 4 (13) 0.7
AF 236 (38) 366 (48) 6 (8) 4 (6) 2 (6) 0.0001
Smoking* 0.9
- Active 9 (1.4) 14 (1.8) 0 (0) 0 (0) 0 (0)
- Ex-smoker 168 (27.0) 229 (30.0 24 30.8 20 (31.7) 16 (50)
- Non-smoker 446 (71.6) 520 (68.2) 54 (69.2) 43 (68.3) 16 (50)
Days of stay# 7 (7) 7 (6) 7 (5) 8 (8) 12 (9) 0.22
Hemodynamic profile (n, %) 0.0001
Lung congestion 506 (81) 572 (75) 12 (15) 4 (6) 3 (10)
Systemic congestion 80 (13) 122 (16) 49 (63) 43 (68) 25 (78)
Pulmonary and systemic congestion 12 (2) 8 (1) 1 (1) 4 (6) 2 (6)
Low CO 25 (4) 61 (8) 16 (21) 12 (20) 2 (6)
ACEi/ARB/ARNI (n,%) 417 (67) 534 (70) 48 (62) 28 (44) 12 (38) 0.05
Beta-blockers (n,%) 241 (39) 379 (50) 5 (6) 3 (5) 2 (6) 0.0001
Ivabradine (n,%) 135 (22) 531 (70) 5 (6) 3 (5) 1 (3) 0.0001
Digoxin (n,%) 126 (20) 224 (29) 4 ((5) 3 (5) 1 (3) 0.0001
Vasodilators (n, %) 112 (18) 123 (16.1) 7 (8.9) 6 (9.5) 0 0.012
Inotropes (n, %) 25 (4) 61 (8) 16 (21) 12 (20) 2 (6) 0.0001
Potassium# 4.4 (0.75) 4.4 (0.8) 4.4 (0.3) 4.5 (0.5) 3.8 (1.1) 0.091
Creatinine# 1.02 (0.68) 1.07 (0.53) 0.96 (0.39) 1.30 (0.45) 2.13 (0.58) 0.0001
GFR# (ml/min/1.73m2) 75 (45) 73 (35) 74 (26) 32 (31) 25 (22) 0.063
NT-ProBNP pg/mL# 11135 (5933) 6563 (4592) 9701 (6092) 19470 (9581) 23251 (11432) 0.121
CA125 U/mL# 83.1 (59.4) 116.1 (89.4) 118 (93.6) 175 (128) 287 (176) 0.0001
Hemoglobin# 12.2 (2.75) 12.8 (2.95) 12.8 (1.98) 11.4 (2.8) 11.6 (4.8) 0.035
Hematocrit# 37.5 (7.4) 39.3 (8.1) 40.0 (4.4) 35.7 (7.8) 36.1 (8.6) 0.017
Preserved LVEF (n,%) 280 (45) 237 (31) 13 (17) 8 (13) 8 (25) 0.003
Mild-reduced LVEF (n,%) 112 (18) 82 (11) 9 (12 5 (8) 1 (3) 0.0001
Reduced LVEF (n,%) 231 (37) 444 (58) 56 (71) 50 (79) 23 (72) 0.0001
Reduced RVF (n,%) 156 (25) 320 (42) 42 (54) 36 (57) 28 (88) 0.0001
Dilated RV (n,%) 118 (19) 152 (20) 23 (29) 20 (32) 20 (63) 0.0001

Abbreviations: ACEi: Angiotensin-converting enzyme inhibitors; AF: Atrial fibrillation; ARB: Angiotensin receptor blockers; ARNI: Angiotensin receptor neprilysin inhibitor;
CO: Cardiac output; COPD: Chronic obstructive pulmonary disease; GFR: Glomerular filtration rate; RVF: Right ventricular function; LVEF: Left ventricular ejection fraction; RV:
Right ventricle.
#
Median and interquartile range.
*
Smoker: Active smoking in the last year. Ex-smoker:1 to 10 years since quitting. Non-smoker: never smoker or more than 10 years since quitting.

although it seems to depend on the clinical profile of the patient2,3.
In this study, patients were grouped by clinical profile in relation to
the amount and variety of diuretics administered to improve their
condition. Five clinical profiles defined by different diuretic com-
binations prescribed during hospitalization were found. These
profiles related to the site of congestion, renal function, CA125
levels on admission, RV dimension, and function.
Although practically every patient with acute HF receives a
diuretic, few studies have compared different combinations and
this choice can impact the clinical outcomes. The latest guidelines
and statements on acute HF have included flowcharts with sug-
gestions regarding which diuretic to start, in which dose, and
when to consider an association of medicaments. However, only a
few specific points were studied in robust clinical trials. Thus, in
this study, the choice of diuretic treatment was made at the
discretion of the physician in charge of the patient (no specific
protocol was followed). On the one hand, the dose of loop di-
uretics can be progressively increased and the response can be
monitored by urinary sodium levels4. There seems to be a ten-
dency for patients on high-dose furosemide to have more intense
diuresis and greater decongestion5,6. However, the current trend is
towards opting for a combination of diuretics that achieves
sequential nephron blockade.
Regarding the baseline characteristics of the sample, age was
higher in profile 1 and lower in profile 5, with no differences in
sex, underlying heart disease, or comorbidities (except AF). Other
studies grouping HF on admission according to other variables
such as blood pressure found no differences between groups in
terms of age or sex7. Despite this, it is well known that there are
age and gender differences in HF, that women are under-
represented in clinical trials, and that there are gender differ-
ences in etiology and associated comorbidities8,9. In this study,
no differences were probably noted since a wide variety of pa-
tients were included, and the different stages of progression of
each of the etiologies were evenly distributed in the different
profiles.

4

pez-Vilella, P. Jover Pastor, V. Donoso Trenado et al.
R. Lo
Figure 3. Clinical profiles according to the treatment of congestion. Footnote: CA125: Carcinoembryonic antigen 125 (U/mL). RV: right ventricle.
No differences were found in terms of days of hospital stay, but
there were differences in terms of hospital readmissions, which
were more frequent in the profiles in which systemic congestion
predominates (profiles 4 and 5, those with more systemic
congestion with more diuretic combination and therefore more
resistant to medical management). CA125 levels have been widely
associated with congestion10, and several studies have linked
elevated CA125 levels to readmission rates and worse clinical
outcomes11,12. On the other hand, creatinine levels, which in this
study are higher in the profiles that require more diuretics, have
been related to a longer hospital stay13. The results do not show
significant differences in terms of hospital stay, but there is a ten-
dency towards longer stays in patients with more congestive pro-
files and worse renal function. The failure to reach statistical
significance is probably due to the smaller number of patients
included in these groups.
Differences in congestion patterns were also observed, with
pulmonary congestion being more frequent in profiles 1 and 2,
while systemic or mixed congestion was predominant in profiles 3,
4, and 5. Classically, hemodynamic patterns in HF have been
5
Hellenic Journal of Cardiology xxx (xxxx) xxx
classified into 4 groups according to the subdivisions of “wet vs
dry” and “warm vs cold”14. Previous studies have attempted to
classify patients admitted for HF with other hemodynamic pat-
terns; according to other variables, such as Singer et al classified
patients according to blood pressure figures on admission as hypo-,
normo- and hypertensive7. However, the present study focused on
congestive patients and the diuretic therapy required to achieve
clinical stabilization for discharge. The assessment of congestion is
one of the main challenges in the treatment of HF; the ESC-HF
position paper on the use of diuretics in HF tries to focus targeted
therapy on clinical congestion15. However, other groups consider
that the difference between pulmonary and systemic congestion
from a purely clinical point of view is not sufficient for targeted
diuretic therapy. These groups propose the existence of different HF
profiles that should integrate not only clinical aspects but also
analytical and echocardiographic parameters, which could be used
to adapt diuretic therapy in each case16. This is the same line that
this study aims to address.
Regarding concomitant medical therapy, we observed that in
profiles 1 and 2 the use of targeted drugs for HF was more widely

pez-Vilella, P. Jover Pastor, V. Donoso Trenado et al.
R. Lo
used compared with the other groups, although the percentage of
patients with depression of both RV and LV systolic function was
higher in profiles 3, 4, and 5. However, these data are consistent
with those from the PATHWAYS-HF registry on the underuse of
optimal medical therapy in HF17. With reference to diuretic dose,
the dose of loop diuretics was higher in groups 3, 4, and 5.
Analytically, patients in profiles 4 and 5 had lower hemoglobin
and hematocrit levels, worse renal function, and higher levels of
CA125, a marker related to congestion. In this respect, high doses of
loop diuretics and poor diuretic response are two conditions
associated with adverse outcomes, and both situations appear
strictly related to worsening renal function occurrence18. In line
with the results obtained, low hemoglobin levels have been asso-
ciated with hemodilution and therefore with volume overload19, as
well as the association of low hemoglobin levels with poorer renal
function and the need for higher doses of diuretics has been
highlighted20. The combination of anemia and renal dysfunction
has also been associated with a higher readmission rate21,22. In
contrast to other studies in which NT-proBNP levels were found to
be higher in patients with a higher degree of congestion23, we
found no significant differences in NT-proBNP levels, but a ten-
dency for higher values in more congested profiles. This was
probably due to the smaller number of patients included in profiles
4 and 5 compared to the other groups and the large numerical
dispersion of this biomarker.
Echocardiographically, patients with the most congestive pro-
files, who require a wider diuretic spectrum, have more impaired
left ventricular function, greater dilatation, and worse RV function
(lower TAPSE with higher estimated pulmonary pressures). Other
studies have related right ventricular dysfunction to worsening
renal function that improves with diuretic treatment as a reflection
of renal congestion24. These results are in the same direction, as
patients with poor RV function have a worse renal function on
admission. The relationship between higher CA125 levels and the
presence of congestive signs, including echocardiographic param-
eters of RV failure, has also been documented25. Studies have
shown that RV size change can serve as a marker of diuretic
response in patients with diuretic resistance26, although this has
not yet been evaluated in this descriptive analysis.
There are other studies such as that of Nun~ ez et al. that guide the
intensity of diuretic treatment based on CA125 levels27,28. In the
current trial, diuretic treatment was adjusted mainly through a
higher or lower dose of loop diuretics and in some cases thiazides,
but there is no protocoled use of other diuretics with different
mechanisms of action as proposed in this study. Furthermore, this
proposal is for therapy guided by a multimodal strategy, which
would be a novel aspect of the approach to congestion, and
therefore shows the strength of this system.
The limitations of the present study are that it is a retrospective
study and the number of patients in profiles 4 and 5 is low. In
addition, the exclusion of deaths during admission from the anal-
ysis may be considered a limitation. On the other hand, clinical
profiles have been determined through the treatment used, and of
course, this is an idea that needs to be validated in future studies.
5. Conclusions
In conclusion, the diuretic combination needed to improve pa-
tients with decompensated HF is associated with certain clinical
characteristics of the patient derived from the site of congestion,
renal function, CA125 level, and RV functionality. This fact would
allow us to theorize whether, given a given clinical profile, the early
6
Hellenic Journal of Cardiology xxx (xxxx) xxx
administration of the diuretic combinations studied would be
advisable to prescribe on admission.
Funding
This research received no grant from any funding agency in the
public, commercial, or not-for-profit sectors.
Conflict of interest
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.hjc.2023.03.009.
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