Primhak et al.

Trials (2022) 23:108

https://doi.org/10.1186/s13063-022-06042-0

STUDY PROTOCOL Open Access

Treatment of Impetigo with

Antiseptics—Replacing Antibiotics (TIARA)
trial: a single blind randomised controlled
trial in school health clinics within
socioeconomically disadvantaged
communities in New Zealand
Sarah Primhak1,2* , Alicia Gataua3, Diana Purvis4, John M. D. Thompson2, Cameron Walker2, Emma Best1,2† and
Alison Leversha5†

Abstract
Background: Impetigo is a common and contagious bacterial skin infection, affecting children worldwide, but it is
particularly prevalent in socioeconomically disadvantaged communities. In New Zealand, widespread prescribing of
the topical antibiotic fusidic acid had led to an increase in antimicrobial resistance of Staphylococcus aureus.
Alternative treatments are urgently being sought, and as impetigo is a superficial infection, it has been suggested
that topical antiseptics such as hydrogen peroxide or simple wound care alone may treat impetigo while avoiding
the risk of increased antimicrobial resistance.
Methods: This protocol for a non-inferiority, single-blind randomised controlled trial compares topical fusidic acid
with topical hydrogen peroxide and with simple wound care in the treatment of childhood impetigo. Participants
are randomised to one of the three treatments for 5 days. The primary outcome is clinical improvement assessed
through paired photographs analysed by graders blinded to treatment arm. The trial is based in school health
clinics in an urban centre in New Zealand. Comparison of antimicrobial resistance patterns pre- and post-treatment
is also performed.
Discussion: Special note is made of the need to involve the communities most affected by impetigo in the design
and implementation of the clinical trial to recruit the children most in need of safe and effective treatments.

* Correspondence: Spri856@aucklanduni.ac.nz
†
Emma Best and Alison Leversha contributed equally to this work.
1
Paediatric Infectious Diseases, Starship Children’s Health, Auckland, New
Zealand
2
University of Auckland, Auckland, New Zealand
Full list of author information is available at the end of the article

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Primhak et al. Trials (2022) 23:108 Page 2 of 9

Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) 12616000356460. Registered on March
10, 2016
Protocol amendment number: 05
EB and AL contributed equally as senior authors.

Introduction impetigo, topical fusidic acid is no longer first line in

Impetigo is a contagious superficial bacterial skin infec- mild-to-moderate disease, superseded by the advice to
tion, predominantly affecting children [1, 2]. It is de- use an antiseptic cream, 1% hydrogen peroxide [11]. The
scribed as one of the top 50 most common diseases [3], UK National Institute of Clinical Excellence (NICE) have
with a global prevalence estimated at 162 million [4]. also released a draft guideline on impetigo proposing the
New Zealand (NZ) is a high-income country in the same change [12]. These prescribing guidelines are based
South Pacific with a diverse population including tangata on evidence from a single randomised controlled trial
whenua- NZ indigenous population (Māori) who make performed in 1993 with no information provided on
up 17% of the population. During western colonisation, fusidic acid resistance rates within the study population.
NZ established the Treaty of Waitangi [5] between the This demonstrated “a tendency towards somewhat lower
Crown and Māori which ensures a legal requirement to efficacy in [hydrogen peroxide] compared to [fusidic
good governance and the right to equitable health out- acid]” with no significant difference between the groups
comes for indigenous people [6]. While the Pacific peo- [13]. Since that time, antimicrobial resistance patterns to
ples of NZ (those from the Polynesian and Melanesian fusidic acid have changed within NZ [7, 8]. and poten-
Pacific islands surrounding NZ) are not part of the treaty tially within other countries where it is used topically or
agreement, they make up a significant proportion of systemically.
NZ’s population (~ 7%), and there is recognition of sig- In the past, clinical trials of impetigo have presented
nificant inequities for both Māori and Pacific popula- challenges and this trial protocol seeks to address these.
tions and the obligation to address these. Primary care is Impetigo is predominantly a disease seen in the commu-
generally funded for children under 13 years of age, but nity with primary care presentations representing only a
socioeconomic barriers to care are still recognised. NZ small proportion of cases. Many families never seek
experiences a particularly high burden of skin and soft medical review, particularly in populations where finan-
tissue infections with as many as 11% of NZ children cial concerns limit health-seeking behaviours [14]. A
aged under 15 years consulting their primary care pro- clinical impetigo trial should, therefore, ideally be based
vider for skin infections annually. There is an inequity in within a community setting. Impetigo is a disease of
the burden of disease with the highest rates seen in chil- childhood, a challenging group to enrol in clinical trials
dren of Māori and Pacific peoples. with previous trials on impetigo treatment including
As a superficial infection, impetigo is frequently large numbers of adults; the RCT upon which the
treated topically rather than systemically. Since the early current practice is based recruited patients with a mean
2000s, New Zealand has experienced high prescribing age of 17 years [13].
rates of the topical antibiotic fusidic acid; rates of dis- Defining primary outcomes in impetigo treatment is
pensing are highest for preschool children, followed by also challenging as demonstrated by the variety of out-
those age 75+ and 5–14 years. Dispensing is also highest comes measures across prior clinical trials. A systematic
in Pacific Island and Māori ethnicities [7, 8]. Following review concluded that more robust outcome measures
the increase in prescribing, a subsequent rise in fusidic were required [15]. Time to reported clinical endpoints
acid resistant S. aureus isolates has been reported; resist- have ranged between 1 and 3 weeks after starting treat-
ance is now demonstrated in 28% of NZ S. aureus iso- ment. Some trials have used complete cure while others
lates [9]. In 2005, a fusidic acid resistant and methicillin are satisfied with clinical improvement of varying defini-
resistant S. aureus (MRSA) clone was identified and has tions. Many are based on observer defined definitions,
become the dominant MRSA clone in New Zealand but even the more objective scores such as the Skin
[10]. This suggests that widespread community use of Infection Rating Score (SIRS) have been used as a
fusidic acid has not only led to selection of fusidic acid primary outcome measure in a variety of ways, in-
resistant clones but also concurrent MRSA. In an at- cluding an absolute reduction in score, predefined ab-
tempt to limit the development of further antimicrobial solute decrease in score, or as a percentage decrease
resistance by avoidance of topical antibiotics, NZ has up- from the baseline [6, 16].
dated national impetigo guidance. While oral antibiotics To best inform our practice, our trial requires a major-
remain the first line for severe or multi-lesional ity recruitment of children of Māori and Pacific children,
Primhak et al. Trials (2022) 23:108 Page 3 of 9

the groups most affected by impetigo in NZ. There are Eligibility criteria
marked inequities in health outcomes for Māori and Pa- Children meeting the eligibility criteria are identified
cific Island children, and it is critical that health research and their caregivers contacted to explain the study and
is focused on understanding and addressing these in- obtain consent. Caregivers must provide verbal informed
equities. Impetigo is contributing to inequity in health consent before any study procedures occur. This is then
outcomes and therefore is crucially important to Māori followed by written informed consent (see Appendix 1
and Pacific health. With the burden of skin disease af- for sample of informed consent form).
fecting predominately Māori and Pacific children, appro-
priate cultural engagement with these communities was Inclusion criteria
recognised as a key factor, both for successful trial com- Children eligible for the trial must comply with all of the
pletion and ensuring meaningful results which will be following prior to randomisation:
acceptable, generalisable, and implementable for those
most affected by impetigo. 1. Enrolled in one of the participating school clinics
2. Mild-to-moderate impetigo
Objectives 3. Aged 5–13 years
We hypothesize both simple wound care and topical
hydrogen peroxide are non-inferior to topical fusidic Exclusion criteria
acid in the treatment of impetigo.
Therefore, the aims of this clinical trial are: 1. Severe impetigo requiring oral antibiotics; defined
as extensive lesions (> 3 lesions or > 5% body
1) To compare the effectiveness of topical fusidic acid surface area), presence of cellulitis, or fever > 38.5
with topical hydrogen peroxide and simple wound °C
care in the treatment of mild-to-moderate impetigo 2. Children who are immunocompromised
in a community with both high rates of impetigo 3. Known allergy to study drugs
and increasing fusidic acid resistance. 4. Current use, or use within the previous 5 days, of
topical or oral antimicrobials
2) To examine potential changes in the antimicrobial 5. Commencement of antimicrobials for other reasons
resistance of skin pathogens in response to these differ- during the trial period
ent treatments for impetigo. 6. Failure to obtain informed consent for
randomisation or withdrawal of consent
Trial design
TIARA is an open label, single-blind, non-inferiority Excluded children continue with treatment according
randomised controlled trial with three parallel treatment to the existing school health clinic standard operating
groups. The primary endpoint is clinical improvement at procedures (SOP).
seven days. Randomisation is performed 1:1:1 within
each school clinic. Intervention
All lesions are cleaned with saline and scabs gently re-
Methods: participants, interventions, and moved. For the group randomised to fusidic acid, 2%
outcomes fusidic acid ointment (DP Fusidic Acid, Douglas Phar-
Study setting maceuticals Ltd, Auckland, NZ) is applied topically, and
Auckland city has a temperate climate and is a large for the hydrogen peroxide arm, 1% hydrogen peroxide
urban centre of 1.6 million people. Primary school cream (Crystaderm, AFT Pharmaceuticals, Auckland,
health clinics serve the more socioeconomically disad- NZ) is applied topically. In both cases, an adequate
vantaged areas within two of the three district health amount to cover each lesion is used and dressing(s) then
boards in the Auckland region: Auckland and Counties applied. A tube of appropriate topical medication is sup-
Manukau. These health clinics provide primary care, in- plied for the child and/or caregivers to continue applica-
cluding free skin and throat infection management, to tions twice daily for 5 days with dressing changes.
students aged 5–13 years [17, 18]. The school nurses Participants allocated to simple hygiene measures re-
running the clinics are invited to participate in this study ceive no medication but a dressing is applied following
to provide a potential eligible population of ~ 10,000 en- the cleaning of the lesion(s). All participants are pro-
rolled students. Due to their over representation of vided with supplies to allow them to clean and redress
socio-economic disadvantage, over 90% of children in the wound twice daily for 5 days. Low adherent wound
the schools are of Māori or Pacific Island ethnicity, and pads are used so as not to interfere with the wound heal-
there is a high rate of impetigo. ing process. In all groups, scabies is treated if present.
Primhak et al. Trials (2022) 23:108 Page 4 of 9

Modifications 5 days. Two days after enrolment into the trial (day 2), a
All adverse effects, including pain, itch, or allergy to safety check is performed by the school nurse to assess
study medication, will be reported; the study medication for rapid worsening of the impetigo or for adverse ef-
must be withdrawn and the patient changed to routine fects. The safety check can be performed between days 2
treatment as per the SOP of the health clinic. If clinical and 4 if necessary to allow for day 2 falling on a week-
deterioration while on study medication is identified by end. Caregivers are asked to contact the school nurse
the school nurse, the study medication may be with- between visits, if they have concerns about the lesion
drawn at the nurse’s discretion. In this case, the patient getting worse. Seven days after commencing the trial
will be changed to routine treatment as per the standard (day 7), the participant is re-assessed by the nurse. A
operating procedures of the health clinic. second set of photographs and repeat bacterial swab is
taken from the same lesion as originally documented.
Adherence Both child and caregiver complete a verbal question-
Face-to-face reminders of adherence are provided by naire. Caregivers can withdraw a participant from the
nurses at both day 0 and day 2 visits, and adherence over study at any stage. For the full schedule of interventions
the trial period is assessed on days 2 and 7. Sticker charts and assessments see Figs. 1 and 2.
are provided for each participant to encourage adherence.
Sample size
Participant timeline On the assumption of non-inferiority between hygiene
On the first visit (day 0), demographic data, inclusion measures and topical fusidic acid and between topical
and exclusion criteria, and verbal consent are obtained. hydrogen peroxide and fusidic acid, and a predicted effi-
All lesions are cleaned and the single largest lesion is cacy of fusidic acid of 80%, we require 160 patients in
photographed using a digital camera, and a bacterio- each intervention group. This provides 80% power and a
logical swab is taken from the same lesion as the photo- one-sided α of 0·05 to show non-inferiority (10% margin)
graph. The patient is then randomised and the between each group and topical fusidic acid. In order to
appropriate treatment is commenced and continued for allow for 10% loss to follow-up and subsequent

Fig. 1 Schedule of enrolment, interventions, and assessments

Primhak et al. Trials (2022) 23:108 Page 5 of 9

Fig. 2 SPIRIT diagram

exclusions, recruitment of 178 participants to each Data collection methods

group is required. Subsequent exclusions and loss to Demographic characteristics
follow-up are defined as participants not available for Baseline characteristics of participants are collected at
follow-up at day 7 or when two digital images are not the time of randomisation and reported per random-
available to assess. Estimates of efficacy are extrapolated isation group. The following demographic characteris-
from published data [6, 19, 20], and the 10% margin was tics will be reported: age, gender, ethnicity, weight,
considered a clinically significant difference [21]. history of pre-existing skin disease, allergies, and loca-
tion of most severe lesion. All data is collected dir-
Recruitment ectly onto an electronic database used by school
School health teams within recruiting schools will follow health clinics; additional trial questions have been
existing SOPs. Community health workers attend every created and added to this database by the study in-
class 3–5 days each week during the school term and ask vestigators. An equivalent paper proforma was de-
children to self-identify any skin infections. These signed by SP and included in the study materials for
children are then reviewed by the school nurse. If the use if required.
lesions are confirmed as impetigo, then eligibility for
participation is assessed. Primary outcome methods
The primary outcome of this trial is treatment success
Allocation concealment mechanisms and implementation based on comparison of digital photographs taken at
Randomisation is implemented by block randomisa- days 0 and 7. If clinical assessment leads to early discon-
tion within each participating school, sequence alloca- tinuation of the trial medication, this is also considered
tion code was written in R [22]. Children are unsuccessful treatment. To aid standardisation, the pri-
randomly allocated (1:1:1) to topical fusidic acid, mary outcome uses digital photographs independently
topical hydrogen peroxide, or simple hygiene mea- assessed by blinded reviewers. The single largest lesion
sures. Participating schools are randomised separately is photographed prior to commencing treatment, using a
to limit bias caused by excess recruitment to any digital camera at a distance of 15 cm with an adhesive
individual arm within a single school. Allocation is paper tape measure and unique study ID placed next to
performed by school nurses using the pre-generated the lesion. Three digital images are taken at each data
codes contained in sealed, opaque, sequentially num- collection visit, and all are submitted to the study inves-
bered envelopes. Both the participant and school tigators. The single best quality image is then selected by
nurse are aware of treatment allocation due to the the lead investigator (SP) for outcome assessment. Pairs
appearance of the study medications (e.g. hydrogen of images are presented to three individual assessors
peroxide has a silvery sheen) or lack of study medica- blinded to intervention arm. The method of image pres-
tion in the simple hygiene measure arm. However, entation is randomised such that assessors are unaware
investigators, photograph reviewers, and laboratory of which image was taken first and which second. The
staff are blinded to allocation. outcome will be treatment success if the images are
Primhak et al. Trials (2022) 23:108 Page 6 of 9

considered healed or improved and treatment failure if Secondary outcomes

they are the same or worse, or if the reviewers cannot
determine the outcome based on the digital images (e.g.  Clinical success will be compared between groups.
due to poor quality images). Where there is discordance This will be defined by
between assessor opinions, the majority opinion of two  Nursing opinion that the impetigo has improved
out of three reviewers will be considered the correct as- at day 7
sessment. Patients removed from the trial protocol by  Participant and/or caregiver opinion that the
school nurses or general practitioners before 7 days due impetigo has improved at day 7
to clinical deterioration will also be considered treat-  Microbiological secondary outcomes are eradication
ment failures. This process has been standardised previ- of S. pyogenes and/or S. aureus on day 7 and
ously in another large RCT of treatment of impetigo in development of antibiotic resistance on day 7
remote access locations; different from our multicentre compared to baseline
urban setting [21].  Educational impact is assessed by comparison of
school absence over the 7 days of the trial period
 Adverse events will be compared across study arms
Clinical assessments
Clinical assessments are standardised and recorded on Retention
the existing skin assessment database used for school A supermarket voucher worth NZ$20 ise offered to the
health clinics. A written description of the location of family as koha, a thank you gift on successful completion
the lesions and identification of the primary lesion being of the trial protocol.
used for assessment is recorded. A paper template is also
provided to allow nurses the option to mark on a dia- Data management
gram the location of the lesions. Trial data is stored using a study identification number
Seven days after commencing the trial (day 7), the on a password protected access database maintained on
participant is re-assessed by the school nurse, who a secure network. This database is also used to random-
also records whether the lesion has improved. Both ise images and presents anonymised pairs of photo-
child and caregiver are asked to comment on their graphs to the graders for analysis, and records the
satisfaction with treatment and any adverse events re- outcomes of the grading.
lated to the medication, including itch, pain, or al-
lergy. School records are checked for absence over Statistical analyses
the prior 7 days. For baseline data, dichotomous variables will be sum-
marised as proportions of patients in each treatment
Microbiology group, differences between groups will be assessed using
All children have a bacteriological dry cotton swab taken a chi-square statistic, and where small cell sizes (less
from the most severe lesion at presentation and at day 7. than 5) are present, a Fisher’s exact test will be used.
Swabs are cultured onto blood agar and any clinically Continuous variables with an underlying normal distri-
significant growth is reported. The European Committee bution will be summarised as mean and standard devi-
on Antimicrobial Susceptibility Testing (EUCAST) sus- ation, and differences between groups will be assessed
ceptibility method and criteria are used for S. aureus using Student’s t-test. Other distributions will be either
susceptibility testing. Susceptibility is tested to com- transformed if suitable and t-tests performed with
monly used skin and soft tissue antimicrobials; fusidic reporting of geometric means or distributions will be re-
acid, flucloxacillin, erythromycin, clindamycin, and co- ported as median and interquartile range and differences
trimoxazole. If MRSA is identified then extended sus- in groups assessed using Wilcoxon rank non-parametric
ceptibility is performed, including mupirocin and tetra- tests with Hodges-Lehmann estimates and 95% confi-
cyclines. No susceptibility testing is performed on S. dence intervals.
pyogenes. Analysis will be performed after completion of recruit-
ment. Both hydrogen peroxide and simple hygiene
groups will be compared independently with fusidic acid
Outcomes with 95% confidence interval. Non-inferiority will be de-
Primary outcome fined as a treatment success rate of no more than 10%
The primary outcome of this trial is treatment success below that of the fusidic acid success rate. An intention
assessed by comparison of digital photographs or clinical to treat and per protocol analysis will be performed
deterioration based either on digital images or on nurs- using all patients with available primary outcome data.
ing assessment leading to discontinuing trial medication. Patients without primary outcome data or for whom
Primhak et al. Trials (2022) 23:108 Page 7 of 9

caregivers withdrew consent to participate will not be in- an appropriate cohort of children at high risk of
cluded in the analysis. impetigo.
To investigate predictors of treatment success, back- Engaging authentically with Māori and Pacific commu-
wards stepwise random-effects logistic regression will be nities is vital to the success of this project. As outlined
performed on a priori and other variables identified as above, Māori and Pacific communities living in New
different in baseline characteristics between randomisa- Zealand face barriers to accessing appropriate and timely
tion groups. primary healthcare for potentially preventable conditions
such as impetigo [14]. Research is critical to address
Data monitoring these inequities and should be undertaken in a culturally
A data safety monitoring board (DSMB) has been con- appropriate way using a partnership approach with
vened. This comprises an international expert in impe- Māori and Pacific researchers. School nurses who are
tigo, a local expert in paediatric infectious diseases, and known and trusted by the families, and representative of
a statistician. An interim safety analysis blinded to allo- the school communities, will be important to ensure ef-
cation will be performed after recruitment of 150 partici- fective engagement.
pants. If concerns are expressed, the unblinded data may The National Hauora Coalition (NHC), a Māori pri-
be made available to the DSMB on request. Stopping cri- mary health organisation, was consulted early in study
teria may include slow accrual, poor data quality, un- design. A Māori nurse leader (AG) directed key trial im-
acceptable adverse events, and emerging information plementation and engendered the support of the school
that makes the trial irrelevant. The DSMB will discuss nurses who represent both Māori and Pacific Island
the outcome of the analysis with the trial steering com- healthcare workers. Information leaflets have been pro-
mittee. The unblinded data, apart from the outcome of vided in multiple languages, including Te Reo Māori,
the DSMB decision, will not be made available to the au- Tongan, and Samoan, and nursing staff provide add-
thors prior to the completion of the trial and unblinding. itional verbal information as a more acceptable commu-
nication [14]. Specific acts of recognition and practical
reimbursements have been shown to contribute signifi-
Harms
cantly to a sense of value and reduce the financial strain
Any adverse event will be reported; these are defined as
when accessing healthcare [14]. To acknowledge this, a
any untoward medical occurrence in a subject without
gift (koha) of a NZ$20 supermarket voucher is offered to
regard to the possibility of a causal relationship after
each family after completion of the trial.
entry into the study and until the completion of the
Because of the large and disparate pool of recruiters, it
study. At day 2 and day 7 of the trial, a safety check is
is important that the primary outcome is as comparable
performed by the school nurse to assess for rapid wors-
and unbiased as possible. Digital images allow for cen-
ening of the impetigo or for adverse effects. If these
tralised assessment despite the distance between recruit-
occur, then the participant can be withdrawn from the
ing sites. However, this means the existing scoring
trial at the discretion of the nurse. On day 2 and day 7,
system (SIRS) is not practical as variables included in
participants and/or caregivers are directly questioned re-
the scoring such as warmth, pain, and itch are not
garding specific harms including itch, pain, redness, or
amenable to visual assessment alone. For this reason, as-
any other adverse effects of medication. Any require-
sessor defined scoring was used. Erythema is also one of
ment for additional medical intervention is considered a
the elements of the SIRS scoring system, and when
potential harm. All harms will be reported.
assessing children with darker skin, this is often underes-
timated [23], leading to minimisation of the severity of
Auditing lesions in those with darker skin. The use of digital im-
Regular visual review of the data will be performed by ages and multiple reviewers for the primary outcome
the lead investigator (SP) for completeness and quality aims to minimise the bias inherent in the majority of
of the data. previous studies on impetigo and provide a reproducible
outcome, consistent with real world improvement. This
Discussion remains an imperfect measure as it is dependent on
The aim of this study is to investigate the relative effect- good quality digital images and reviewer defined assess-
iveness of non-antibiotic management of impetigo in ment. Due to the visible difference in the topical medica-
children. The use of existing school health clinics lo- tions, neither school nurses nor participants could be
cated within the more socioeconomically deprived com- blinded to treatment. This introduces a potential elem-
munities in Auckland, NZ, allows access to a large ent of bias for those removed from the study early due
population of children within a community who might to clinical treatment failure. It was considered unfeasible
not otherwise seek medical help. This ensures access to to introduce a placebo medication to the simple wound
Primhak et al. Trials (2022) 23:108 Page 8 of 9

hygiene group. Potentially, any ointment without anti- Declarations

microbial properties could provide an environment for
Ethics approval and consent to participate
bacterial growth or negatively affect bacterial growth, This study has been approved by the Northern A Committee of the Human
potentially changing the outcome for this group. and Disability Ethics Committee of New Zealand (HDEC) 16/NTA/113/AM03.
Topical antibiotics remain the mainstay of treatment Locality approval has been obtained from the research offices of both
Auckland and Counties Manukau District Health Boards and Māori research
for mild-to-moderate impetigo in many countries approvals obtained at each locality.
around the world, including New Zealand. Widespread Verbal consent from the caregiver is obtained on an individual basis at the
community use and a tendency for prolonged courses point of identification of impetigo and then followed with written informed
consent. Children older than 7 years of age have the opportunity to sign an
mean that they excel at inducing antimicrobial resist- assent form. Consent is obtained by the school nursing staff after training by
ance. Evidence for antiseptic use or simple hygiene mea- the research trial team.
sures in impetigo is extremely limited: this will be only
the second trial to compare these topical antiseptics and Consent for publication
No patient-identifiable information will be published.
antibiotics and the first to take current antimicrobial re-
sistance patterns into account. On the background of a
Competing interests
worldwide increase in antimicrobial resistance and with The authors declare that they have no competing interests.
increasing recognition of the importance of antimicro-
bial stewardship, it is timely to re-address the evidence Author details
1
Paediatric Infectious Diseases, Starship Children’s Health, Auckland, New
for the role of antiseptics and antibiotics in the treat- Zealand. 2University of Auckland, Auckland, New Zealand. 3National Hauora
ment of impetigo. This is only possible, however, if the Coalition, Auckland, New Zealand. 4Paediatric Dermatology, Starship
most affected communities are appropriately engaged in Children’s Health, Auckland, New Zealand. 5Community Paediatrics, Starship
Children’s Health, Auckland, New Zealand.
this research.
Received: 18 August 2021 Accepted: 19 January 2022
Supplementary Information
The online version contains supplementary material available at https://doi.
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