Efficacy and Tolerability of Peritendinous Hyaluronic Acid in Patients with Supraspinatus Tendinopathy: a Multicenter, Randomized, Controlled Trial
Flores et al. Sports Medicine - Open
Efficacy and Tolerability of Peritendinous Hyaluronic Acid in Patients with Supraspinatus Tendinopathy: a Multicenter, Randomized, Controlled Trial
César Flores 3 5
Ramón Balius 2 5
Guillermo Álvarez 1 5
Miguel A. Buil 4 5
Luisa Varela 0 5
Carlos Cano 5 7
Joaquín Casariego 5 6
0 Department of Clinical Research, OPKO Health Europe , Plaza Europa, 13-15, Hospitalet de Llobregat, 08908 Barcelona , Spain
1 Department of Sports Medicine, AMS - Centro Médico del Ejercicio , Málaga , Spain
2 Department of Sports Medicine, Centre d'Estudis d'Alt Rendiment Esportiu (CEARE), Consell Català de l'Esport , Barcelona , Spain
3 Department of Orthopaedic Surgery and Sports Medicine, Clínica CEMTRO , Madrid , Spain
4 Department of Sports Medicine, IVRE-Institut Valencià de
5 Recuperació Esportiva , Valencia , Spain
6 Medical Department, OPKO Health Europe , Barcelona , Spain
7 Department of Physical Therapy, AMS-Centro Médico del Ejercicio , Málaga , Spain
Background: Physical therapy and peritendinous hyaluronic acid (HA) injections have both shown promising results in the treatment of shoulder tendinopathies. However, the superiority of treatment combining physical therapy and HA is unclear. Methods: Patients with ultrasound-confirmed supraspinatus tendinopathy were randomized to receive either physical therapy + subacromial HA injections or physical therapy only. Treatment efficacy was assessed using a Visual Analog Scale (VAS) for pain and an Activities of Daily Living (ADL) scale. Other measures were the number of rehabilitation sessions and days needed for recovery, the Tampa Scale for Kinesiophobia (TSK), and the physician and patient's perception of efficacy and tolerability. Patients were followed up for 90 days. Results: Overall, VAS and ADL scores showed a progressive decrease during the follow-up (P < 0.01 at all visits for both groups), without significant differences between groups. The TSK score decreased significantly more in the HA group than in the control group (3.6 vs. 2.4; P < 0.001). Patients in the control group needed more rehabilitation sessions (28 vs. 22 in the HA group; P = 0.006) and more days for returning to their pre-injury activity (32 vs. 20 in the HA group; P = 0.013). Both patients and investigators perceived higher efficacy in the HA group than in the control group (P = 0.034). Both treatments were safe and well tolerated. Conclusions: Subacromial HA injections combined with physical therapy have high efficacy in the treatment of supraspinatus tendinopathy, leading to an earlier return to pre-injury activity and the need for fewer rehabilitation sessions, which may benefit both patients and the healthcare system.
Tendinopathy is a common injury in athletic populations,
secondary to overuse [1, 2]. However, it may also occur in
the overall population as a result of repetitive or excessive
loading, and abnormal or unusual movements . Also,
metabolic- and hormone-related clinical conditions such
as diabetes, menopause, and adiposity have been identified
as systemic risk factors for tendinopathies [4–6]. Although
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the incidence of tendinopathies in the overall population
has not been established, different authors have reported a
rising trend associated with increasing interest in sport
activities in high-income societies [1, 2, 7].
The first-line pharmacological treatment for
tendinopathies is most often based on non-steroidal
antiinflammatory drugs (NSAIDs), which are useful for pain
control but may cause patients to ignore warning
symptoms, resulting in further damage to the affected tendon
[3, 8]. Intratendinous injections of corticosteroids are
also common in the standard management of
tendinopathies and appear to successfully reduce inflammation
and pain at short-term; however, the risk-benefit ratio of
their use in the treatment of tendinopathies is currently
controversial [7, 9]. Owing to the limitations of
pharmacological treatments in modifying the structure of the
tendon, the management of tendinopathies usually
includes other non-pharmacological interventions with
proven benefits in tendon recovery such as relative rest,
cold, ultrasound, and physical therapy, specifically
eccentric style exercises and stretching to prevent stiffness
[1, 3]. Other non-pharmacological interventions
proposed include shock wave therapy, iontophoresis,
sclerotherapy, and nitric oxide patches; however, results are not
very consistent and multicenter trials are needed to
confirm their efficacy. Among all of the physical therapeutic
interventions, eccentric strengthening has shown
remarkably good therapeutic outcomes in the treatment of
various tendinopathies such as those affecting the patellar,
Achilles, supraspinatus, and wrist tendons [1, 10–14].
Among the recent advances in the management of
tendon disorders, the peritendinous administration of
hyaluronic acid (HA) has shown promising results in clinical
trials including patients with tennis elbow , patellar
tendinopathy , Achilles tendinopathy [17, 18], and
various disorders involving tendons in the rotator cuff
[19–22]. HA is the primary component of synovial fluid
and provides the joint with lubrication and shock
absorption . Although the mechanisms of action in the
treatment of tendinopathies are not well established,
peritendinous injection of HA has shown to reduce
tendon adhesion, provide mechanical protection, and
upregulate the vascular endothelial growth factor and type IV
collagen, resulting in the acceleration of tendon healing
[24–26]. In the particular case of tendinopathies involving
the rotator cuff, the use of HA injections led to a significant
improvement of shoulder function in all published trials
[19, 20, 22, 27, 28]. However, the superiority of HA over
other interventions in scales assessing pain is controversial,
and few studies have evaluated the efficacy of HA in the
treatment of lesions affecting a particular tendon. In this
regard, some authors have highlighted the need for further
randomized trials to better establish which grade of lesions
may benefit most from peritendinous injection of HA .
In this parallel-group, randomized, controlled trial, we
investigated the efficacy and safety of peritendinous
injection of HA in patients with persistent supraspinatus
tendinopathy. To this end, we compared the therapeutic
outcome of treatment with HA as an adjuvant to
physical therapy with that of physical therapy as sole
This was a prospective, randomized, open-label,
parallelgroup, phase IV trial to explore the efficacy of subacromial
injection of HA as adjuvant treatment for supraspinatus
tendinosis. Patients were recruited between March 2014
and August 2015 from four Spanish centers, including
one general hospital and three sports medicine centers.
The study protocol was approved by the ethics committee
of the Catalan Sports Council (Barcelona, Spain), and all
patients gave their written informed consent before
entering the study. All data were managed in agreement with
local personal data protection law (LOPD 15/1999).
Upon entering the study, patients were randomized
into two study groups using the Random Allocation
Software (version 1.0): the HA group was treated with
physical therapy + subacromial injection of HA (40 mg
sodium hyaluronate/2 mL, OSTENIL® TENDON, MW
1.6 MDa), and the control group was treated with phys
ical therapy only. The exercise plan within the physical
therapy standard of care (provided in the Additional file
1) was the same for both groups, and it was performed
at a physiotherapy center under individual guidance. All
patients started with three sessions per week, and the
schedule was then tailored at physician discretion on the
basis of patient progress. The physical therapy did not
include any intervention based on physical energy.
Patients in the HA group received two ultrasound-guided,
subacromial bursa injections at the baseline visit and at
day 7. Injections were performed with the patient in a
sitting position and the injured arm on the back, in
internal rotation. After identifying the inflamed
subacromial bursa in the ultrasound image, the needle was
inserted between the two bursa layers and the HA was
gently injected. In the case of presence of liquid inside
the bursa, a small amount of liquid was drawn before
injecting the HA. All participants were urged not to
undertake physical labor (e.g., bearing weight, practicing
sports, overstraining, etc.) with the affected arm during
the follow-up period. Concomitant treatment with
NSAIDs (400 mg ibuprofen up to 1200 mg daily,
according to the routine practice of participant centers) was
permitted. Patients were followed up at days 7, 15, 30,
and 90 after starting treatment. The patient discharge
was considered at physician discretion based on the
results of the ultrasound scanning.
The study population comprised subjects aged between
18 and 60 years with chronic, ultrasound-confirmed
supraspinatus tendinopathy of at least 4 weeks duration
and referring moderate pain (VAS score ≥6).
Recruitment was limited to active subjects (i.e., those who
performed daily physical labor in their workday and/or
attended the gym at least 2–3 times a week, where they
performed an aerobic activity for at least 50 min during
each session, with at least three sessions per week).
Patients who had undertaken physical rehabilitation for the
same injury in the 6 months prior to the study were
excluded from the record. Other exclusion criteria were
the presence of systemic diseases, previous shoulder
surgery, radiology-confirmed acromion type III in the Bigliani
scale , and other shoulder injuries: fracture or
dislocation, adhesive capsulitis, calcifying tendinopathy, total or
partial rotator cuff tears, and acromioclavicular and/or
glenohumeral joint diseases.
Study Endpoints and Variables
The primary endpoint was the assessment of efficacy
using the American Shoulder and Elbow Surgeons (ASES)
standardized shoulder assessment form [30–32]. The
ASES form includes the evaluation of pain by means of
the Visual Analog Scale (VAS) and the Activities of Daily
Living (ADL) scale, which scores the difficulties for
performing 10 everyday activities between 0 and 3. Secondary
endpoints included indirect measures of efficacy such as
the Tampa Scale for Kinesiophobia (TSK) , the
number of rehabilitation sessions needed for recovery (i.e.,
absolute discharge, confirmed by ultrasound imaging, and
return to daily activities, work and/or sporting activities),
the number of days required to return to work or to sport
activity, and physician and patient perception of the
efficacy of the treatment received (rated on a 0–4 scale,
where 0 was “very poor” and 4 was “excellent”). In
addition to recording all adverse events occurring during
the follow-up, the perception of patients and physicians
on treatment tolerability was assessed on a 4-point scale.
All variables were assessed at each visit.
The sample size was estimated considering a precision
in the mean ASES score of 14.5 (average between 12 and
17, considered the minimum difference in the mean
score to detect a relevant change in patients with rotator
cuff disease ), and a standard deviation (SD) of 17.5
(the average reported in previous studies [30, 34]).
Considering these assumptions, a study sample of at least 31
patients per group would provide a statistical power of
90% with a significance α level of 0.05.
The analysis was planned as an intention to treat
analysis; hence, patients lost to follow-up after the first visit
were included in the analysis. Continuous variables were
summarized using means and measures of variance,
whereas categorical variables were summarized using
frequencies and percentages. The means of the baseline
characteristics in each group were compared using the T
test, whereas the percentages were compared using
Fisher’s exact test. The differences in scores of the efficacy
scales between the baseline and the other study visits
within each group were assessed using the T test for
paired samples, whereas differences between the study
groups throughout the study were compared using an
ANCOVA test. On the other hand, the perceptions of
physicians and patients of tolerability and efficacy in each
study group were compared using the non-parametric
Mann-Whitney U test. The analysis was performed on
available data only, and thus no imputations were done
for missing values, which were eliminated pairwise. The
significance threshold was set at a α value of 0.05,
and all analyses were computed by an external
statistical team (Onmedic) using the SAS System statistics
software (Version 9.4.).
Of 84 patients starting the study, 42 were allocated to the
treatment group and 42 to the control group (Fig. 1). All
patients assigned to the HA group successfully received
treatment with HA according to the established schedule.
Patients who were lost to follow-up withdrew from the
study after visit 3 (one patient) and visit 5 (three patients)
referring no specific reasons for study withdrawal.
At baseline, patients allocated to the HA group and
the control group had no significant differences in their
Fig. 1 Flow diagram of the patients included in the study
demographic characteristics (Table 1). Regarding clinical
characteristics, the scores of all scales used in the efficacy
assessment were equal between the two groups, except
the TSK, which was significantly higher in the HA group
(25.4 [4.1] and 29.8 [4.3] mean [SD] for the control and
the HA group, respectively; P < 0.001). In this scale,
questions relating to the perceived threat of getting a poorer
health condition displayed the greatest differences
between groups. The overall baseline scores in the VAS and
ADL scales indicated a moderate affectation grade in our
study patients. Most patients had taken NSAIDs during
the month prior to the study start, but in most cases,
consumption was occasional.
Main Efficacy Scales
Patients in both groups experienced a significant
improvement in the VAS and ADL scores during the
follow-up period (P < 0.01 paired t test in all visits for both
scores in both intervention groups). After 90 days of
follow-up, the mean VAS score decreased 5.3 (SD 2.1;
95% CI 4.6–6.0) points in the control group and 6.4 (SD
1.54; 95% CI 5.9–6.9) points in the HA group; the
corresponding decline in the ADL score was 9.8 (SD 6.0; 95%
CI 7.9–11.6) and 11.0 (SD 4.7; 95% CI 9.5 – 12.5) points
in the control and the HA group, respectively. However,
the comparative analysis of the VAS and the ADL score
between groups did not reveal significant differences
Table 1 Baseline characteristics of study patients (percentages of
patients in categorical variables were calculated for each group)
HA group Control group P valuea
Age (years), mean (SD) 40.2 (12.4) 42.3 (11.5) 38.0 (13.1)
BMI (kg/m2), mean (SD) 24.5 (3.3) 24.6 (3.31) 24.5 (3.3)
between patients treated with HA and physical therapy
and those treated with physical therapy only (Fig. 2a, b).
Indirect Measures of Efficacy
In addition to the assessment of scales related to
function and pain, we investigated the impact of treatment
on indirect measures of efficacy such as the perceived
threat of movement and pain (by means of the TSK
scale), number of rehabilitation sessions and number of
days needed for complete recovery, and patient and
physician perception of efficacy. TSK scores were
significantly higher in the HA than in the control group in all
visits (Fig. 2d). However, patients in the HA group
experienced a significant improvement compared to baseline
from day 15 (P < 0.001 for comparisons between baseline
and visits at days 15, 30, and 90), whereas in the control
group, the variation of the TSK score from baseline was
only significant at day 90. In addition, the decrease in
TSK scores from baseline was significantly greater in the
HA group than in the control group from day 7 (P < 0.001
in all ANOVA paired test for comparisons at visits at days
7, 15, 30, and 90). After 90 days of follow-up, the decline
in mean (SD) TSK score was significantly greater in
the HA group: the mean TSK score decreased 2.4
(SD 4.2; 95% CI 1.1–3.8) in the control group and 3.6
(5.1; 95% CI 1.9–5.2) in the HA group from baseline to
day 90 (P < 0.001). The cumulative number of
rehabilitation sessions was significantly greater in the control group
at visits at days 30 and 90 (Fig. 2c). At the end of the
follow-up period, patients in the control group needed a
mean of 28 (SD 8; 95% CI 26–31) sessions, whereas those
in the HA group accounted a mean of 22 (SD 10; 95% CI
19–26) sessions (P = 0.006). On average, patients in the
HA group returned 12 days earlier to their pre-injury
activity (either work or sport) than those in the control
group (mean days was 32 [SD 21; 95% CI 26–39] in the
control group and 20 [SD 21; 95% CI 13–27] in the HA
group; P = 0.013). Treatment efficacy was also assessed by
means of patient and physician perception of each
treatment. Patients in the HA group rated the efficacy as
higher than those in the control group in all visits;
however, the differences in mean scores between groups were
only significant at days 15 and 90 (Fig. 3a). At the end of
the follow-up period, the mean scores (on a 4-point Likert
scale) were 3.1 (SD 1.0; 95% CI 2.8–3.4) and 3.5 (SD 0.8;
95% CI 3.2–3.7) in the control and the HA group,
respectively (P = 0.034). Accordingly, investigators considered
treatment with HA plus rehabilitation to be more
efficacious during the entire follow-up; in this case, significant
differences with the treatment based solely on physical
therapy were found at days 7, 15, and 30 (Fig. 3b). Lastly,
the NSAID consumption showed a progressive trend
towards a reduction during follow-up in the overall group
(from 39 patients taking NSAIDs at baseline to 16 patients
Affected shoulder, n (%)
44 (53%) 24 (59%) 20 (48%)
39 (47%) 17 (41%) 22 (52%)
52 (62%) 27 (64%) 25 (60%)
32 (38%) 15 (36%) 17 (40%)
7.22 (0.95) 7.33 (0.88) 7.11 (1.01)
17.2 (4.3) 16.9 (3.7) 17.5 (4.7)
27.6 (4.7) 29.8 (4.3) 25.4 (4.1)
NSAID consumption during the last month, n (%)
43 (51%) 24 (57%) 19 (45%)
35 (42%) 18 (43%) 17 (40%)
Fig. 2 Main efficacy outcomes. ASES American Shoulder and Elbow Surgeons standardized shoulder assessment form: ADL Activities of Daily Living
domain (a), VAS Visual Analogue Scale domain (b). Number of rehabilitation sessions needed for recovery (c). Tampa Scale for Kinesophobia (d). **p <
0.01 for control vs. HA groups comparison. ***p < 0.001 for control vs. HA groups comparison
at day 90). The percentage of patients who reported any
NSAID consumption at visits 2 to 5 were 50, 31, 15, and
18% in the HA group and 43, 33, 21, and 22% in the
control group. However, no significant differences were
observed between groups at any visit.
Tolerability and Safety
Based on patient perception, treatment with HA injections
and physical therapy was tolerated equally to that based on
physical therapy only (Fig. 3c). Accordingly, investigators
rated the tolerability of both interventions equally during
the first 15 days of treatment but considered that at days 30
and 90, treatment with HA and physical therapy had
greater tolerability than physical therapy only (Fig. 3d).
During the follow-up period, 10 patients (12%) reported
13 adverse events, all of which were considered mild: 5 in
the HA group, and 8 in the control group. Of 5 adverse
events reported in the HA group, 4 were found to be
related to treatment with HA, all of them pain after injection.
In this multicenter, parallel-group, randomized trial
including patients with supraspinatus tendinopathy, we
found that both physical therapy alone and physical
therapy combined with subacromial HA injections had
good tolerability and resulted in significant pain
reduction and successful functional recovery. When compared
to physical therapy only, patients treated with physical
therapy and HA returned significantly earlier to work
and needed fewer rehabilitation sessions.
The study groups were well balanced regarding the
baseline demographic and clinic characteristics,
including the prevalence of the affected shoulder, which was
mostly the right one, as expected for an overuse injury.
NSAID consumption was greater in the HA group;
however, no significant differences arose between the two
groups. Likewise, we did not observe significant
differences in the baseline scores of the assessed scales, except
the TSK, which was significantly higher in the HA
group. The TSK has been little used in the assessment of
HA treatment efficacy and measures the perceived threat
of movement and expected pain in injured patients. In
this regard, the fear of an injected treatment (not
existing in the control group, as no placebo treatment was
administered) could explain the discrepancy between the
different TSK score and the homogeneity in other
baseline measures of pain, such as the VAS score or NSAID
consumption. Overall, the baseline scores of the TSK,
Fig. 3 Perceived efficacy (a, b) and tolerability (c, d) outcomes, assessed on a 4-point Likert scale. *p < 0.05 for control vs. HA groups comparison.
**p < 0.01 for control vs. HA groups comparison. ***p < 0.001 for control vs. HA groups comparison
VAS, and ADL scales revealed a moderate severity of the
tendinopathy in our study patients.
After 90 days of follow-up, patients in both groups
experienced a significant improvement in the VAS, ADL,
and TSK scores, irrespective of the intervention
received. This result is consistent with previous studies
proving that treatment based solely on eccentric
strengthening is sufficient for mid-term improvement in
pain and function . When compared with physical
therapy only, we found that the addition of treatment
with subacromial HA significantly reduced the number
of rehabilitation sessions and the treatment days needed
for recovery. The reduction in the TSK score during the
follow-up period was also greater and occurred earlier in
the HA group, although the baseline differences between
scores in each group might have influenced the
differences observed during follow-up. In line with the better
therapeutic outcome observed in the HA group, both
patients and physicians rated significantly higher the
efficacy of the combined treatment of physical therapy
and subacromial HA than physical therapy only. In
the case of physician perception, combined treatment
was rated significantly higher than physical therapy
from the first visit (day 7).
In light of the differences observed between study
groups in the indirect measures of efficacy, we would
also expect more remarkable differences between groups
in treatment outcomes related to pain and the ability to
perform ADL. However, NSAID consumption and the
assessment of the VAS and ADL scores did not reveal
significant differences between patients treated with
physical therapy only and those treated with physical
therapy and subacromial HA injections. Of note, as a
clinical study performed on a medical device, the doses
of concomitant medicines were not recorded, and
therefore, no dose adjustment was performed in the
comparative analysis. Considering the proven efficacy of physical
therapy in the treatment of tendinopathies of the rotator
cuff, it seems reasonable that a larger sample size would
provide clearer differences between groups.
Nevertheless, the superiority of HA treatment in pain
improvement is unclear, and results in previous studies assessing
the efficacy of HA injections in patients with
tendinopathies affecting the rotator cuff are inconsistent. Merolla
et al. found that HA monotherapy significantly reduced
pain in more visits than physical therapy only ,
whereas Sengul et al. reported similar pain scores in
patients receiving both interventions . Similar
discrepancies have been found when investigating the efficacy
of a combined treatment using HA injections and
physical therapy. Thus, Meloni et al. concluded that
rehabilitation exercises and HA injections were significantly
more efficacious in pain reduction than the same
exercises accompanied with placebo injections containing
sodium chloride . On the other hand, Ozgen et al.
compared the efficacy of HA injections with that of
physical therapy and found no differences in pain
improvement in most of the follow-up visits . Of note,
the baseline VAS scores reported by Ozgen et al. in the
study sample were remarkably small (below 1), which
may have contributed to narrow the differences between
groups. On the other hand, the ADL score has been
barely assessed in trials investigating the efficacy of
injected HA in patients with tendinopathies of the
rotator cuff. In our study, all participants received clear
instructions not to undertake physical labor with the
affected arm until recovery. Such indication, not
included in pivotal trials assessing the reliability of the
ASES score [30, 31], allowed us to limit the bias related
to the different jobs and activities performed by each
patient; however, it was likely to influence the overall ADL
score, as patients may have limited their day-to-day
activities, regardless of their functional recovery and pain.
In line with safety data previously reported in the
literature [19, 20, 22], both interventions were safe and
well tolerated, with a 12% rate of adverse events rate—all
of them mild—, mostly reported by patients in the
control group. Furthermore, both patients and physicians
rated tolerability over 2.5 points on a 4-point Likert
scale during the entire follow-up. Perceived tolerability
progressively increased throughout the follow-up period,
and no significant differences were observed between
the study groups.
The main limitation of our study is the lack of control
groups. Unlike other studies, aimed at investigating the
efficacy of HA injections alone, our objective was to
compare the combined treatment with the gold-standard
for the management of tendinopathies. The presence of a
placebo group with non-active peritendinous injections
might have limited possible biases, particularly in
patientreported efficacy. Accordingly, the inclusion of a sham
physical therapy would have yielded more extreme
differences between groups. However, including more than two
intervention groups would have dramatically reduced the
size of each group. In fact, the final sample size (84
patients) was larger than that in most studies assessing the
efficacy of HA injections in tendinopathies of the rotator
cuff , but it still limited the observation of significant
differences in some scales. Along the same lines, the
open-label HA administration may introduce a bias in
both the physician and patient efficacy assessment. Finally,
due to the sample size limitations, all centers were
considered as a whole and no cluster analyses were performed to
explore the center bias.
Despite the limitations of our study, the results obtained
in most of the assessed scales are consistent and support
the use of subacromial HA injections as adjuvant
treatment to physical therapy in the management of
supraspinatus tendinopathy. In our experience, treatment
based only on physical therapy was sufficient to reduce
pain and improve function. In addition, the combination
of physical therapy with subacromial HA reduced the
number of rehabilitation sessions and recovery time.
These findings suggest that combined treatment with
physical therapy and HA may not only increase patients’
quality of life but it might also benefit the healthcare
system and society by reducing rehabilitation costs and
time off work.
Additional file 1: Rehabilitation protocol. (PDF 681 kb)
Authors would like to thank Montse Pujol, Fernando García, and Jaume Pérez
for their assistance in patient recruitment and data collection. Authors would
like to thank Onmedic Networks S.L. for help with statistical analysis and
Gerard Carot-Sans (PhD) for providing medical writing assistance during the
preparation of the manuscript.
Ramon Balius has received consulting fees for the study plan and financial
support for travel to meetings for the study from OPKO Health Spain, S.L.U.;
Guillermo Álvarez and Miguel A. Buil have received financial support for travel
to meetings for the study from OPKO Health Spain, S.L.U.; Luisa Varela and
Joaquín Casariego are employed by OPKO Health Spain, S.L.U. as Clinical
Research Manager and Medical Director, respectively. César Flores and Carlos
Cano declare that they have no conflicts of interest.
CF, RB, GA, MAB, LV, and CC were responsible for the study conception and
design. CF, RB, GA, MAB, and CC were responsible for the data collection. RB,
LV, and JC analyzed the dataset. CF, RB, MAB, LV, CC, and JC drafted the
original form of the manuscript. GA, LV, and JC performed critical revision of
the manuscript drafts. All authors read and approved the final version of the
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in
accordance with the ethical standards of the institutional and/or national
research committee and with the 1964 Helsinki declaration and its later
amendments or comparable ethical standards.
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