Effect of lidocaine iontophoresis combined with exercise intervention on gait and spasticity in children with spastic hemiplegic cerebral palsy: A randomized controlled trial

Abstract

BACKGROUND:

Gait deviations and spasticity are common impairments seen in children with cerebral palsy (CP) and may interfere with functional performance and effective walking pattern. Lidocaine iontophoresis is effective for reducing muscle spasticity in adults.

PURPOSE:

To investigate the effect of lidocaine epinephrine iontophoresis combined with exercises on gait and spasticity in children with spastic hemiplegic cerebral palsy (HCP).

METHODS:

Thirty children with spastic HCP aged 4–6 (5.20±0.32) years were randomly assigned to the experimental group (n = 15) and control group (n = 15). Children in both groups received one hour of exercises, three times a week for three months. Children in the experimental group received 2% lidocaine iontophoresis immediately before the exercises. The lidocaine iontophoresis was delivered for 20 minutes (1mA/min). Spatio-temporal gait parameters were assessed within one week before and after the intervention using 3D motion analysis. Surface electromyography was used to assess muscle tone using H/M ratio of the soleus muscle. ANOVA was used to investigate the differences between experimental and control groups. Statistical significance was set at P value less than 0.05.

RESULTS:

There was no difference between groups at baseline. Post-intervention, the experimental group showed significant improvements when compared to the control group for gait speed (p = 0.03), stride length (p = 0.04), cadence (p = 0.0001), cycle time (p = 0.0001), and H/M ratio (p = 0.02).

CONCLUSION:

Lidocaine iontophoresis combined with exercises was effective in improving gait spatiotemporal parameters and reducing spasticity in children with CP.

Keywords

Cerebral palsy lidocaine iontophoresis gait analysis EMG spasticity exercises

1 Introduction

Cerebral palsy (CP) is a well-recognized heterogeneous non-progressive neurodevelopmental disorder commencing in early childhood and persisting through the lifespan (Pakula et al., 2009). The prevalence of CP in developing countries has been reported to be between 1.5 and 2.5 per 1,000 live births (Korzeniewski, 2006). The clinical presentations of CP are variable and may include impairment in motor and sensory systems, communication, perception, emotion and cognitive function.

Impairments of motor function in children with hemiplegic cerebral palsy (HCP) involve paralysis or paresis of the muscles on one side of the body. These children usually present with abnormal gait pattern to varying degrees (Aminian et al., 2003). The most common gait pattern seen in children with HCP consists of equinus/equinovarus with in-toeing and a crouch (increased knee flexion on the hemiplegic side) in stance and a stiff knee in swing (Wren et al., 2005). Gait speed is decreased with shorter stride. The combined effects of spasticity and contracture in the gastro-soleus and the tibialis posterior are among the main contributing factors to gait abnormalities seen in these children (Graham, 2001).

Children with spastic HCP present with abnormal regulation of spinal motor neurons, causing alterations in postural and stretch reflexes, spasticity and voluntary movements. Spasticity is a common impairment seen in children with CP (Fragala et al., 2002; Lin, 2003) and may interfere with functional performance and ease of caregiving (Fragala et al., 2002). Spasticity may result in development of secondary problems (Love et al., 2001) such as contractures and stiffness.

Spasticity may contribute to limitations in motor function (Damiano et al., 2001) and may interfere with effective walking. Although there are many assumptions regarding the relation between spasticity and function, spasticity is thought to be inversely related to function, so the greater the spasticity the lower the level of function (Ross & Engsberg, 2007; Scholtes et al., 2006). Although there is limited research on the relationship between spasticity and gait in children with CP, a previous report has shown that spasticity in the lower extremity is associated with abnormal gait pattern (Tuzson et al., 2003). Improving walking and reducing muscle spasticity are crucial components in the rehabilitation of children with CP.

Treatment modalities for management of spasticity include positioning, stretching, exercises, splinting, oral medications, intrathecal baclofen, chemodenervation, neurolysis, botulinum toxin (BTX) injection and surgery (Flett, 2003). Lidocaine has been used in individuals with neurological disorders for management of pain and spasticity. Several studies have shown that intravenous, interathecal or local injection of lidocaine is effective in management of neurogenic pain and spasticity (Buffenoir et al., 2008, 2013). Lidocaine has been used initially as an anesthetic nerve block to evaluate the indications of surgery for management of spasticity. Previous reports showed that nerve blocks using lidocaine resulted in reduction in spasticity (Buffenoir et al., 2008, 2013; Ghroubi et al., 2014; Lee & Lee, 2008; Mezaki et al., 1999; RA, 1988) and improved gait function (Buffenoir et al., 2008). Lidocaine has been used locally as a topical anesthesia and can be applied directly to the surface of the skin or sprayed on the skin. Previous studies reported reduction in muscle spasticity following topical applications of local anesthetics (Sabbahi & De Luca, 1991). One advantage of the application of local anesthetics is that they are not associated with any systemic effects such as loss of consciousness and sleep.

Iontophoresis is used as a means of delivering drugs using bipolar electric fields to propel molecules across skin and into underlying tissue (Anderson et al., 2003). In addition, it allows transdermal induction of medications through the aqueous pores (i.e. hair follicles and sweat ducts) (Chen et al., 2013; T. Chen et al., 1998; Kumar & Banga, 2012). The potential benefits of transdermal delivery include direct application to the target tissues resulting in higher concentrations of medications without the systemic effects associated with the use of medications. The use of iontophoresis for transdermal drug transportation is common (Banga & Panus, 1998; Coglianese et al., 2011; Costello & Jeske, 1995; Karami et al., 2000; Li & Scudds, 1995) and has been used for the management of a variety of medical conditions. Lidocaine iontophoresis has been used clinically to decrease local tissue sensation as a treatment of pain and muscle spasm.

A previous study has shown that lidocaine delivered iontophoretically is effective for reducing muscle spasticity in adults (Coglianese et al., 2011). To the best of our knowledge, there are no studies found in the literature that examine the combined effects of lidocaine delivered iontophoretically combined with exercises intervention in children with spastic CP. Muscle spasticity may limit improvements and response to rehabilitation. It has been postulated that reduction of spasticity in children with cerebral palsy may allow the learning of normal movement patterns and utilization of selective motor control more effectively and functionally.

Lidocaine iontophoresis has the potential to reduce muscle tone. Combining lidocaine iontophoresis intervention with standard rehabilitation may offer greater benefits than standard rehabilitation only. Reduction of muscle spasticity followed immediately by therapeutic intervention may help to increase range of motion and allow the child to work on treatment activities and learn functional skills such as walking without interference of spasticity. The purpose of this study was to evaluate the effectiveness of lidocaine iontophoresis administered immediately before the exercises, as an adjunct to standard rehabilitation. We hypothesized that the addition of lidocaine iontophoresis would improve gait, reduce muscle spasticity and result in better outcomes when compared to standard rehabilitation in children with spastic HCP.

2 Methods

2.1 Trial design

This was a parallel group, single- blind, randomized controlled trial.

2.2 Setting and participants

In this randomized control study, participants were recruited from the outpatient rehabilitation unit, Faculty of Physical Therapy, Cairo University. The participants were children with spastic hemiplegic cerebral palsy (HCP) who were referred to receive a physiotherapy program in the outpatient rehabilitation unit. A random sample (n = 30) was selected to participate in the present study as shown in the flowchart (Fig. 1).

Fig. 1

Recruitment flowchart.

Subjects were recruited according to the following inclusion criteria: 1) a clinical diagnosis of spastic hemiplegic cerebral palsy; 2) age ranged from 4–6 years; 3) degree of spasticity ranged from mild to moderate spasticity [Grade1–2] for the affected lower limb according to the Modified Ashworth Scale (Akpinar et al., 2017); 4) ability to walk independently without any assistive devices. Children were excluded from this study if they had: 1) attention deficit disorders; 2) lower limbs structural deformities or fixed contractures; 3) orthopaedic surgery in the lower limbs 12 months back to participation in the study; 4) Botulinum toxins (BTX) injection in the last six months prior to participation in the study; and 5) Cognitive, visual, perceptual or auditory defects which could interfere with the evaluation procedures.

A written informed consent form was obtained from each participant’s care givers before enrollment in the study. All parents or care givers were informed about the study objectives prior to the study. The study was approved by the Human Research Ethics Committee, Cairo University, Egypt. This clinical trial has been registered in the Pan African Clinical Trial Registry under number PACTR201703002114301. The current study report followed the CONSORT statement guidelines for reporting parallel group randomized trials.

2.3 Sample size calculation

Considering the statistical significance level set at p < 0.05 and the statistical power of the study at 80%; the following formula was used to calculate the sample size (Charan & Biswas, 2013): $Sample size = \frac{2 S D^{2} {(Z \propto / 2 + Z_{β})}^{2}}{d^{2}}$ (1)

SD: standard deviation from a previous pilot study (SD = 0.7). Z_α/2 is the standard normal variate which equals 1.96 (from Z table) at 5% type 1 error (p < 0.05). Z_β: 0.842 (from Z table) at 80% power. d: effect size. In the current study it was assumed to be d = 0.8 [obtained from a previous pilot study done by our research group]. Hence, the calculation would be: $Sample size = \frac{2 {(0.7)}^{2} {(1.96 + 0.84)}^{2}}{{(0.8)}^{2}} = 12$ (2)

This means that the minimal size for each group is 12 subjects (a total of 24). Therefore, thirty participants (n = 30) were considered for the current study assuming any missing data during the study due to participant withdrawal.

2.4 Random assignment

After confirming eligibility, receiving consent and prior to baseline assessment, the participants were randomly allocated to the experimental group or control group (ratio 1 : 1) using the block randomization method with varying block sizes to ensure an equal number of participants were allocated in each group.

A computer-generated block randomization was created by an independent statistician who was blinded to the study objectives and participants’ identity. Allocation was concealed from the recruiter through the use of sealed consecutively numbered opaque envelopes. The recruiter had received these envelops just before recruiting the participants. Each envelop was opened only in the presence of the recruited participant. Participants were randomly assigned to an experimental group (n = 15) or a control group (n = 15) as shown in Fig. (1).

2.5 Intervention

Children in both groups received one hour of traditional exercise interventions three times a week for three months. The exercise interventions targeted the development of gross motor skills such as balance and walking. Exercise intervention included flexibility exercises, facilitation techniques, and balance and gait training activities.

Children in the experimental group received 2% lidocaine epinephrine (Lidoderm, Endo Pharmaceuticals, Chadds Ford, PA, USA) iontophoresis 20 minutes prior to each exercise session (Iontophor TM Model 611, Life Tech, Inc., Houston, TX, USA). The iontophoresis protocol was reported in previous studies (Coglianese et al., 2011; Kumar & Banga, 2012). The lidocaine epinephrine iontophoresis was administered by the principal investigator. The lidocaine was delivered via 20 minutes (1 mA/min per muscle) iontophoresis treatment. The lidocaine was applied to gastrocnemius/soleus, quadriceps and hip adductor muscles. Lidocaine iontophoresis was followed immediately by a one hour exercise intervention. After completion of the iontophoresis and removal of the electrodes, the medications delivery and its retention in local tissue were monitored by the principal investigator by observing evidence of localized cutaneous vasoconstriction under the delivery site.

2.6 Assessment

Both groups were evaluated within one week before and after the intervention program by an independent investigator who was blinded to the study objectives, participants’ allocation, groups and participants’ identity to avoid bias. This investigator had over seven years of experience in the EMG and gait analysis lab; furthermore, he attended a four hour workshop prior to the study to ensure that he could perform the measurements properly. The outcome measures were EMG and gait analysis. Gait was assessed using Qualisys motion capture system (Proreflex MCU 500 Hz, Qualisys Medical AB, Gothenburg, Sweden), and surface electromyography (EMG) was used to assess muscle tone using Hoffman reflex/Myogenic (H/M) response ratio of the soleus muscle.

The Qualisys motion capture system consists of six infrared cameras and reflective markers used to capture each child’s gait. A set of lower body reflective markers were attached bilaterally on the following anatomical landmarks: iliac crests, posterior iliac spines, greater trochanters, lateral femoral condyles, lateral malleolus and heads of the fifth metatarsals. The cameras were positioned in a manner that ensured that each marker was captured at any point in time by a minimum of three cameras. The cameras were calibrated before each data collection session. Each trial was analyzed using the QGait software package. The variables of interest were gait speed, stride length, cadence and cycle time.

Electromyography was used to assess muscle tone using Hoffman reflex/Myogenic (H/M) response ratio of the soleus muscle (Sabbahi & De Luca, 1991). Hoffman reflex was recorded using a four channel Toennies electromyograph and NeuroScreenplus software (Erich Jaeger GmbH, Hoechberg, Germany). Surface electrodes were used for recording EMG signals from the soleus muscle following stimulation of the tibial nerve in the popliteal fossa.

The testing procedure was performed while the child was in prone position with the tested leg supported but the ankle motion was not limited. Muscle was palpated to confirm proper electrode placement. The skin was cleaned with alcohol prior to placement of electrodes. The active electrode was placed on the distal third of the soleus muscle below the insertion of the gastrocnemius muscle onto the Achilles’ tendon in order to selectively record signals from soleus muscle, while, the reference electrode was placed 3 cm distal to the active electrode. A similar protocol was reported previously (Ferris et al., 2001; Palmieri et al., 2002).

Maximum Hoffman reflex (HR) and maximum myogenic response (MR) were recorded along with the ratio of the Hoffman response and motor response (H/M ratio) in order to measure the motor neuron pool excitability which reflects the level of spasticity as an indication of central nervous system excitability (Voerman et al., 2005). The validity and reliability of the H/M ratio of the soleus muscle as a method of assessing spasticity have been supported. All assessments were performed in the motion analysis and EMG laboratory.

2.6.1 Data analysis

Normality of data distribution was investigated using the Shapiro-wilk test. Descriptive statistics (mean and SD) were used to describe participants’ demographics. The dependent variables in this study were H/M ratio and spatial and temporal gait parameters including gait speed, stride length cadence and cycle time. The post-training differences in the dependent variables were compared in the study groups using 2×2 repeated measures analysis of variance (ANOVA). Data was analyzed using SPSS version 23 (IBM corp., Armonk, NY, USA). For all statistical tests we used a significance level of p < 0.05. An intention to treat analysis was considered as an approach for managing data in the current study.

3 Results

Of the 55 children screened, 30 were eligible and agreed to participate in the study. A total of 30 children with hemiplegic cerebral palsy (HCP) (17 with right side HCP and 13 with left side HCP) participated and completed the study (Fig. 1). The age of the participants ranged from 4–6 years old with a mean±SD of (5.20±0.32 years).

There were no missing data in the current study as all the participants continued intervention and analysis. The clinical characteristics of the participants are shown in Table 1. There was no significant difference between the experimental and control groups in the demographic characteristics (Table 2). No significant differences were found for the outcome measures between the experimental and control group at the start of the study (P > 0.05).

Table 1
Demographic characteristics of the study participants (n = 30)

Subjects Age (years) Sex Diagnosis MASKE MASAP

1 5.9 M Rt HCP 1 1

2 6 F Rt HCP 1+ 1+

3 4 F Rt HCP 2 2

4 6 M Rt HCP 2 2

5 5.7 M Lt HCP 1+ 1+

6 4.8 F Lt HCP 1+ 1+

7 5.6 M Rt HCP 1 1

8 4.8 F Lt HCP 1 1

9 5.2 F Lt HCP 1+ 1+

10 6 F Rt HCP 1+ 1+

11 5.8 M Rt HCP 1 1

12 5.6 M Rt HCP 1+ 1+

13 5.2 M Lt HCP 2 2

14 6 M Lt HCP 1+ 1+

15 4 F Rt HCP 1 1

16 4.3 M Rt HCP 2 2

17 6 F Lt HCP 1 1

18 6 F Rt HCP 1+ 1+

19 5.8 M Lt HCP 2 2

20 4.2 M Rt HCP 2 2

21 5.7 F Rt HCP 1+ 1+

22 4.9 M Lt HCP 1+ 1+

23 6 M Lt HCP 2 2

24 5 F Lt HCP 1 1

25 5.3 F Lt HCP 1+ 1+

26 5.8 F Rt HCP 1 1

27 6 M Lt HCP 2 2

28 4.8 F Rt HCP 1 1

29 4.7 F Rt HCP 2 2

30 4.9 M Rt HCP 2 2

Subjects	Age (years)	Sex	Diagnosis	MASKE	MASAP
1	5.9	M	Rt HCP	1	1
2	6	F	Rt HCP	1+	1+
3	4	F	Rt HCP	2	2
4	6	M	Rt HCP	2	2
5	5.7	M	Lt HCP	1+	1+
6	4.8	F	Lt HCP	1+	1+
7	5.6	M	Rt HCP	1	1
8	4.8	F	Lt HCP	1	1
9	5.2	F	Lt HCP	1+	1+
10	6	F	Rt HCP	1+	1+
11	5.8	M	Rt HCP	1	1
12	5.6	M	Rt HCP	1+	1+
13	5.2	M	Lt HCP	2	2
14	6	M	Lt HCP	1+	1+
15	4	F	Rt HCP	1	1
16	4.3	M	Rt HCP	2	2
17	6	F	Lt HCP	1	1
18	6	F	Rt HCP	1+	1+
19	5.8	M	Lt HCP	2	2
20	4.2	M	Rt HCP	2	2
21	5.7	F	Rt HCP	1+	1+
22	4.9	M	Lt HCP	1+	1+
23	6	M	Lt HCP	2	2
24	5	F	Lt HCP	1	1
25	5.3	F	Lt HCP	1+	1+
26	5.8	F	Rt HCP	1	1
27	6	M	Lt HCP	2	2
28	4.8	F	Rt HCP	1	1
29	4.7	F	Rt HCP	2	2
30	4.9	M	Rt HCP	2	2

M: Male; F: Female; MASKE: Modified Ashworth Score for Knee Extensors; MASAP: Modified Ashworth Score of Planter Flexors; HCP: Hemiplegic cerebral palsy; Rt: Right; Lt: Left.

Table 2

Descriptive statistics of the experimental and control groups

Variables	Experimental group	Control group
	(n = 15)	(n = 15)
Age (years)	5.21 (0.32)	5.28 (0.30)
Height (meter)	1.30 (0.04)	1.32 (0.05)
Weight (kg)	27.43 (0.91)	27.56 (0.89)
BMI	16.25 (0.61)	16.31 (0.65)
Male	8 (53.3%)	7 (46.7%)
Female	7 (46.7%)	8 (53.3%)
RT HCP	9 (60%)	8 (53.3%)
LT HCP	6 (40%)	7 (46.7%)

Data are presented as mean (standard deviation) for quantitative variables, whereas categorical data are presented as an absolute value (percentage %). RT HCP: Right hemiplegic cerebral palsy; LT HCP: Left hemiplegic cerebral palsy.

There was a statistically significant difference between the experimental and control group for the H/M ratio (p = 0.03). A statistically significant difference was found between experimental group and control group in gait speed (p = 0.03), stride length (p = 0.04), cadence (p = 0.0001) and cycle time (p = 0.0001), as presented in Table 3. There was no adverse response reported as a result of lidocaine iontophoresis or participation in the study (Fig. 2).

Fig. 2

Spatio-temoral gait parameters and H/M ratio for the experimental and control groups.

Table 3

Pre- and post-intervention measures for the experimental and control groups

Variable	Pre-intervention (n = 15)		Post-intervention (n = 15)		MD	P-value
	Mean (SD)		Mean (SD)		(post-intervention)
	Experimental	Control	Experimental	Control
Gait speed (m/sec)	0.63 (0.08)	0.58 (0.09)	0.82 (0.07)	0.74 (0.16)	0.80	0.03
Stride length (m)	0.56 (0.08)	0.51 (0.09)	0.79 (0.07)	0.70(0.10)	0.90	0.04
Cadence	135.93 (5.02)	138 (4.85)	120.86 (5.01)	128.26 (5.45)	7.40	0.0001
Cycle time (sec)	0.78 (0.09)	0.76 (0.08)	0.96 (0.07)	0.92 (0.07)	0.40	0.0001
H/M ratio	0.81 (0.46)	0.77 (0.42)	0.68 (0.45)	0.74 (0.39)	0.13	0.03

m: Meters; m/sec: Meters/second; sec: Seconds; MD: Mean difference; P value: Probability value.

4 Discussion

Our results showed that lidocaine iontophoresis in conjunction with exercise interventions three times a week for three months resulted in a reduction in muscle spasticity and improved gait in children with hemiplegic cerebral palsy (HCP). These improvements are important because gait abnormality is usually seen in these children and is frequently responsible for limited community participation, limited ability to participate in activities such as playing with their peers and long-term disability in children with cerebral palsy (CP).

The feasibility of the intervention was supported by adequate recruitment, ease of application of the lidocaine iontophoresis and implementation of the exercise interventions. Moreover, there were no adverse events or injuries reported following the application of lidocaine iontophoresis. The safety data is an important consideration when delivering medications or using physical modalities in young children or children with disabilities including children with CP. The strength of this study is the application of lidocaine iontophoresis combined/followed immediately by exercise intervention. In general, studies that utilized anti-spastic measures to control spasticity either did not include exercise intervention or physical therapy was not implemented immediately following the application of anti-spastic measures.

To the best of our knowledge, this is the first study that examined the effects of lidocaine iontophoresis combined with exercise intervention in children with spastic HCP. Comparison among our findings and other studies is difficult since there are no other studies that examined the effects of lidocaine iontophoresis combined with exercise in children with CP.

The important findings of this study were that: 1) application of lidocaine iontophoresis followed immediately by exercise intervention was feasible and safe for children with spastic HCP; and 2) the combined effects of lidocaine iontophoresis and exercise intervention offered greater benefits than standard rehabilitation only. Our results showed that the application of lidocaine iontophoresis combined with exercise produced significant reduction in spasticity and improvements in gait parameters in children with spastic HCP.

In children with spasticity, intervention should not focus on treatment of spasticity because it is present but treatment should instead focus on minimizing the impacts of spasticity on function (Nahm et al., 2018). Thus management of muscle spasticity should be directed at allowing sensory motor experience, ability to move and experience new movement patterns without interference from spasticity. Exercise interventions play a critical role in the management of children with CP. Although exercise interventions may or may not reduce spasticity, the interventions can be valuable to allow the child to experience new movement pattern and assist the child to acquire skills that are difficult to perform and/or acquire in the presence of spasticity.

Currently, there is no ideal treatment for children with CP. Standard management typically includes combination of various treatment modalities such as anti-spastic treatment and exercise interventions. While lidocaine iontophoresis alone has been shown to reduce spasticity, we believe that the use of lidocaine iontophoresis in conjunction with exercise interventions synergistically resulted in the improvement in gait function observed in this study. It has been postulated that reduction of spasticity in children with cerebral palsy may allow the learning of normal movement patterns (Love et al., 2001) and enable utilization of selective motor control more effectively and functionally (Flett, 2003). We believe that reduction in muscle spasticity combined with exercise interventions may have provided the children with sensorimotor experiences and opportunities to experience normal movement patterns; and may have allowed the children to work on treatment activities and learn functional skills such as walking without interference of spasticity. This might have allowed the children to refine their movements and develop more normal walking pattern, which may have contributed to improvements in gait functions seen in this study.

The clinical literature has fairly well established that children with spastic hemiplegia have impairments in muscle tone and mobility function including gait. Children with CP typically present with slower gait speed and short stride length. Management of gait in children with spastic CP is challenging. Our results showed that the children in the experimental group have faster gait speed and longer stride length than children in the control group. This is particularly important as improvement in gait parameters and progress toward normal gait speed and stride length reflect improvements in functional abilities.

4.1 Limitations and future research

There were several limitations to the present study that should be considered. A major limitation in the present study is that the treating and evaluating investigator was not blind to the study groups. The lack of a follow-up period did not allow for examination of the ability to maintain improvement in gait after the cessation of medication combined with exercise intervention. Future studies should include a follow-up period to determine the long-term effect of the interventions. Future studies should identify the appropriate dose and duration of application. Further studies are needed to determine the effects of lidocaine iontophoresis combined with exercise on other forms of CP and other levels of functional abilities. Finally, this study could have been strengthened if we included a true control group of children who did not participate in exercise during the study.

In the present study, children with spastic HCP were treated with lidocaine iontophoresis combined with exercise intervention showed improvement in gait parameters and reduction in muscle tone compared to children in the control group. The improvement in gait parameters might be due to combined effects of reduced muscle tone and exercise intervention. Reduction in muscle tone might have provided sensorimotor experiences and opportunity to experience normal movement patterns during exercise intervention and allowed children to gain more selective motor control. The combined effects of lidocaine iontophoresis and exercise intervention of longer duration or using different outcome measures such as gross motor function measures still must be explored. Furthermore, future studies should examine benefits of the intervention model used in this study for children with other types of spastic CP, particularly children who are not ambulatory or have gait limitations secondary to spasticity.

Conflict of interest

None to report.

Funding

None to report.

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