The effect of anti-nausea wristbands and STW-5 in children suffering from dyspepsia – a randomized double-blind placebo-controlled pilot-study

Abstract

Background

Functional dyspepsia (FD) is common in children and refers to discomfort in the epigastric/duodenal region, which cannot be explained by structural or biochemical abnormalities. Since the pathophysiology is still not fully understood, no guidelines in terms of treatment do exist.

Aim

The aim of this study was to compare the therapeutical effect of plant extracts (STW-5) and acupressure in children with functional dyspepsia.

Methods

This is a randomized, double-blind placebo-controlled trial. Before and after the allocated intervention of four weeks, participants had to fill in a cross-cultural validated questionnaire consisting of 52 questions to assess quality of life, as well as the extent of their discomfort (using a standardized visual analog scale (VAS)).

Results

33 patients were included in the study: 12 male and 21 female with an average age of 12.09 years (range: 7–17 years). Symptoms improved after four weeks of intervention in most treatment-groups: By 68% in children, who received STW-5, by 40% in the wristband (WB)- group and by 35% in the wrist-band-Placebo-group (WBPL). Patients receiving STW-5- Placebo showed even an increase of symptoms.

Discussion

This double-blind, placebo-controlled pilot study showed, that STW-5 and/or anti-nausea wristbands are a cheap and effective option to treat children and teenagers suffering from functional dyspepsia.

 

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Zusammenfassung

Hintergrund

Funktionelle Dyspepsie (FD) ist bei Kindern häufig und bezieht sich auf Beschwerden in der epigastrischen/duodenalen Region, die nicht durch strukturelle oder biochemische Anomalien erklärt werden können. Da die Pathophysiologie noch immer nicht vollständig geklärt ist, gibt es keine Leitlinien für deren Behandlung.

Ziel

Das Ziel dieser Studie war es, die therapeutische Wirkung von Pflanzenextrakten (STW-5) und Akupressur bei Kindern mit funktioneller Dyspepsie zu vergleichen.

Methoden

Es handelt sich um eine randomisierte, doppelblinde, Placebo-kontrollierte Studie. Vor und nach der jeweiligen vierwöchigen Intervention mussten die Teilnehmer einen kulturübergreifenden, validierten Fragebogen mit 52 Fragen ausfüllen, um die Lebensqualität sowie das Ausmaß ihrer Beschwerden (anhand einer standardisierten visuellen Analogskala (VAS)) zu bewerten. Ergebnisse: 33 Patienten wurden in die Studie eingeschlossen: 12 Männer und 21 Frauen mit einem Durchschnittsalter von 12,09 Jahren Range: 7–17 Jahre). Die Symptome verbesserten sich in den meisten Behandlungsgruppen nach der vierwöchiger Behandlung: Um 68% bei Kindern, die STW-5 erhielten, um 40% in der Armband (WB)-Gruppe und um 35% in der Armband-Placebo-Gruppe (WBPL). Patienten, die STW-5-Placebo erhielten, zeigten sogar eine Zunahme der Symptome.

Diskussion

Diese doppelblinde, Placebo-kontrollierte Pilotstudie hat gezeigt, dass STW-5 und/oder Anti-Nausea-Armbänder eine kostengünstige und wirksame Option zur Behandlung von Kindern und Jugendlichen sind, die an funktioneller Dyspepsie leiden.

 

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Keywords

children - functional dyspepsia - anti-nausea bands - Placebo

Schlüsselwörter

Kinder - funktionelle Dyspepsie - anti-Nausea Bänder - Placebo

What is known

▪many children suffer from functional epigastric discomfort ▪ the pathophysiology is complex, therefore no standard guidelines for the treatment exist

 

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What is new

▪STW-5 and anti-nausea wristbands are a cheap and effective options to treat children suffering from functional dyspepsia ▪a reduction of gastrointestinal symptoms did not correlate with an improvement of cognitive performance

 

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Background

Functional gastrointestinal disorders (FGIDs) are very common in children of all ages. It is an umbrella term for discomfort in any part of the gastrointestinal tract, which cannot be explained by structural or biochemical abnormalities [1]. FGIDs are diagnosed according to the symptom-based Rome criteria, which have been revised in 2016 (Rome IV criteria, [2]) and rely on the medical history and physical examination. Dyspepsia refers to the Greek words ‘dys’ and ‘peptos’ and is translated with ‘hard to digest’. Functional dyspepsia (FD) is a sub-group of FGIDs, it is a clinical syndrome comprising chronic symptoms arising from the gastroduodenal region. According to the Rome criteria, the prototypical symptoms are postprandial fullness, early satiation, epigastric pain or burning not associated with defecation. The diagnosis of FD can be made in children and teenagers, once one of those symptoms occur a minimum of four times a month for at least two months and after appropriate evaluation, to ensure that the symptoms cannot be explained by another medical condition [2]. The pathophysiology is still not fully understood, but it seems to rely on a combination of visceral hypersensitivity, motility disturbances, alteration in gastrointestinal microbiota, mucosal and immune function and central nervous processing [3].

Treatment of FD is challenging and based on empiric strategies due to the lack of published treatment trials on chronic nausea, especially in children. Studies suggest that hypnotherapy targets the aetiologic biopsychosocial factors and therefore modifies visceral hypersensitivity [4].

Herbal medications have multiple mechanisms of action in virtue of diverse components potentially regulating various, complex aetiologies simultaneously and comprehensively improve symptoms of FGIDs. The herbal combination STW-5 (Iberogast) was shown to relax muscle activity in the fundus area of the stomach but to enhance the contractions in the antrum area in an animal study [5]. In a study with healthy adults, administration of STW-5 led to a significant increase in proximal gastric volume measured with a gastric barostat, whilst the antral pressure wave increased [6]. STW-5 is a liquid preparation including fresh plant extracts from eight dried herbs and is sold across Europe as over-the-counter medication. Overall, it regulates motility by acting on the gastrointestinal smooth muscles in an area-specific manner, stimulates gastric secretion and exerts spasmolytic, choleretic, anti-inflammatory and carminative effects [7] [8]. Several studies proved its efficacy in adults suffering from FD [9] [10], but no data for children is available.

Another – on first sight unusual – approach to overcome nausea is the use of acupuncture (needling), acustimulation (electrical stimulation) or constant pressure (acupressure) to the P6 acupuncture point (located on the side of the wrist), which is recognized as a target pint in Chinese and acupuncture medicine for reducing nausea and vomiting. It seems, that the effect of this method is an electrical stimulus of low frequency on sensory receptors in the skin, which are activators of A delta and A beta fibers. These fibers synapse in the posterior horn and this might result in release of endorphin in the hypothalamus [11]. The increase in beta-endorphin concentration in human CSF after acupuncture stimulus has been described [12].

The aim of this study is to compare the therapeutical effect of plant extracts and acupressure in children with functional dyspepsia and perform a standardized test of cognitive psychology.

 

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Methods

This is a randomized controlled double-blind trial of paediatric patients with FD. Children between the age of 6 and 18 years, who complained about gastric symptoms (pain, nausea, fullness) and had a normal full blood count, a normal thyroid function, a negative coeliac screening (normal t-transglutaminase antibodies, normal total IgA) and most importantly normal macro- and microscopic findings on oesophago-gastro-duodenoscopy (all had biopsies taken from duodenum, stomach and oesophagus) were informed about the study between September 2016 and September 2020. Exclusion criteria were gastrointestinal infection less than two weeks ago, an underlying gastrointestinal disease, use of drugs two weeks prior to starting the study. After signing the informed consent by the participant and/or legal representative respectively, patients were asked to fill in the Kidscreen-52, a cross-cultural validated questionnaire consisting of 52 questions to assess the health-related quality of life [13], as well as the extent of their discomfort (using a standardized visual analog scale (VAS), points 1–10). In addition, participants had to take a quick test on the computer: Eriksen flanker task [14], a validated task used to study cognitive processing, attention and control processes (e. g. interference, activation and inhibition). Patients themselves drew a lot, where the type of treatment (Iberogast/wrist band) was determined, of course neither the patient nor the study nurse knew whether an original product or the placebo equivalent was given. Patients were randomized allocated to four different treatment-groups

1. Children get treated with STW-5 (Iberogast (IB)), dosage as per recommendation of the producer (Children<12 years: 3x 20 drops a day; Children<12 years: 3x15 drops a day): They received the original STW-5 in a neutral bottle without primary package and label

2. Children get treated with an Iberogast-Placebo (IBPL), same dosage as original STW-5: They received the same neutral bottle, containing Placebo. To get the same acerbity as the original product, quinine and brown food coloring for the appearance was used. This was also prepared and blinded by the Hospital Pharmacy.

3. Children receive a wristband (WB) with the effect of an acupressure (psiBands): They received an official acupressure wrist band, that must be worn over the whole time (the correct area is in between the two tendons on the underside of the wrist- two finger widths from first crease in wrist) without the original packaging

4. Children receive a Placebo wristband ((WBPL), same wristband without an effect of acupressure), which must be worn all the time (the correct area is in between the two tendons on the underside of the wrist- two finger widths from first crease in wrist) without the original packaging.

Participants had to take the allocated medication or wear the wristbands for a total of four weeks and keep a diary about the daily complaints. At the end of the four weeks, participants had to fill out the same questionnaire concerning quality of life and extent of medical condition, and they were asked to re-do the flanker task. [Fig. 1] displays the course of the study.

Fig. 1 Study method.

Statistical analysis

Statistical analysis was performed with SPSS 22.0 for Windows. As the visual analog scale possesses interval and ratio properties, it was treated as numerical data. One-way ANOVA was used to compare baseline values between the four groups. Subsequently, 4 groups by 2 (time: baseline, post-intervention) ANOVA with repeated measures on the second factor was employed to analyse the effect of therapy on functional nausea. Main effects and interactions were reported. When significant F-ratios were obtained, Bonferroni was used as post hoc test for individual comparison. For all statistical comparisons, an alpha level of p≤0.05 was considered significant. Eta-squared (eta²) was measured as effect size and interpreted after Cohen [15] as following: > 0.01 (small), > 0.06 (medium) and >0.14 (large).

 

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Ethical statement

The present study was approved by the ethical committee. Furthermore, the study was conducted in accordance to the ethical principles laid down in the Declaration of Helsinki and its later amendments.

 

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Results

From 273 children suffering from nausea with normal macroscopic and histological findings in an upper endoscopy, 60 patients agreed to participate in the study, of which 27 terminated the participation due to fading symptoms whilst the trial. Therefore, a total of 33 patients were included in the study: 12 male and 21 female with an average age of 12.09 years (7–17 years), an average weight of 47.2 kg (range: 22–105 kg) and an average length of 151 cm (range: 120–179 cm). For further patient characteristics and allocation to the different treatment groups, we refer to [Table 1].

Table 1 Patient’s characteristics

	Male				Female				In total (female and male)
	n	Mean age (years)	Mean weight (kg)	Mean height (cm)	n	Mean age (years)	Mean weight (kg)	Mean height (cm)	n	age in years (range)	weight in kg (range)	Height in cm (range)
IBPL	2	13.5	48.2	155.5	4	14	67	168	6	13.8 (12–16.5)	60.7 (34–90)	163.8 (153–179)
IB	1	13.5	42.5	168	6	12.4	47.4	149.8	7	12.6 (8.3–17.8)	46.7 (18.8–105)	152.4 (122–179)
WB	6	9.9	31.8	134.2	9	11.4	40.8	147.7	15	10.8 (7.5–17)	37.3 (20–65)	142.3 (117–170)
WBPL	3	9.8	38.8	136.6	2	11.25	35.5	142	5	10.4 (6.5–12.5)	37.5 (26–59.5)	138.8 (122–155)

IBPL: Iberogast-Placebo; IB: Iberogast; WB: Wrist band; WBPL: Wrist band Placebo

Subjectively, symptoms improved after four weeks of intervention in most treatment-groups: By 68% in children, who received Iberogast (IB), by 40% in the wristband (WB)- group and by 35% in the wrist-band-Placebo-group (WBPL). Patients receiving Iberogast-Placebo (IBPL) showed an increase in symptoms by 10% over the treatment course of four weeks. [Fig. 2] illustrates the subjective, overall state of health pre- and postinterventional of the four treatment-groups as described above.

Fig. 2 a The course of the overall, subjective state of health b ) The course of the overall, subjective state of health.

The analysis of the Kidscreen-52 showed, that she sleeping pattern and physical state improved in all four treatment groups, also the number of symptom-free days increased in all patients. Overall happiness showed a positive shift after four weeks of treatment, except for the patients treated with IBPL.

When comparing the results of the Flanker task, there were no statistically significant changes after the intervention, except for the WBPL intervention group, which showed a significant improvement in the accuracy of reaction. All results mentioned and further statistical results can be found in [table 2].

Table 2 Results

			pre-intervention		post-intervention
			mean (range)	SD	mean (range)	SD	d	F	p	eta2
Results Questionnaire Quality of life	Overall (degree of symptoms in the previous 7 days, from 0–10 using the VAS)	IB	4.14 (2–6)	2.04	1.29 (0–4)	1.50	1.60
		IBPL	3.00 (0–6)	2.00	3.33 (0–6)	1.75	− 0.18
		WB	4.00 (0–8)	1.81	2.40 (0–8)	2.69	0.70
		WBPL	2.80 (0–6)	1.79	1.80 (0–3)	1.10	0.67
	Symptom-free (on how many days of the previous week was the patient completely without any symptoms; 1–7)	IB	3.14 (0–7)	2.91	4.14 (2–7)	1.68	− 0.42
		IBPL	2.38 (0–7)	2.88	3.63 (0–7)	2.39	− 0.47
		WB	2.06 (0–7)	1.92	3.12 (0–7)	2.37	− 0.49
		WBPL	4.33 (2–7)	1.73	4.78 (2–7)	1.92	− 0.24
	Sleep (difficulty falling/staying asleep, amount of distress about sleep; 0–28 points)	IB	8.86 (4–17)	5.34	6.14 (o-21)	7.27	0.43
		IBPL	11.25 (2–18)	6.63	9.00 (0–21)	8.23	0.30
		WB	8.53 (0–19)	5.70	6.16 (0–16)	5.24	0.43
		WBPL	8.44 (1–20)	5.22	6.44 (0–23)	7.30	0.32
	Physical state (did the patient feel fit and able-bodied, be comfortable; 4–20 points)	IB	15.00 (11–22)	4.58	18.71 (10–22)	4.27	− 0.84
		IBPL	16.50 (13–23)	4.34	17.25 (12–22)	4.65	− 0.17
		WB	17.79 (10–24)	4.44	19.11 (7–24)	5.05	− 0.28
		WBPL	16.67 (12–22)	3.35	18.22 (10–23)	3.99	− 0.42
	Emotion (was the patient happy, content and pleased to be alive in the last 7 days; 6–30 points)	IB	23.00 (19–29)	3.37	25.86 (19–30)	3.63	− 0.82
		IBPL	25.00 (18–30)	4.21	24.38 (18–29)	4.47	0.14
		WB	25.32 (15–28)	3.83	26.63 (23–30)	2.54	− 0.40
		WBPL	23.22 (12–28)	4.94	23.89 (12–30)	6.23	− 0.12
Results Flanker-Test	Interference (response time due to inhibition)	IB	0.55	94.94	15.41	63.20	− 0.18	0.18	0.91	0.02
		IBPL	18.99	44.37	31.29	25.69	− 0.34
		WB	43.43	56.70	52.38	68.01	− 0.14
		WBPL	− 42.33	164.54	0.43	24.69	− 0.36
	Switching (response time due to switching)	IB	515.54	170.31	589.25	243.64	− 0.35	1.52	0.24	0.16
		IBPL	600.26	112.37	509.99	116.98	0.79
		WB	598.45	202.72	538.34	125.51	0.36
		WBPL	471.98	122.96	513.55	111.79	− 0.35
	Accuracy (Accuracy at flanker, corresponds to inhibition)	IB	0.95	0.07	0.99	0.014	0.67	1.16	0.34	0.13
		IBPL	0.95	0.06	0.97	0.01	0.46
		WB	0.98	0.03	0.95	0.12	− 0.32
		WBPL	0.83	0.29	0.96	0.04	0.61
	Switching accuracy (Accuracy in switch trials of the flanker task, corresponds to cognitive flexibility)	IB	0.76	0.17	0.86	0.11	0.68	0.96	0.42	0.07
		IBPL	0.89	0.08	0.88	0.08	− 0.12
		WB	0.90	0.07	0.90	0.11	0.00
		WBPL	0.90	0.07	0.88	0.09	− 0.30

One patient complained about a wristband, which was too tight, but he solved the problem by over-stretching it. Otherwise, no adverse events occurred.

 

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Discussion

This randomized double-blind, placebo-controlled pilot-study in children suffering from FD revealed following key-findings: Over the course of four weeks, patients of all treatment groups had a subjectively improved sleeping pattern, an overall better physical state and were symptom-free on more days per week. All interventions -except for IBPL- also lead to a more positive state of mind and a reduction of symptoms, represented by VAS.

The pathophysiology of FGDI’s is a complex, multifaceted interaction of visceral hypersensitivity, central sensitization, gut microbiota and its metabolic products (such as short-chain fatty acids), early-life programming (surgeries, infections etc.), gastrointestinal motility, neuroimmune interaction [16] and psychological factors.In our study, the objective and subjective findings did not correlate, which is absolutely in line with literature, demonstrating the correlation of psychosocial factors and the presence of FGDI’s: Children and adolescents with FGDI’s tend to have a poorer mental health, elevated levels of anxiety, depression, higher stress levels, exposure to stressful life events, a lower quality of life and present with a higher frequency of extra-intestinal somatic symptoms, such as headaches, fatigue and sleep disturbances, compared to their healthy peers [17]. Also, social contextual factors, such as parental chronic pain, have been associated with a higher frequency of pain episodes in children [18]. Evidence suggests, that parental influence -explained by frameworks such as social learning theory and the social communication model of pain- plays a crucial role in shaping children’s pain perception [19] [20]. Meaning, parents may inadvertently encourage their children to mimic their pain expressions, thereby influencing the child’s pain experience and behavior. Given that functional disorders are understood to be multifactorial in origin, with socio-emotional factors and pain management playing a significant role in the perception of pain, it is not surprising that the efficacy of pharmacological approaches (e. g. antispasmodics, antibiotics, antihistaminic, antiemetic) in children with FGDIs is not satisfying [21].

In this study, most of the patient’s condition subjectively improved regardless of the intervention. One contributing factor might be the security the patients received from learning that the result of the endoscopy was normal, although it was shown that a negative endoscopy alone does not improve the clinical outcome of children with FGIDs [22]. Hollier et al. [23] have shown that somatization and catastrophizing are mediating anxiety and depression, which increases the abdominal discomfort. Therefore, early prevention of somatization by objective parameters could prevent long-term functional abdominal pain, but with the possibility that the tendency to somatization disorder may persist and focus on another organ.

The debate of the role of wristbands in the treatment of nausea is still on-going. A randomized controlled trial of 90 women suffering from hyperemesis gravidarum showed milder symptoms in patients receiving acupressure via wristband vs. the control group having standard medication [24]. A meta-analysis of twelve studies assessing the effectiveness of acupressure in preventing chemotherapy-induced nausea and vomiting was performed [25]: Over 1400 patients were included and showed that acupressure reduced statistically significant the severity of acute and delayed nausea, but no beneficial effect on the incidence or frequency of vomiting was found. A randomized, single-blind, placebo-controlled clinical trial [26] involving 90 patients with acute myocardial infarction and persistent nausea despite the use of anti-emetic medications found a significant (p<0.05) reduction in vomiting in the acupressure group, using the same wrist-bands we used in this study, compared to the placebo and control groups.Lately, acupressure seems to be undergoing an image change to a serious science, which is reflected by a publication in The British Journal of Anaesthesia, the highest-ranking journal worldwide in the field of anaesthesia: Wang et al. [27] performed a study in almost 300 women undergoing hysteroscopic surgery, where besides pain, postoperative nausea and vomiting (PONV) is the most common complication of surgery and anaesthesia. Patients received a bracelet with transcutaneous electrical acupoint stimulation for 24h postoperatively and were compared to patients wearing the same bracelets being switched off. The incidence of vomiting was statistically significant lower in the intervention group (36% vs. 18%, p= 0.003), whereas the nausea was not significantly different.

Whilst adults benefit from anti-nausea wristbands to some extent, literature search revealed that no data from paediatric trials are yet available. In our cohort, children did improve after an intervention with the wristband, however, so did the children wearing WBPL. An extensive education about the disease might explain the good response rate to the WBPL: Not only children, but also parents were intensively informed about the aetiology and the different therapeutical approaches in FD to ensure they do not fear any disadvantages arising from participating in the study. American psychologists [28] tested a cognitive-behavioral intervention delivered to parents of children with FGID’s and found an improvement of the child’s symptoms by educating/strengthening parents. This theory, however, does not explain that the IBPL-group did not benefit from the intervention, although they did receive the same education.

STW-5 (Iberogast), an herbal combination, has been developed over 5 decades ago to treat patients suffering from FD. It was not only shown to increase antral motility [5], reduce inflammation [29], but a review of 12 clinical trials of double-blind and randomized studies found statistically significant effects on patient’s symptoms with a comparable efficacy to a standard prokinetic, and a favorable tolerability, which is relevant for long-term treatment [30]. A double-blind, randomized, placebo-controlled crossover trial in adult patients with FD and reflux symptoms demonstrated a significant reduction in the total number of acidic reflux events following four weeks of treatment with STW-5 compared to placebo, confirmed by pH-metry studies [31]. Authors concluded that while STW-5 had no observable effect on oesophageal motility, it significantly reduced acid exposure time. This finding implies that a reduced volume of refluxed acid, possibly due to improved gastric emptying and enhanced gastric motility, may underlie the pharmacological effects of STW-5. This might also explain the benefit our patients experienced, as a swift gastric emptying clearly prohibits fullness and discomfort.

As FD causes considerable strain on many children’s lives, an international pediatric committee performed a systematically assessment of evidence, efficacy and safety of pharmacological treatments of FD in children aged 4–18 years [32], where no evidence was found to support the use of pharmacological drugs. It was recommended to treat the different subtypes of FD (epigastric pain and postprandial distress syndrome) based on adult data and customized. For the postprandial distress type, the committee recommends the use of fundal relaxant medications, which equals STW-5. Our findings of a good response to STW-5 are therefore not only in line with those recommendation, but also with a prospective observational study of 980 children between 3 and 14 years [33], where a very good effect of STW-5 was shown with only 0.7% reporting adverse events. STW-5 seems to be a good and safe option for children suffering from FD with a pharmacologic effect, which is underlined by the fact, that the placebo-group did not show any improvement of symptoms, in contrast.

A clear limitation of the present study is the small number of included patients. Although over 200 children were offered participation in the study, only a few agreed to participate in the trial. The most frequently mentioned reasons for declining participation were, that ‘they only wanted to rule out somatic diseases’ and ‘a lack of time’- both reasons were provided by the parents. Also, only a fraction of patients fully completed the 4-week intervention with pre- and post-testing, many participants suddenly did not answer calls and/or Emails and therefore dropped out. From a statistical perspective, this presented us with the problem of an absent statistical significance, indicated as p-values, as this correlates strongly with the sample size. In awareness of this problem, the effect size (eta2) was calculated, which showed a big effect for the overall subjective improvement of condition. The high drop-out rate of our participants might be explained by findings from different studies [34] [35], showing that parents of children with chronic pain struggle with the time consumption of attending doctor and therapy appointments, which is only possible when a strong social support network is in place to provide assistance and flexibility for the changing needs, whilst a low socioeconomic status is associated with a higher frequency of recurrent pain in children [36] [37]. In short, the care of children with chronic pain is extremely time-intensive, which can push parents to their limits of capacity and, consequently, leave them feeling overwhelmed by the prospect of participating in a study.

As a side study, participants had to perform the Flanker task. The idea behind this test was our hypothesis, that chronic epigastric discomfort could impair cerebral performance, consequentlyan improvement in symptoms could be objectified with an improved mental function. There are no data available on this subject. Surprisingly, only the WBPL-intervention group, which also showed a subjective improvement in symptoms, showed an improvement in cerebral responsiveness. The data from the Flanker task are not coherent with the reported, subjective gastrointestinal symptoms, which is most likely due to the patient groups being too small.

 

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Conclusion

The pathophysiology of FD is complex and multifactorial, involving hypersensitivity, altered microbiota and central nervous processing as well as behavioral patterns. Our double-blind, placebo-controlled pilot study showed, that STW-5 and/or anti-nausea wristbands are a cheap and effective option to treat children and teenagers suffering from FD. It certainly is only a method to reduce discomfort selectively, long-term data are not available.

 

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Contributor’s Statement

C.Légeret and R. Furlano formed the study concept and provided the funding. M. D’Aujourdhui, S. Schneider, A. Acket and H.Köhler performed data acquisition, S. Ludyga performed statistical analysis, C. Légeret wrote the first draft of the manuscript, all authors read and agreed to the latest version of the manuscript.

 

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Fundref Information

Gottfried and Julia Bangerter-Rhyner-Foundation —

 

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Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Article published online:
21 August 2025