Rogers BD, Rengarajan A, Ribolsi M, Ghisa M, et al. Postreflux swallow-induced peristaltic wave index from pH-impedance monitoring associates with esophageal body motility and esophageal acid burden. Neurogastroenterology & Motility. 2021;33(2):e13973.

Авторы: Rogers B.D. / Rengarajan A. / Ribolsi M. / Ghisa M. / Quader F. / Penagini R. / de Bortoli N. / Mauro A. / Cicala M. / Savarino E.V. / Gyawali C.P.

Postreflux swallow-induced peristaltic wave index from pH-impedance monitoring associates with esophageal body motility and esophageal acid burden

Benjamin D. Rogers¹, Arvind Rengarajan¹, Mentore Ribolsi², Matteo Ghisa³,
Farhan Quader¹, Roberto Penagini^4,5, Nicola de Bortoli⁶, Aurelio Mauro^4,5,
Michele Cicala², Edoardo Savarino³, C. Prakash Gyawali¹

¹ Division of Gastroenterology, Washington University School of Medicine, St Louis, MO, USA
² Unit of Gastroenterology, Campus Bio Medico University, Rome, Italy
³ Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
⁴ Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
⁵ Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Milan, Italy
⁶ Division of Gastroenterology, Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Cisanello Hospital, Pisa, Italy

Correspondence. C. Prakash Gyawali, Professor of Medicine, Division of Gastroenterology, 660 South Euclid Ave., Campus Box 8124, Saint Louis, MO 63110. Email: cprakash@ wustl.edu

Funding information. No funding was obtained for this study.

Abstract

Background: Postreflux swallow-induced peristaltic wave (PSPW) on pH-impedance monitoring and contraction vigor on high-resolution manometry (HRM) both assess esophageal peristaltic response. We aimed to evaluate relationships between PSPW and esophageal peristalsis on HRM in the context of reflux disease in this multicenter cohort study.

Methods: pH-impedance and HRM studies performed on patients with persisting reflux symptoms were reviewed from 6 centers (5 in Europe and 1 in US). Total, upright and supine acid exposure time (AET) were evaluated from pH-impedance studies; PSPW index (PSPWI) and mean nocturnal baseline impedance (MNBI) were calculated using standard methodology. Esophageal body contraction vigor was analyzed using distal contractile integral (DCI), and DCI ratio > 1 between single swallows and multiple rapid swallows (MRS) defined presence of contraction reserve. Student's t test, ANOVA, and linear regression were utilized to investigate relationships between PSPW, contraction vigor, and contraction reserve.

Key Results: Of 296 patients (52.8 ± 0.8 yr, 63% F), median PSPWI was 0.475. Only 24.0% had intact DCI; the remainder had varying degrees of hypomotility. As hypomotility increased, PSPWI and MNBI decreased significantly, while total AET and reflux episodes had an inverse response (P ≤ .002 for each). MRS data were available in 167 (56.4%), 72.5% had contraction reserve. MRS cohorts with normal PSPWI had significantly lower reflux burden compared to low PSPWI, regardless of presence or absence of contraction reserve (P ≤ .001).

Conclusions and Inferences: PSPWI correlates with esophageal hypomotility and reflux burden, and complements clinical reflux evaluation. Intact PSPW is more relevant to esophageal reflux clearance than contraction reserve.

Keywords: abnormal acid exposure, ambulatory reflux monitoring, high-resolution manometry, hypomotility, PSPW

How to cite this article: Rogers BD, Rengarajan A, Ribolsi M, et al. Postreflux swallow-induced peristaltic wave index from pH-impedance monitoring associates with esophageal body motility and esophageal acid burden. Neurogastroenterology & Motility. 2021;33(2):e13973. ht tps://doi.org/10.1111/nmo.13973

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Key Points

• Postreflux swallow-induced peristaltic wave (PSPW) is a esophageal peristaltic response proposed as the mechanism for chemical clearance of distal esophageal refluxate. Multiple rapid swallows (MRS) during high-resolution manometry (HRM) evaluate integrity of esophageal neural and motor function (contraction reserve).


• We demonstrate a relationship between PSPW index and both esophageal acid burden on reflux monitoring and esophageal hypomotility on HRM, but not between PSPW index and contraction reserve on MRS.


• Intact PSPW is more relevant to esophageal acid burden than intact MRS.


• Low PSPW index increases confidence in a reflux mechanism when other esophageal testing metrics are inconclusive.

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1 | INTRODUCTION

High-resolution manometry (HRM) has proven benefit in the evaluation of esophageal transit symptoms^1,2 and has an emerging role in providing adjunctive evidence in gastroesophageal reflux disease (GERD).^3-5 Several HRM parameters and diagnoses including esophagogastric junction (EGJ) morphology, EGJ contractile integral (EGJ-CI), severe ineffective esophageal motility (IEM), and absent contractility identify patients at risk of elevated acid exposure.^4,6 Intact esophageal peristalsis is a potential prerequisite for optimal reflux clearance. On pH-impedance monitoring, antegrade propagation of an impedance drop, the postreflux swallow-induced peristaltic wave (PSPW), is thought to represent a primary peristaltic wave in response to refluxate in the distal esophagus.^7,8 The proportion of reflux events that are associated with PSPW on pH-impedance monitoring is termed the PSPW index (PSPWI). Low PSPWI has been shown to correlate with elevated reflux burden and PPI refractory symptoms.^9-11

Hypomotile disorders have an established relationship with elevated acid exposure, with a gradient of increasing reflux burden as proportions of ineffective and failed peristalsis increase.^12,13 Contraction reserve, the manometric demonstration of the capacity to augment esophageal smooth muscle contraction vigor with provocative testing such as multiple rapid swallows (MRS), may be associated with reduced reflux burden in individuals with hypomotile disorders.⁶ However, relationships between PSPW, esophageal body contraction metrics, and reflux burden remain unclear.

Our hypothesis for this study was that PSPWI negatively correlates with increasing degrees of esophageal body hypomotility. Our primary aim was to determine whether a relationship exists between PSPW, contractions patterns on HRM, and acid exposure time (AET) metrics on pH impedance monitoring. A secondary aim was to evaluate whether MRS contraction reserve associated with PSPW index.

2 | METHODS

All adults (age > 18 years) who underwent esophageal evaluation testing over a 2-year period at 5 international tertiary care centers (4 in Italy, 1 in the US) for persisting reflux symptoms despite antisecretory therapy or prior to invasive GERD management were eligible for inclusion. All HRM studies were performed using Sierra equipment (now Medtronic, Duluth, GA), and pH-impedance studies were performed using Sandhill Scientific equipment (Boulder, CO). Patients who completed HRM studies with 10 successful water swallows were included in the study if they also had adequate pH-impedance monitoring off acid-suppressive therapy. Each participating center provided demographics (including age, gender, presenting symptoms), esophageal HRM metrics, and pH-impedance data for their respective cohorts. Exclusion criteria consisted of inadequate studies (equipment malfunction, poor study quality), incomplete data (fewer than ten swallows, reflux monitoring < 16 hours), testing performed on antisecretory therapy, major foregut surgery, and established diagnosis of achalasia or outflow obstruction. The study protocol was approved by the Institutional Review Boards at each respective institution, and data sharing agreements were completed by each collaborating institution for pooled analysis of de-identified clinical and esophageal testing data.

2.1 | High-resolution manometry

All manometry studies were high resolution, using catheters with high fidelity circumferential sensors spaced no more than 1 cm apart. Catheters were placed through an anesthetized nostril by experienced staff at each center following an overnight fast, with the three distal-most sensors in the intragastric location, whenever possible.¹ Ten test swallows of 5 mL ambient temperature water each were performed in a supine, semi-recumbent position every 20 to 30 seconds. Routine analysis was performed according to the Chicago Classification version 3.0 (CCv3.0),² using proprietary software (ManoView; Medtronic, Duluth, GA).

Esophageal body contraction vigor was stratified using distal contractile integral (DCI, mmHg•cm•s). Individual swallows were characterized as failed, weak, or intact (≤100 mmHg•cm•s, 100-450 mmHg•cm•s, and ≥ 450 mmHg•cm•s, respectively); failed and weak swallows were considered ineffective. Swallows with ≥ 5 cm breaks (fragmented) were included in the “ineffective” category, based on recent data suggesting these sequences contribute to abnormal reflux burden.¹³ Using CCv3.0, IEM was defined as ≥ 50% ineffective sequences²; this was further divided into mild (50%-70% ineffective) and severe (≥80% ineffective) IEM.^13,14 At the two extremes, 100% preserved peristalsis consisted of 10 effective swallows, while absent contractility had 10 failed and no effective swallows.

Provocative testing consisted of five sequential rapid swallows (MRS), each consisting of 2 mL of water within intervals of < 3 seconds between swallows.^15,16 Contraction reserve was present when the ratio between MRS DCI and single swallow DCI was > 1.¹⁵ Although evaluated where available, lack of adequate MRS was not considered exclusionary. Number of MRS sequences was not standardized across institutions, and a single MRS sequence was considered sufficient if adequately performed.

2.2 | pH-Impedance monitoring

Antisecretory therapy was stopped at least 7 days and anti-histamine-2 receptor antagonists and prokinetics were held for at least 3 days prior to pH-impedance monitoring.³ The lower esophageal sphincter (LES) was identified using HRM and the distal pH sensor was positioned 5 cm above its proximal margin. Patients recorded meals, activities, and symptoms per standard protocol and meal times were excluded from analysis.³ Total AET thresholds consisted of: pathologic (>6%), physiologic (<4%), and indeterminate (4%-6%).⁴ Upright AET was considered pathologic when > 6% and supine AET was considered pathologic when > 2%.^4,17,18 Reflux-symptom association was assessed using symptom association probability (SAP) when available.

Mean nocturnal baseline impedance (MNBI) was calculated by averaging three 10 minutes segments of recumbent impedance values (typically from 1-3 AM) from 5 cm proximal to the LES to correspond with the pH recording.^9,19 PSPW consists of antegrade propagation of an impedance drop triggered by a reflux event to bring salivary bicarbonate to the acidified distal esophagus. The following characteristics defined adequate PSPW: onset in the most proximal channel within 30 seconds of bolus clearance in the most distal impedance channel, antegrade progression, and at least 50% drop in impedance in the distal-most channel^9,20(Figure 1). The PSPWI consisted of the proportion of impedance detected reflux episodes followed by a PSPW. Normal values for PSPWI were used according to previously published standards.²¹

Figure 1. Postreflux swallow-induced peristaltic wave (PSPW), identified as an antegrade impedance drop indicating a swallow within 30 seconds of the end of a reflux episode in the distal-most channel. This brings saliva to the distal esophagus for neutralization of mucosal acidification from the reflux episode. PSPW index (PSPWI) is the ratio of PSPW to total number of reflux episodes

2.3 | Data analysis

Data are reported as the mean ± standard error of the mean (SEM) or median (interquartile range, IQR) as indicated. Categorical data were compared using the chi-squared and Fisher's exact test, and continuous data were analyzed using the 2-tailed Student's t test, ANOVA, or Kruskal-Wallis test with Bonferroni correction for multiple comparisons as appropriate. Within the context of esophageal reflux burden, relationships between normal or abnormal PSPWI and presence or absence of contraction reserve were compared. Further analysis was performed by dichotomizing the study cohort based on median PSPWI, and comparing motor diagnoses in patients with PSPWI over and under this value (a median split analysis). A P value of < .05 was considered significant. SPSS Statistics v26.0 (Armonk, NY) was utilized for all statistical analyses.

3 | RESULTS

Over the study period, 296 patients (52.8 ± 0.8 yr, 63% F) fulfilled inclusion criteria from the 5 centers. Of these, 30.4% had abnormal total acid exposure, 41.2% had abnormal upright, and 40.3% had abnormal supine acid exposure (Table 1). A minority of patients had 100% effective sequences (71, 24.0%) or 100% absent sequences (13, 4.4%). The remaining 212 patients (71.6%) had varying proportions of ineffective sequences (Table 1). At least one MRS sequence was available in 167 patients, and contraction reserve was present in 121 of these individuals (72.5%).

The relationships between PSPW index and esophageal body motor patterns were first evaluated. As the degree of hypomotility increased, PSPWI decreased, and these differences were statistically significant across groups (P < .001, Table 2 and Figure 2). Conversely, with increasing hypomotility, AET had an inverse trend, demonstrating increasing supine, upright, and total acid exposure and decreasing MNBI (P = .11 for supine AET, P = .01 for upright AET, and P ≤ .002 for total AET and MNBI, Table 2 and Figure 2). Numbers of reflux episodes progressively increased (P = .001) with increasing hypomotility (Table 2). Data regarding reflux-symptom association (SAP) was available in 237 patients. Median PSPWI was 0.45 (IQR, 0.28-0.59) when SAP was positive and 0.52 (IQR, 0.36-0.73) when negative (P = .002). Additionally, proportions with PSPWI more than 0.61 were higher in those with negative SAP compared to positive SAP (41.0% vs. 20.4%, P = .001).

Figure 2. Interrelationships between acid exposure time (AET), postreflux swallow-induced peristaltic index (PSPWI), and highresolution manometry motor (HRM) patterns. As numbers of ineffective swallows increased, acid burden increased proportionally and PSPWI decreased


The median PSPWI was 0.475 (interquartile range 0.31-0.66). In order to further evaluate the relationship between PSPW and motor patterns, we divided the cohort into two groups using a median split at this value. More patients with 100% preserved peristalsis were in the higher PSPWI group, and this difference was statistically significant (P = .01, Figure 3). In contrast, more patients with ≥ 80% ineffective sequences were in the lower PSPWI group (P = .03). Additionally, there was a strong trend in the 50%-70% ineffective group, favoring lower PSPWI (P = .11). The differences in proportions overall were statistically significant across groups (P = .005, Figure 3), although PSPW were noted to be present even in the setting of severe hypomotility and absent contractility.


Figure 3. Comparison of esophageal motor patterns using median split (median 0.475) of postreflux swallow-induced peristaltic wave index (PSPWI). When all swallows were intact, more patients were above the median PSPWI (P = .01). Conversely, as proportions of ineffective sequences increased, more patients were below the median PSPWI, reaching statistical significance at ≥ 80% ineffective sequences (P = .03)


Within the cohort with MRS data, 40 (24.0%) patients had PSPWI above the published normative threshold of 0.61. There was no correlation between PSPWI and contraction reserve (Spearman's rho: −0.05, P = .5). Median PSPWI was 0.42 (IQR, 0.28-0.59) with contraction reserve and 0.43 (IQR, 0.17-0.65) without (P = .5). Further, proportions with PSPWI more than 0.61 were similar between those with and without contraction reserve (20.7% vs. 32.6%, respectively, P = .15). However, the combination of normal PSPWI and contraction reserve was associated with lower total, upright, and supine acid burden and higher MNBI compared to abnormally low PSPWI and absent contraction reserve (P ≤ .001, Figure 4). Additionally, subgroups with normal PSPWI had similar reflux burden regardless of presence or absence of contraction reserve (P = 1.0, Figure 4). Conversely, subgroups with abnormal PSPWI had similarly high acid burden regardless of contraction reserve (P ≥ .4, Figure 4). Numbers of reflux episodes were also noted to be elevated in those with abnormal PSPWI regardless of contraction reserve (54 with contraction reserve vs. 55 without contraction reserve, P = 1.0) compared to those with normal PSPWI (30 with contraction reserve vs. 35 without contraction reserve, P = 1.0). Additionally, numbers of reflux episodes were significantly different across subgroups, with increasing rates in those with reduced PSPWI (P < .001).

Figure 4. Box and whiskers plots of acid exposure metrics by postreflux swallow-induced peristaltic wave (PSPW) and contraction reserve (CR) on multiple rapid swallows. When PSPW was normal (>0.61), acid burden was low regardless of whether CR was present or absent (P = 1.0). In contrast, acid burden was high when PSPW was low, again regardless of CR (P ≥ .4). Groups with normal PSPW had significantly lower acid burden (P ≤ .001)

4 | DISCUSSION

In this multicenter observational cohort study, we demonstrate a negative correlation between PSPWI and esophageal body motor function where increasing degree of hypomotility is associated with lower PSPWI. The combination of normal PSPWI and contraction reserve on MRS is associated with the lowest esophageal acid burden. However, our data also demonstrate that where PSPWI is normal, acid burden is reduced, regardless of presence or absence of contraction reserve. Conversely, where contraction reserve is present without normal PSPWI, reflux burden remains high. This finding suggests that preservation of the esophageal salivary reflex arc is protective beyond intact contraction reserve or primary motor patterns as current definitions stand. Our conclusions, in line with prior investigations, suggest that PSPW and esophageal body peristaltic performance influence esophageal reflux burden, but a causal relationship between the two needs further study. Furthermore, the relationship between PSPW and esophageal body motility on HRM is not perfect since PSPW was found even in those with absent contractility, even though higher degrees of hypomotility correlate with lower PSPWI. Therefore, the two parameters are different but complementary, and helpful adjuncts to routine clinical esophageal testing. In particular, a low PSPWI may enhance confidence in a reflux mechanism in patients where other evidence is inconclusive.

Esophageal acid clearance occurs in two steps, as has been demonstrated on concurrent manometry and radionuclide imaging. Volume clearance occurs by gravity or by secondary esophageal peristalsis, and mucosal acidification is thought to be subsequently neutralized by swallowed saliva via reflex initiation of primary peristalsis (PSPW).²² When these mechanisms fail, reflux esophagitis can be refractory to management and Barrett's esophagus can potentially advance.^23,24 Saliva is brought to the distal esophagus in response to reflux, and this is hypothesized to require integrity of a reflex arc which stimulates salivary secretion and initiates primary peristalsis. This is recognized on pH impedance as the antegrade progression of impedance decline within 30 seconds of a reflux episode, termed PSPW.²⁵ Regardless of the underlying mechanism, our findings indicate that PSPW is potentially more important for the prevention of pathological reflux than previously realized. This is consistent with prior studies that have shown that PSPW has excellent sensitivity and specificity (99%-100%, 92%, respectively) in differentiating erosive esophagitis and pathological acid exposure from functional heartburn and healthy controls,²⁵ although a causal relationship has not been established.

Hypomotile disorders have previously been shown to correlate with increased esophageal acid burden.^12,13,26,27 Animal studies show that reflux can lead to esophageal mucosal damage and subsequent reduction in contraction vigor.²⁸ Although this was a reversible finding in those trials, healing of esophagitis with PPI has not been proven to improve motor function in humans.²⁹ In contrast, symptomatic disorders with non-pathologic or low reflux burden--functional heartburn and non-erosive reflux disease--may be associated with higher esophageal body contraction amplitudes, despite typical symptoms.^26,27 In fact, if acid boluses are provided to patients with heartburn related to esophageal hypersensitivity, esophageal body contraction vigor increases.³⁰ This suggests that in some individuals, acid exposure may serve to augment esophageal body peristalsis, contributing to better esophageal body clearance and lower esophageal acid burden. Our data showing lower median PSPWI and lower proportions with PSPWI ≥ 0.61 in patients with positive SAP suggest that prolonged acid contact in the absence of PSPW may participate in symptom generation.

Although esophageal body motor function is commonly normal in GERD, weak peristalsis is often encountered.^31-33 Our data demonstrate that as numbers of ineffective swallows increase, the PSPWI decreases. Conversely, an intact PSPWI associates with lower acid burden, leading us to speculate that when esophageal motor function is intact, a primary peristaltic wave potentially does propagate into the smooth muscle esophagus in response to distal esophageal reflux. However, in the upright position, it is well known that gravity plays an important role in antegrade propagation of the swallowed bolus. It is possible that PSPW is merely a reflection of antegrade saliva propagation on pH-impedance tracings, with or without smooth muscle contraction in the esophageal body, and that PSPW occurs as long as a swallow initiates in the oropharynx and proximal esophagus. This can explain why patients with severe esophageal hypomotility and even absent contractility can have PSPWI of 0.41- 0.42 (Table 2). Alternatively, an argument could also be made that hypomotile disorders potentially represent a neural defect, relating these disorders pathophysiologically to PSPWI. It is clear from available data that the exact pathophysiological mechanisms underlying PSPW remain incompletely understood and will require concurrent ambulatory manometry and pH-impedance monitoring for better elucidation of the physiology of this reflex.

Esophageal smooth muscle can be challenged with provocative maneuvers such as MRS and can respond by augmenting contraction. The ability of the esophageal muscle to augment contraction, termed contraction reserve, correlates with abnormal reflux burden in prior studies.⁶ In another study limited to endoscopy negative patients with heartburn, contraction reserve correlated with PSPWI in patients with normal HRM, abnormal AET (>4.2%), and elevated reflux episodes (>54 episodes/24 hours).³⁴ In contrast, contraction reserve did not correlate with PSPWI in our cohort, likely because we included patients with varying degrees of hypomotility rather than just normal HRM, and any GERD symptom rather than heartburn alone. Instead, PSPWI proved to be more significant in protecting against elevated acid burden. We postulate that this is due to differing underlying physiology between MRS contraction reserve and PSPWI. In the former, deglutitive inhibition induces a refractory period during repetitive swallowing prior to contraction¹⁶ whereas the latter appears to be a more direct response to esophageal stimulation from reflux.²⁴ Therefore, even though esophageal neural and muscular integrity is required for both, they are initiated via different mechanisms. This lack of correlation with contraction reserve further supports our speculation that PSPW does not always require esophageal contraction to be present, despite the relationship to hypomotile disorders. This also indicates that PSPWI and contraction reserve likely have differing underlying mechanisms and serve separate purposes. However, no direct physiologic evidence exists to support these hypotheses, so further research is needed for clarification.

The strengths of our study lie in the large cohort of patients from multiple international centers. We meticulously extracted emerging metrics using the most current methodologies from prospectively collected data. Extraction of PSPW was performed by experts with experience in this novel metric, which adds to the value of our work. However, our study is tempered by several limitations including the lack of concurrent symptom data. Although we used a 30-second window after the reflux episode for the identification of PSPW,³⁵ this timeframe has not been well validated and is based on limited original data.³⁶ While information was available regarding conventional HRM and pH impedance metrics for each patient, allowing for MNBI and PSPWI extraction, MRS protocols were not standard across centers. Esophageal acid burden on reflux monitoring was used as an outcome metric rather than symptoms, since this study was limited to analysis and interpretation of shelved de-identified data. Numbers of reflux episodes, which are integral to PSPWI calculation, could be confounded by re-reflux episodes, hiatus hernia, or unrecognized behavioral syndromes like rumination. We also did not analyze symptoms, reflux-symptom association, GERD phenotypes, esophagitis, or EGJ morphology as predictors of PSPWI. We acknowledge inter-reviewer variation in the identification of reflux episodes and PSPW, which could have impacted PSPWI calculation but could not be avoided. Interpretation of PSPW lacks automation, which when available will augment the value of pH-impedance monitoring, and add to the generalizability of our findings. Nevertheless, we feel that our data provides insights helpful in the understanding of reflux clearance mechanisms relevant to esophageal acid burden. Further research is needed to understand if these relationships are related to the sensory or the motor part of the PSPW reflex arc.

In conclusion, we demonstrate that PSPWI, esophageal body contraction vigor, and contraction reserve provide complementary evidence regarding esophageal neuromuscular function in the context of reflux disease. Compromised esophageal contraction seen in hypomotility disorders associates with lower PSPWI in addition to abnormal acid burden in the esophagus, but normal esophageal body contraction is not essential for PSPW to be identified on pH-impedance monitoring. Intact PSPWI may be more important than contraction reserve in reflux clearance. Evaluation of PSPWI as part of pH impedance monitoring, and esophageal body motor function using HRM, therefore, provide complementary GERD evidence when routine metrics are inconclusive, and have potential implications for GERD symptom presentation, refractoriness to therapy, and clinical management.

CONFLICT OF INTEREST

The authors have no conflicts of interest to declare. Disclosures: BR, AR, MR, MG, FQ, RP, NB, AM, MR: no disclosures, ES: Consultant: Abbvie, Allergan, MSD, Takeda, Sofar, and Janssen, Teaching and speaking: Medtronic, Reckitt-Benckiser, Malesci, and Zambon; CPG: Consulting: Ironwood, Torax, Quintiles; Teaching and speaking: Medtronic, Diversatek. No additional personal conflicts exist for any of the authors.

AUTHOR CONTRIBUTION

BR: data collection, data analysis, manuscript preparation and review; AR: data collection, analysis, manuscript review; MC, MG, FQ, RP, NB, AM, MR, ES: data collection and critical manuscript review; CPG: study concept and design, data analysis, manuscript preparation, critical review and final approval of manuscript.

ORCID

Mentore Ribolsi ht tps://orcid.org/0000-0001-5102-1758
Roberto Penagini h ttps://orcid.org/0000-0001-6918-9479
Nicola de Bortoli ht tps://orcid.org/0000-0003-1995-1060
Aurelio Mauro ht tps://orcid.org/0000-0002-8475-5464
C. Prakash Gyawali ht tps://orcid.org/0000-0002-3388-0660

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