download
PDF
|
Treatment of sleep disordered breathing relapse after surgery
Abstract
This narrative review provides a general overview of the management of relapses after surgery for the treatment of sleep disordered breathing. This clinical scenario represents a challenging field, but fortunately several therapeutic options are included in sleep surgeons’ armamentarium. Each therapeutic modality is described in detail in a dedicated section.
Introduction
Never give up
Sleep Disordered Breathing (SDB) encompasses a wide range of different clinical conditions including the most common prevalent as Simple Snoring (SS) and Obstructive Sleep Apnoea (OSA) 1.
OSA treatment is one of the most difficult challenges of modern medicine for many and unrelated reasons. First of all, OSA is by nature a worsening disease with a natural trend to become more and more severe over time 2.
In essence, dealing with OSA is like swimming against the current. Any possible treatment has to reckon with this natural trend of OSA to become more severe as time passes, and relapse if treated. Among the reasons for this natural history of OSA is the natural tendency for the muscles and soft tissues of the upper airways to become less effective and laxer with age and the frequent increase in body mass index (BMI) throughout life. Ageing is in itself associated with a decrease in sleep quality; SDB may further alter sleep architecture in elderly subjects 3.
SDB treatment goals
The goals of any OSA treatment are multiple: to normalise the cardio-respiratory index of sleep registration and prevent cardiovascular complications, to treat neuropsychological impairments, to eliminate or improve snoring, and, in a more holistic perspective, to improve the quality of life, as measured by different scales or scoring systems 4.
Different long term surgery failures
Unfortunately, the effects of surgery as well of any alternative treatment options on the above-mentioned different goals are not equal, and not stable in the same way over time 5.
From the practical point of view, it implies that our intervention may be very effective in reducing snoring and Apnoea Hypopnea Index (AHI), but quite ineffective in controlling excessive daytime sleepiness, producing a dissociated outcome profile. A second and not unusual situation is a transient positive effect on snoring, and snoring relapse after a few months, with a relatively stable control of cardiorespiratory index 6.
How to measure multi-dimensional outcomes
Probably the best way to describe OSA treatment outcomes is to define a multi-dimensional profile including different axes, possibly independent 7:
- relational axis: snoring;
- cardio-respiratory axis: Apnoea Index (AI), AHI, Respiratory Disturbance Index (RDI), Lowest Oxygen Saturation (LOS), Blood Pressure (BP) etc.;
- neuropsychological axis: Epworth Sleepines Scale (EPSS), Multiple Sleep Latency Test (MLST) etc.;
- quality of life axis: Functional Outcomes of Sleep Questionnaire (FOSQ), Sleep Apnoea Quality of Life Index (SAQLI);
- comprehensive axis: Pang Sleep Goal (PSG).
A work-up consisting of questionnaires, polygraphy/polysomnography, clinical examination and Drug-Induced Sleep Endoscopy (DISE) is needed in order to record all the above-mentioned outcomes. It is quite common to register a different degree of improvement along the different outcome axes after a planned post-operative check. However, it is probably much more frequent to disclose variable evolutions of the different outcomes over time, producing a complex combination of poorly controlled parameters coexisting with well controlled ones. We will discuss in detail and in a separate way the main multi-dimensional axis long term failures, in a prominent rescue perspective: how to address the problem? 8.
SDB treatments
For simply practical purposes, SDB treatments may be divided into surgical ones and non-surgical ones 9-11.
Surgery includes a wide range of solutions to address soft tissue or bone-framework abnormalities of the upper airways, very commonly planned as multilevel surgery (surgery targeted to the nose, pharynx, tongue in the same patient) 12.
Bariatric surgery is a possibility for obese patients. Even more complex is the spectrum of non-surgical options. Continuous Positive Airway Pressure (CPAP), oral appliances, positional devices, weight loss, and myofunctional therapy are among the most popular treatments. The more recent conceptualisation of OSA endotypes and phenotypes has made it possible to stratify the different therapeutical actions for OSA and to differentiate anatomical from functional patterns 13-15.
Anatomical trait means upper airway obstruction and/or collapse, and may be counteracted by CPAP, Mandibular Advancement Devices (MAD), weight loss and positional therapy, i.e. the so-called anatomical treatments. Functional traits include insufficient muscle reaction to collapse, increased loop gain and lowered arousal threshold 16.
The set of possible treatment options includes drugs, myofunctional training and a special type of surgery, namely hypoglossal nerve stimulation. In the time domain, the different treatment options may be devised as single stand-alone treatment (e.g.: CPAP as first line, or surgery as unique selected therapy), or ab initio multistep staged surgical strategy (e.g.: Stanford phase one and phase two). The concept of multimodal therapy implies a pre-planned strategy which offers the patient a logical association or sequence of different options in order to increase the possibility for final success. Some examples include palate surgery supported by the post-operative adoption of MAD, surgical reduction of nose resistance in order to increase CPAP acceptance and compliance, and association of palate and/or tongue surgery with myofunctional therapy.
Rescue options
Several options for the primary treatment of SDB may also be offered as rescue options. We will discuss separately the non-surgical and surgical ones (Fig. 1).
Non-surgical
The main criterium of choice in this group of solutions lies in the patient’s preference who must be fully informed about the relative pro and cons of the different solutions.
WAIT AND SEE
It is not considered a real option after a surgical late failure. However, in a very limited number of snoring relapses without OSA recurrence it may be discussed with the patient, mainly as a provisional therapy while waiting to select the best additional procedure.
CPAP
Coming back to ventilation is perceived as a really frustrating solution for most patients who received surgery. In a minority of subjects, the most symptomatic ones, CPAP is adopted again without significant problems. CPAP is the most effective in the anatomical treatment armamentarium, and follows the same rules of engagement as for an untreated patient. Recurrent OSA is its main target. Recurrent snoring is not routinely included. In the classic literature of the Uvulo-Palato-Pharyngoplasty (UPPP) era, a main matter of discussion was the difficulties in adapting to ventilation some anecdotal case of palate over-resection (air leakage and loss of pressure) 17. In our personal experience, taking into account the lack of consistent evidence, after the switch to non-resective palatoplasties (Expansion Sphincter Pharyngoplasty, ESP; Barbed Repositioning Pharyngoplasty, BRP) this event was no longer observed. On the other hand, to readapt CPAP to an operated patient, especially in cases of multilevel surgery, besides the psychological impact, it is usually technically easier. The reduced nose resistance and increased pharynx stability allows a lower pressure setting, leading to increasing acceptance and compliance 18.
MANDIBULAR ADVANCEMENT DEVICES
These are one of the most popular treatments for SDB (simple snoring and sleep apnoea) after CPAP, operating in the same anatomical area. When properly customised and titrated, it may affect the overall stability of the upper airways in the retro-palatal and retro-lingual areas. Both snoring and OSA are included in the MAD area. Its adoption for surgical failure after CPAP drop out in our personal experience seems to be far superior to returning to ventilation. The literature on MAD back up after surgery is minimal, but always supports the efficacy of oral appliances in most cases 19. A matter of open discussion in Italy is the problem that oral appliances are not reimbursed by the Public Health System, and the cost is not negligible.
POSITIONAL THERAPY
The theoretical background of this increasingly popular anatomical non-surgical option is worthy of comment:
- most cases of the surgical failed OSA became positional after surgery, even if not positional before surgery 20;
- it is possible to try to manipulate sleep position in order to maintain the patient in a position different from the most critical one as long as possible: lying on his back. The most classic and popular group of mechanical or electronic devices try to stabilise patients in a lateral lying position (tennis ball in the back, electronic vibrating devices). A special mattress with a hole for the face was proposed in order to allow to breathe in a prone face down position. Last but not least, our group is collecting an increasing amount of evidence about the use of 30° Fowler’s position in managing positional OSA in a more comprehensive way 21;
- the latest generation of electronic devices offers a wide range of different vibration patterns in order to prevent patient arousal, and allows a continuous feedback by internet to the clinician, who is informed about real use and efficacy of the device. Unfortunately, positional therapy is not reimbursed by the Italian Public Health System. However, positional therapy as failed surgery back up is becoming more and more popular and well accepted.
WEIGHT LOSS
In sleep surgery, the weight curve over time tends to run parallel to the outcome curve after surgery. Immediately after surgery and for a few months the weight loss induced by swallowing pain and dysphagia contributes to improve the success rate. Too commonly in the following months, the weight curve overshoots the pre-surgery values and the success rate decreases. Hypo-caloric diet and physical exercise are the mainstay of this inexpensive approach 22.
MYOFUNCTIONAL
“Oral and facial Muscular function Therapy (OMT) can be used as a simple and non-invasive new technique to improve the AHI, minimum oxygen saturation, EPSS, and snoring intensity in patients with mild and moderate OSA and the lowest oxygen saturation in patients with severe OSA” 23. Furthermore “oro-facial myofunctional therapy can be considered as an effective complementary treatment for OSA patients with oral breathing after adenotonsillectomy” 24. Data about the use of post-operative myofunctional therapy in OSA relapse are not yet reported in the literature. According to our preliminary experience, OMT may be offered during post-operative follow-up even months/years after surgery as a salvage option. Further studies are required to confirm this possibility.
DRUGS
Different drugs are under evaluation for the targeted treatment of the non-anatomical traits of OSA. In case of persistent or recurrent OSA after correct upper airways surgery (one of the main options for anatomical treatment), a negative effect of a concomitant pathological functional trait must be considered. High loop gain may be treated by O2 or acetazolamide, a low arousal threshold may be modified by sedatives (e.g.: trazodone) 25. This is a promising field of interest, requiring further studies to gain a sound place in clinical practice.
Surgical
The choice of surgical options to address SDB recurrence requires careful global reassessment including physical exam, biometrics, awake endoscopy and in most the cases DISE. The surgeon must identify the best procedure and the patient is requested to accept the suggested one. Many surgeries may be considered as rescue procedures, and each will be summarised
TONSILLECTOMY
In case of failed palato/pharyngoplasty, irrespective of the previous technique, tonsillectomy may be considered as a rescue procedure if not previously done. It is more important and may be effective if tonsil score is 2 or more 26. Sjöblom et al. recently confirmed that stand-alone tonsillectomy without concomitant pharyngoplasty may be an effective treatment for OSA in adults with tonsillar hypertrophy 27. According to Matarredona et al. tonsil volume was found to be linked to the success rate of tonsillectomy and pharyngoplasty with barbed sutures 28. For this reason, completion tonsillectomy must be included into the available salvage tool set for recurrent OSA after pharyngoplasty without tonsillectomy.
PARTIAL RESECTION OF TORUS TUBARIUS
Hypertrophic torus tubarius was described as a cause of recurrent symptoms after adenoidectomy in childhood by Kim et al. (Fig. 2) 29. Microscopic coblator-assisted partial section is probably the only targeted surgical technique specifically devised for recurrence of sleep-disordered breathing symptoms in some children after successful adenoidectomy. In the described series, microscopic coblator-assisted partial resection of torus tubarius was successful. There were no complications related to partial resection of the torus tubarius, such as nasopharyngeal, choanal stenosis, or Eustachian tube scarring with subsequent middle ear problems.
RADIO-FREQUENCY VOLUME REDUCTION
Temperature-controlled radio-frequency tissue volume reduction of the soft palate has been introduced as a minimally invasive, outpatient procedure for treatment of habitual snoring and mild OSA 30,31. A relapse of palatal snoring over time seems to be a problem for at least some patients, although additional treatments with the same technique may be beneficial in these cases. With regards to the fact that a relapse of snoring is a general problem in surgical treatment, the possibility of repeated treatment sessions in cases of snoring relapse has to be regarded as an advantage 32. Radio-frequency technology, as an office-based minimally-invasive procedure is an interesting tool to address relapsed snoring.
UVULO PALATAL FLAP (UPF)
Introduced by Powell et al. this has been demonstrated to be a safe and effective procedure that results in long-term success for OSA by Neruntarat (Fig. 3) 33,34. After one year of experience, the procedure was dismissed as primary surgery in our institution for significant incidence of foreign body sensation. It nonetheless remains an interesting option in case of residual or recurring snoring in previous palatoplasties with very thin and long palate. Tissue duplication allows a useful stiffening effect to be produced.
BARBED REPOSITION PHARYNGOPLASTY
Barbed reposition pharyngoplasty has proven to be an easy to learn, quick, safe and effective new palatopharyngeal procedure that can be used in a single level surgery or as a part of multilevel procedure 35. In our experience, it has been applied also as revision procedure in failed UPPP and failed ESP, and in a few cases, in failed laser assisted uvulopalatoplasty (LAUP). The basic BRP technique is easy to implement in an already operated palate, with significant results in reducing snoring and addressing residual or relapsing OSA (Figs. 4, 5). The procedure is well accepted by the patient, and now it is open to discussion as a possibility to offer to all patients the idea of pre-planned repeated BRPs in case of relapse, as in face face-lift 36.
MODIFIED TOH PALATAL FLAPS TECHNIQUE
The technique was devised to address nasopharyngeal stenosis. It is an uncommon acquired pathological condition characterised by the reduction and, sometimes, by the complete obstruction of the nasopharyngeal isthmus. This particular condition is usually an iatrogenic entity following therapeutic procedures such as: tonsillectomy, adenoidectomy and UPPP. Our group reported on a surgical variation in a series of patients affected by OSA and nasopharyngeal stenosis as a consequence of different surgeries 37.
In our technique, a nasopharyngeal mucosal flap of the soft palate is tailored and then split vertically to obtain a right and left palatal flap. Interrupted sutures are applied in order to tie the muscular layer anteriorly to the oral mucosal layer of the soft palate and at the same time pull both lateral palatal flaps anteriorly and laterally to the oral palatal mucosa.
The purpose of our technique is to reduce the incidence of post-operative complications such as velo-pharyngeal insufficiency by splitting the soft palate into two flaps and suture the muscular layers of both flaps anteriorly and laterally in order to increase the retro-pharyngeal volume in a replicable, less-invasive, and effective way (Fig. 6).
TRANS-ORAL ROBOTIC SURGERY (TORS)
TORS for OSA was devised for trans-oral reduction of a large tongue base, related to lingual tonsil hyperplasia or muscle hypertrophy/collapse. Iannella et al. in a retrospective study demonstrated a very low rate of lymphoid tissue regrow after robotic removal 38. They never registered a functional recurrence (OSA relapse), but few anatomical recurrences as not significant lymphatics regrew. In one case, revision TORS was offered for tongue base biopsy, which proved to be negative for malignancy.
EPIGLOTTOPLASTY
In our experience, rescue Trans-Oral Laser Epiglottoplasty (TOLE) has been applied in a couple of cases. In the first, before introduction of DISE a floppy epiglottis was overlooked and the patient was operated on by bi-maxillary advancement with relapse of OSA. TOLE was carried out and epiglottis collapse was addressed. In a second patient, after TORS removal of more than 20 cc of lingual tonsil we registered a short term recurrence of snoring related to floppy supraglottic area vibration. A staged laser supraglottoplasty was successfully applied.
FREE FLAPS
Free flap reconstruction is routinely applied to wide tissue loss after cancer resection. Free flaps have also been described to address upper airway strictures after caustic ingestion, extensive burns or neck trauma. In cooperation with the ENT clinic in Pavia, we managed an obstructive recurrence of OSA after TORS referred us to another institution. Unfortunately, this 56-year-old man operated on elsewhere by UPPP and tongue base TORS developed a velo-pharyngeal incompetence as well as a progressive hypo-pharyngeal circular stenosis (web stenosis), that was addressed by scar resection and reconstruction with forearm free flap. To our knowledge, this is the only case of free flap application after OSA recurrence following previous TORS for sleep apnoea.
HNS
Liu et al. firstly described a patient who was successfully treated with phase 1 and 2 operations more than a decade previously 39. He returned at 65 years of age with relapse of moderate OSA, and after workup with polysomnography and drug-induced sleep endoscopy underwent upper airway stimulation of the hypoglossal nerve that resulted in cure of OSA (Fig. 7). This case demonstrates why upper airway stimulation may be an appropriate option for patients with OSA relapse after previously successful maxillo-mandibular advancement.
PROPOSAL OF MANAGEMENT FLOW-CHARTS (Figs. 8-9).
Figure 8 shows how the relapse of snoring can be addressed primarily on the basis of patient preference. If surgery is not accepted, weight loss, mandibular advancement devices, myofunctional therapy, and positional devices may be differently associated.
If local anaesthesia is preferred, palate radiofrequency is offered. In general anesthesia palatoplasty is still a valid option.
In the event of relapse of OSA, sleep endoscopy is critical in selecting palate, tongue, supraglottis or multilevel revision. Conservative approaches like weight loss, MAD positional or myofunctional may be additional solutions (Fig. 9).
Conclusions
OSA relapses after surgery represent a clinical challenge for sleep surgeons. An adequate comprehension of pathophysiological endotypes and anatomical conditions is mandatory in order to address patients to the most appropriate therapeutic choice. Among treatment options, ventilatory therapy, oral appliances, second look surgery and positional therapy are certainly the most viable solutions.
Conflict of interest statement
The authors declare no conflict of interest.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author contributions
The authors equally contributed to the draft of the manuscript.
Ethical consideration
Not applicable.
Figures and tables
References
- Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014; 146:1387-1394. DOI
- Sahlman J, Pukkila M, Seppä J, Tuomilehto H. Evolution of mild obstructive sleep apnea after different treatments. Laryngoscope. 2007; 117:1107-1111. DOI
- Feinsilver SH. Normal and abnormal sleep in the elderly. Clin Geriatr Med. 2021; 37:377-386. DOI
- Evans EC, Sulyman O, Froymovich O. The goals of treating obstructive sleep apnea. Otolaryngol Clin North Am. 2020; 53:319-328. DOI
- Vicini C, Marani M, Frasconi PC. Failures in snoring and OSAS surgery. Facial Plast Surg. 1999; 15:327-335. DOI
- La roncopatia cronica. Relazione ufficiale, XCI Congresso Nazionale SIO.
- Iannella G, Magliulo G, Lo Iacono CAM. Quality of life and excessive daytime sleepiness in adults with obstructive sleep apnea who are treated with multilevel surgery or adherent to continuous positive airway pressure. J Clin Med. 2022; 11:2375. DOI
- Iannella G, Magliulo G, Greco A. Obstructive Sleep Apnea Syndrome: from symptoms to treatment. Int J Environ Res Public Health. 2022; 19:2459. DOI
- Creamer JL, Arora SK, Rusling MR. Surgical treatments for obstructive sleep apnea: updated guidelines from the American Academy of Sleep Medicine. Am Fam Physician. 2022; 106:723-724.
- Vimal J, Dutt P, Singh N. To compare different non-surgical treatment modalities on treatment of obstructive sleep apnea: a systematic review and meta-analysis. J Indian Prosthodont Soc. 2022; 22:314-327. DOI
- Cammaroto G, Migliorelli A, Vicini C. OSA: treatments beyond CPAP. J Clin Med. 2022; 11:5938. DOI
- Cammaroto G, Bianchi G, Zhang H. Sleep medicine in otolaryngology units: an international survey. Sleep Breath. 2021; 25:2153. DOI
- Bosi M, De Vito A, Kotecha B. Phenotyping the pathophysiology of obstructive sleep apnea using polygraphy/polysomnography: a review of the literature. Sleep Breath. 2018; 22:579-592. DOI
- Malhotra A, Mesarwi O, Pepin JL. Endotypes and phenotypes in obstructive sleep apnea. Curr Opin Pulm Med. 2020; 26:609-614. DOI
- De Vito A, Woodson BT, Koka V. OSA Upper airways surgery: a targeted approach. Medicina (Kaunas). 2021; 57:690. DOI
- Bosi M, De Vito A, Eckert D. Qualitative phenotyping of Obstructive Sleep Apnea and its clinical usefulness for the sleep specialist. Int J Environ Res Public Health. 2020; 17:2058. DOI
- Han F, He ZM, Song WC. Effects of uvulopalatopharyngoplasty surgery on subsequent continuous positive airway pressure in patients with obstructive sleep apnea-hypopnea syndrome. Zhonghua Jie He He Hu Xi Za Zhi. 2005; 28:372-376.
- Inoue A, Chiba S, Matsuura K. Nasal function and CPAP compliance. Auris Nasus Larynx. 2019; 46:548-558. DOI
- Millman RP, Rosenberg CL, Carlisle CC. The efficacy of oral appliances in the treatment of persistent sleep apnea after uvulopalatopharyngoplasty. Chest. 1998; 113:992-996. DOI
- Benoist LBL, Verhagen M, Torensma B. Positional therapy in patients with residual positional obstructive sleep apnea after upper airway surgery. Sleep Breath. 2017; 21:279-288. DOI
- Iannella G, Cammaroto G, Meccariello G. Head-Of-Bed Elevation (HOBE) for improving Positional Obstructive Sleep Apnea (POSA): an experimental study. J Clin Med. 2022; 11:5620. DOI
- Meurling IJ, Shea DO, Garvey JF. Obesity and sleep: a growing concern. Curr Opin Pulm Med. 2019; 25:602-608. DOI
- Zhang F, Tian Z, Shu Y, Zou B. Efficiency of oro-facial myofunctional therapy in treating obstructive sleep apnoea: a meta-analysis of observational studies. J Oral Rehabil. 2022; 49:734-745. DOI
- Koka V, De Vito A, Roisman G. Orofacial myofunctional therapy in Obstructive Sleep Apnea Syndrome: a pathophysiological perspective. Medicina (Kaunas). 2021; 57:323. DOI
- Hedner J, Zou D. New pharmacologic agents for obstructive sleep apnoea: what do we know and what can we expect?. Curr Opin Pulm Med. 2022; 28:522-528. DOI
- Brodsky L. Modern assessment of tonsils and adenoids. Pediatr Clin North Am. 1989; 36:1551-1569. DOI
- Sjöblom HM, Nahkuri M, Suomela M. Treatment of sleep apnoea with tonsillectomy: a retrospective analysis using long-term follow-up data. Eur Arch Otorhinolaryngol. 2022; 279:3727-3732. DOI
- Matarredona-Quiles S, Carrasco-Llatas M, Apodaca PM. Is there a relationship between tonsil volume and the success of pharyngeal surgery among adult patients with obstructive sleep apnea?. Braz J Otorhinolaryngol. 2022; 88:S156-S161. DOI
- Kim JW, Rhee CS, Jung HJ. Partial resection of hypertrophic torus tubarius for recurred snoring: case series. Medicine (Baltimore). 2020; 99:e19329. DOI
- Boudewyns A, Van De Heyning P. Temperature-controlled radiofrequency tissue volume reduction of the soft palate (somnoplasty) in the treatment of habitual snoring: results of a European multicenter trial. Acta Otolaryngol. 2000; 120:981-985. DOI
- De Vito A, Frassineti S, Panatta ML. Multilevel radiofrequency ablation for snoring and OSAHS patients therapy: long-term outcomes. Eur Arch Otorhinolaryngol. 2012; 269:321-330. DOI
- Stuck BA, Starzak K, Hein G. Combined radiofrequency surgery of the tongue base and soft palate in obstructive sleep apnoea. Acta Otolaryngol. 2004; 124:827-832. DOI
- Powell N, Riley R, Guilleminault C. A reversible uvulopalatal flap for snoring and sleep apnea syndrome. Sleep. 1996; 19:593-599. DOI
- Neruntarat C. Uvulopalatal flap for obstructive sleep apnea: short-term and long-term results. Laryngoscope. 2011; 121:683-687. DOI
- Iannella G, Magliulo G, Cammaroto G. Effectiveness of drug-induced sleep endoscopy in improving outcomes of barbed pharyngoplasty for obstructive sleep apnea surgery: a prospective randomized trial. Sleep Breath. 2022; 26:1621-1632. DOI
- Bahgat A, Alkan U, Carrasco Ilatas M. International palate surgery questionnaire. Sleep Breath. 2022. DOI
- Cammaroto G, Stringa LM, Cerritelli L. Acquired nasopharyngeal stenosis correction using a modified palatal flaps technique in Obstructive Sleep Apnea (OSA) patients. Int J Environ Res Public Health. 2020; 17:2048. DOI
- Iannella G, Magliulo G, Montevecchi F. Lingual tonsil lymphatic tissue regrowth in patients undergoing transoral robotic surgery. Laryngoscope. 2019; 129:2652-2657. DOI
- Liu SY, Riley RW. Continuing the original stanford sleep surgery protocol from upper airway reconstruction to upper airway stimulation: our first successful case. J Oral Maxillofac Surg. 2017; 75:1514-1518. DOI
Affiliations
License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Copyright
© Società Italiana di Otorinolaringoiatria e chirurgia cervico facciale , 2023
- Abstract viewed - 361 times
- PDF downloaded - 121 times