Abstract
Gastrointestinal (GI) endoscopy and visceral surgery have been tightly merging to change GI disease diagnosis and the course of treatment. In addition to facilitating minimally invasive therapeutic procedures and improving postoperative outcomes, this synergistic strategy increases diagnostic precision. Recent technical advancements, such as high-definition endoscopic imaging, robotic-assisted surgery, and artificial intelligence integration, have refined patient care. The historical development, current therapeutic application, interdisciplinary collaborations, and potential future directions of integrating endoscopy and visceral surgery are covered in this review. It also discusses the difficulties in putting advanced approaches into clinical practice, including the need for specialized training and ethical issues. It is important to fully realize how endoscopic and surgical cooperation could translate into GI healthcare.
Keywords: cooperation, gastrointestinal endoscopy, high-definition endoscopic imaging, robotic-assisted surgery, visceral surgery
Introduction
While transforming early gastrointestinal (GI) diagnosis and treatment, endoscopy has drastically reduced the need for invasive surgical procedures. Thanks to the continuous improvement of endoscopic treatments, which have evolved from simple imaging to complex therapeutic interventions like endoscopic ultrasound (EUS) guided interventions, endoscopic submucosal dissection (ESD), and so on, alternatives to conventional surgery have become realistic. These developments have improved diagnostic precision and enabled the treatment of surgically high-risk patients and early-stage malignancies with minimal side effects.1,2
On the other hand, laparoscopy and robotic-assisted operations are examples of minimally invasive techniques that have significantly replaced open operations in visceral surgery. These methods have significantly decreased postoperative morbidity, expedited patient recovery, and shortened hospital stays. Reducing surgical trauma and improving patient outcomes have been the driving forces behind the paradigm change from open surgery to minimally invasive techniques. The true promise of these developments, however, is achieved by combining endoscopic and surgical methods in a way that maximizes both diagnostic precision and therapeutic effectiveness, resulting in hybrid treatments. 3
The collaboration between surgeons and gastrointestinal endoscopists has enhanced the development of innovative hybrid techniques, such as natural orifice transluminal endoscopic surgery (NOTES) and laparoscopic-endoscopic cooperative surgery (LECS). These approaches combine the minimally invasive nature of endoscopy with the precision of laparoscopy, resulting in reduced tissue trauma, enhanced patient safety, and improved cosmetic as well as medical outcomes. Such collaborations require a multidisciplinary team, involving not only surgeons and gastroenterologists but also anesthesiologists, pathologists, radiologists, and other disciplines to ensure comprehensive patient care in GI. 4
Development and applications in visceral surgery and GI endoscopy
Historical points
Endoscopy originated in the early 19th century when Bozzini created the Lichtleiter, a crude endoscope for seeing within bodily cavities. 5 Up until the middle of the 20th century, the field was mostly unchanged until fiber-optic technology transformed endoscopy and allowed flexible vision and improved diagnosis capacity. The evolution of video endoscopy improved vision even more and helped to document endoscopic results. 6
Concurrent with this development from open surgical methods to less invasive laparoscopic techniques, which became rather popular in the late 20th century, the history of visceral surgery changed. Adoption of laparoscopy for cholecystectomy in the 1980s constituted a turning point and helped to open the path for the spread of minimally invasive techniques across several surgical fields. The goal to lower surgical trauma, limit postoperative pain, and cut recovery times drove the change from open to laparoscopic surgery. 7
Relevant technological development
Thanks to amazing technical developments recently, endoscopic and surgical operations have been greatly improved. Real-time mucosa characterization and lesion identification have been transformed by advanced imaging technologies, including narrow-band imaging (NBI), blue laser imaging (BLI), and similar image-enhanced endoscopy, which are amplified by magnified technology. Further increasing diagnostic accuracy is real chromoendoscopy, which highlights mucosal changes using dyes. Real-time tissue analysis uses high-resolution imaging methods including optical coherence tomography (OCT), hyperspectral imaging (HSI), and confocal laser endomicroscopy (CLE). These advanced modalities help endoscopists to see even cellular and subcellular features, therefore enabling early identification of malignancies and precancerous lesions.8,9
Devices such as the da Vinci surgical systems have transformed minimally invasive surgery by giving surgeons more precision, dexterity, and ergonomic benefits. Robotic surgery systems allow difficult surgical operations to be carried out with more accuracy and less trauma, therefore improving patient outcomes. One developing method that reduces invasiveness even more is single-port robotic surgery. 10
Besides robotic surgical platforms, other innovations such as indocyanine green (ICG) fluorescence imaging have become integral to modern visceral surgery. This technology allows for real-time assessment of tissue perfusion during procedures, particularly in colorectal surgery for evaluating anastomotic blood flow, which is a critical factor in reducing leak rates and decreasing the indication of reoperation. It also enhances lymph node detection and the staging accuracy, adding a valuable functional dimension to surgical and endoscopic visualization.11,12
Early cancer diagnosis, automated polyp classification, and predictive analytics for surgical planning are now possible by artificial intelligence (AI) integration into endoscopy and surgery. While AI-powered surgical planning tools can maximize surgical approaches and reduce complications, AI-driven image analysis can help endoscopists find small lesions and predict the likelihood of malignancy. Polyp detection and lesion characterization based on texture and vascular patterns are applications of deep learning methods.13,14
Particularly with pancreatic cancer, EUS has become an invaluable instrument for the detection and staging of gastrointestinal malignancies. High-resolution imaging of the gastrointestinal wall and surrounding structures by EUS allows a more precise evaluation of tumor invasion and local metastases. Confirming diagnosis and enabling tissue sampling, EUS-guided fine-needle aspiration/biopsy (FNA/FNB) plays an essential role in GI oncology. 15
By means of over-the-scope clips and full-thickness resection devices, endoscopic full-thickness resection techniques have expanded the possibilities of therapeutic endoscopy, enabling the removal of deeper lesions and even early-stage cancers hitherto considered unresectable by conventional endoscopic methods. 16
These relevant developments of endoscopy, along with visceral surgery and many other technological advances, are shaping new horizons in GI healthcare.
Clinical applications of endoscopy in visceral surgery
Endoscopic diagnostics and therapeutics
Preoperative endoscopy is very important for evaluating, marking tumor margins, deciding whether resectability is possible, and guiding surgical procedures. Often removing the need for surgery, advanced treatment techniques, including EMR and ESD, enable the total excision of superficial malignant tumors. In patients with advanced malignancies, endoscopic stenting can also help to relieve obstructive symptoms. Hemostasis and closure of perforations can be accomplished via endoscopic suturing and clipping methods.17,18
Endoscopic tattooing with specific ink before or during surgery is an impactful practice for localization and demarcation of non-resectable lesions if using endoscopy only, such as invasive cancers, which ensures precise margins of laparoscopic resection. 19 Moreover, the development of endoscopic suturing systems (e.g., Apollo OverStitch) has significantly improved the management of endoscopic and surgical complications, providing a minimally invasive method to close perforations, leaks, and fistulas that might otherwise require urgent operation. 20
Gastrointestinal tumor treatment
Early identification, biopsy collection, and staging of gastrointestinal malignancies critically depend on endoscopy. LECS and NOTES are among the hybrid techniques that guarantee efficient tumor removal while maintaining organ function and reducing surgical trauma. Early-stage tumors and precancerous lesions can be treated using endoscopic resections such as EMR, ESD and ablative procedures like cryoablation, argon plasma coagulation (APC). In addition to surgery, visceral tumors in the liver and pancreas can be managed by radiofrequency ablation (RFA) under EUS-guidance.21,22
Endoscopic assistance in minimally invasive surgery
LECS methods reduce the risk of problems by means of intraoperative endoscopic guidance, therefore facilitating visceral operations by assuring exact resection margins. It is also used to verify the completeness of tumor resections and spot any leftover lesions using intraoperative endoscopy. In addition, endoscopic methods can help with laparoscopic bariatric operations such as sleeve gastrectomy and gastric bypass.4,23
The shift from surgery to endoscopy
Open surgery is giving way to minimally invasive endoscopic treatments in gastrointestinal intervention. Technology and patient-centered treatment are driving this transformation, reducing morbidity and speeding recovery. Endoscopic tumor resections, which remove neoplastic lesions without surgery, are rising. The novel Peroral Endoscopic Myotomy (POEM) treatment for esophageal motility problems is less invasive than Heller myotomy. Recently, third-space endoscopy, which navigates the submucosal layer, has expanded diagnostic and therapeutic options. The ability to treat submucosal cancers, muscularis propria lesions, and other disorders formerly only treatable by surgery solidifies endoscopy’s place in modern gastrointestinal care.
A typical example of the shift from surgery to endoscopy is percutaneous endoscopic gastrostomy (PEG), which is now the standard of care for long-term enteral nutrition. 24 Furthermore, endoscopic detorsion has become the first-line intervention for sigmoid volvulus, effectively avoiding emergency surgery in many patients. 25 New endoscopic approaches, such as endoscopic retrograde appendicitis therapy (ERAT) for uncomplicated acute appendicitis, are initially showing as potential therapy, though more data are needed, further illustrating the expanding footprint of interventional endoscopy into the traditional surgical field. 26
Remarkably, the treatment of complicated gastrointestinal disorders has been transformed by EUS-guided treatments, which are gradually taking the place of big invasive surgeries. This change is demonstrated by procedures such as EUS-guided biliary drainage (EUS-BD), necrosectomy for walled-off pancreatic necrosis, and gastroenteroanastomosis using lumen-apposing metal stents (LAMS), which offer safer and more efficient substitutes for conventional surgical procedures while also greatly lowering patient trauma.15,27,28
These common clinical implications are summarized in Table 1.
Table 1.
Synergistic surgical-endoscopic management of common pathologies in gastrointestinal care.
| Clinical scenario | Traditional surgical approach | Traditional endoscopic approach | Synergistic management |
|---|---|---|---|
| Gastrointestinal Submucosal Tumor | Laparoscopic resection with partial gastrectomy or enterectomy | EUS for diagnosis and staging; Endoscopic resection (ESD, EFTR) for select lesions. | LECS: Endoscopic resection and visualization guide precise laparoscopic resection, maximizing organ preservation. |
| Early Gastrointestinal Cancer | Surgical gastrectomy/colectomy with lymph node dissection | ESD/FTRD for lesions with specific criteria. | EUS determines invasion depth. If ESD is non-curative, it guides the extent of subsequent surgical minimal resection with endoscopic guidance (LECS or NOTES). |
| Postoperative Anastomotic Leak | Surgical re-exploration, washout, and repair/re-anastomosis | EVT, internal stenting, clipping. | Endoscopy is first approach; surgery is reserved for failure of endoscopic therapy. |
| Symptomatic Choledocystolithiasis | Laparoscopic common bile duct exploration and cholecystectomy | ERCP with sphincterotomy and stone extraction. | Single-Anesthesia Combined Protocol: ERCP followed by laparoscopic cholecystectomy, avoids second anesthesia. |
| Distal Malignant Biliary Obstruction | Pancreaticoduodenectomy, hepaticojejunostomy | Endoscopic Stenting/Sampling | EUS-CPN can be performed simultaneously for pain control. Endoscopic stenting relieves jaundice before operation. |
CPN, celiac plexus neurolysis; EFTR, endoscopic full-thickness resection; ESD, endoscopic submucosal dissection; EUS, endoscopic ultrasound; EVT, endoscopic vacuum therapy; ERCP: Endoscopic Retrograde Cholangiopancreatography; FTRD, full-thickness resection devices; LECS, laparoscopic-endoscopic cooperative surgery; NOTES, natural orifice transluminal endoscopic surgery.
Advantages of cooperation between disciplines
Improved diagnosis precision
Endoscopy and visceral surgery taken together greatly increase the accuracy of diagnostic tests, enabling correct staging of malignancies and better localization of pathogenic lesions. Particularly in GI cancer care, EUS has evolved into an invaluable instrument in guiding surgical decisions since it offers comprehensive pictures of the tumor and surrounding structures. Combining endoscopy with other imaging modalities, such as CT and MRI, in multimodal imaging helps to improve diagnostic accuracy even more. For example, the combination of Positron emission tomography–computed tomography (PET-CT), Magnetic Resonance Cholangiopancreatography (MRCP), and EUS can offer both structural and functional data, therefore enhancing the staging of cancers. Furthermore, providing excellent localization is the intraoperative use of endoscopy during laparoscopic/open surgery.29,30
Minimizing surgery time
Endoscopic guiding avoids unnecessary incision and resection, reduces operating times, and lowers the risk of intraoperative complications by means of its integration into surgical operations. For LECS, for instance, intraoperative endoscopy guarantees exact resection margins, hence lowering the demand for thorough surgical dissection. In addition, enabling more exact manipulation and faster operating periods is the use of real-time endoscopic images during robotic surgery. Moreover, preoperative marking of lesions using endoscopic techniques might direct the surgeon during laparoscopic resections, therefore minimizing the necessity for thorough dissection and reduction of operating times. 4
Reduction and management of surgical complications
By lowering the need for large incisions, endoscopic procedures help to lower the risk of postoperative adhesions, incisional hernias, anastomotic insufficiency, and wound infections. In addition, producing less postoperative discomfort and faster recovery times are minimally invasive techniques. For the repair of gastrointestinal perforations, for example, the use of endoscopic clipping and suturing procedures substitutes for major abdominal surgery and lowers the risk of postoperative problems. Moreover, endoscopic stenting helps to control anastomotic leaks following surgery, thus, less reoperation is required. Using POEM for achalasia lessens postoperative pain and reduces the necessity for large surgical myotomy.4,21
Endoscopy plays an increasingly significant role in the management of operative complications. With less invasion and faster recovery times, the endoscopic treatment of surgical problems such as strictures, leaks, and fistulas is becoming more and more popular. This transformation is supported by rising evidence showing that endoscopic management, when applied appropriately, can reach good clinical success rates while remarkably reducing the morbidity, mortality, and associated costs. However, it is crucial to be aware that endoscopy is not a panacea; its outcome is highly dependent on multiple factors such as the size of the defect, location, as well as the local expertise of endoscopists and surgeons. It should be clarified that while acute iatrogenic perforations during endoscopic interventions may often be closed endoscopically, most delayed or spontaneous perforations (e.g., from a deep duodenal ulcer) still require surgical repair and peritoneal lavage. Therefore, a multidisciplinary approach is essential to determine the optimal therapy, ensuring that patients who really need surgery are not delayed, and endoscopic interventions are applied appropriately where they offer a clear benefit.31–33
Improved resource utilization
Reducing unnecessary diagnostic tests and increasing cost-effectiveness help a multidisciplinary approach maximize the utilization of hospital resources. As an example, preoperative EUS can precisely stage tumors, therefore reducing the need for surgical exploration. Furthermore, lowering the requirement for emergency surgery and intensive care unit hospitalizations is the use of endoscopic procedures for the management of gastrointestinal bleeding. Early cancers can be treated with endoscopic resections instead of more involved surgical operations, which also helps to lower hospital stay, minimize the consumption of equipment and materials.15,22
Enhanced patients’ outcome
Reduced morbidity, mortality, and length of hospital stay are among the better patient outcomes resulting from the cooperative efforts of endoscopy and visceral surgery. Along with faster recovery and less pain, patients get a greater cosmetic appearance. While hybrid techniques show the promising outcome of an interdisciplinary collaboration, their application must be grounded in comparisons with established surgical standards. For instance, LECS for gastric submucosal tumors has demonstrated comparable oncological efficacy to laparoscopic resection with better outcomes in the short term, including significantly shorter operative times and reduced blood loss.
Similarly, a comparative trial demonstrated that POEM for achalasia was non-inferior to laparoscopic Heller myotomy (LHM) in providing treatment success at 6 months; however, it achieved a significantly shorter procedure time (113 and 125 min, p < 0.05). These comparisons demonstrate that the value of hybrid approaches often lies not in completely replacing surgery, but in offering comparable efficacy with enhanced recovery profiles under careful selection of the indicated cases.4,28,34
Technological innovations and future views
Robotics and AI developments
Robotic-assisted endoscopic surgeries are becoming more popular since new technology allows for autonomous endoscopic navigation and AI-driven decision support systems. Advanced imaging modalities and AI algorithms could be included in future robotic systems to execute intricate endoscopic operations with low human involvement. Furthermore, AI is helping in real-time picture analysis, polyp detection, and risk stratification. By use of soft robotics and micro-robots for surgery, even less intrusive treatments and access to hitherto unreachable sections of the gastrointestinal system will be possible. Moreover, the incorporation of robotic endoscopic systems will enhance the tactile feeling of the surgeon as well endoscopist and raise the intervention accuracy.35,36
Remote surgery and tele-endoscopy
The spread of telemedicine has made real-time remote help for endoscopic procedures possible, therefore enabling expert advice in geographically difficult-to-reach areas. Remote surgery and tele-endoscopy can help to lower healthcare inequalities and increase access to specific treatment. Enhanced connectivity and 5G technologies will help tele-endoscopy to become even more capable. More exact remote interventions will be made possible by the development of haptic feedback devices, hence improving the tactile sense during remote operations. Using virtual reality for remote surgical direction would also enable professionals to direct treatments instantly.37,38
Virtual reality and augmented reality
Endoscopy and surgery are including VR and AR technologies to offer immersive teaching opportunities and improve surgical planning and navigation. While AR can overlay real-time endoscopic images with 3D anatomical models, hence boosting surgical accuracy, VR simulations let trainees practice procedures in a safe and regulated setting. Additionally, increasing tumor resection accuracy is seen in the use of AR for intraoperative navigation. Moreover, preoperative planning using VR would enable surgeons and endoscopists to replicate difficult procedures and raise patient safety.39,40
Prospective research topics
Research on the long-term effects of hybrid approaches, the financial viability of robotic-assisted therapies, and the part AI plays in automating endoscopic procedures is in continuous flux. Optimizing these cooperative approaches should be the main emphasis of future studies to guarantee improved clinical results and economical healthcare delivery. Furthermore, looking at the use of new imaging technologies, such as HSI, OCT, for real-time tissue characterization during endoscopy and surgery is advisable. Moreover, enhancing the possibilities of hybrid operations will result in the development of new endoscopic tools and surgical as well as endoscopic robots. Using genomes and proteomics can individually customize endoscopic and surgical procedures to patients; research should also center on the creation of personalized medicine strategies. Important areas of study also include the creation of fresh markers for early GI cancer detection and innovative endoscopic/laparoscopic treatments for advanced tumors.2,35,41
Challenges and limitations
The intricacies of hybrid endoscopic-surgical techniques
The integration of endoscopy with surgical operations requires advanced knowledge and specific skills. The intrinsic intricacy of these hybrid procedures requires that surgeons and endoscopists attain proficiency in both endoscopic and surgical techniques to guarantee safe and effective performance. In resource-constrained environments, the necessity for specialized equipment and infrastructure might be a considerable obstacle. Moreover, the establishment of defined protocols and guidelines for hybrid operations is essential. Technical challenges may emerge from the amalgamation of many technologies, including sophisticated imaging modalities and robotic surgery systems.
Despite this significant development, it is crucial to maintain a balanced perspective. A large number of patients with gastrointestinal surgical pathologies still need operative treatment. The therapeutic spectrum of interventional endoscopy, while growing, remains limited to specific indications such as early-stage neoplasia. Acknowledging these limitations is essential to avoid overstatement and to ensure that patients are directed to the most appropriate, evidence-based therapy, whether endoscopic, surgical, or hybrid treatment. Ultimately, effective communication and coordination among diverse teams are crucial for the successful execution of these hybrid interventions.4,15,42
Training and education
It is necessary to emphasize that both advanced endoscopic and visceral surgical interventions are technically demanding and require a high level of specialized training. Not all gastroenterologists are qualified to perform endoscopic surgery interventions, and similarly, not all surgeons have the specific training required for complex therapeutic endoscopy. A successful collaboration lies in the complementarity of their respective expertise. Importantly, there must be no compromise on the quality of procedures; every intervention must be performed by a professional with the appropriate, specialized training and credentialing to ensure optimal patient care.43–45
There is an urgent necessity for standardized training programs that equip endoscopists and surgeons with the requisite expertise for hybrid procedures. To ensure proficiency in both endoscopic and surgical techniques, these courses must include didactic lectures, practical simulations, and supervised clinical training. Furthermore, improving the accessibility and effectiveness of training involves the development of simulation-based courses utilizing virtual reality and augmented reality. Furthermore, there is a necessity for the expansion of fellowship programs centered on surgical and hybrid endoscopic procedures. Moreover, enhancing the accessibility of training in remote areas involves the utilization of tele-mentoring.46,47
Financial and ethical issues
Modern technologies such as AI-driven endoscopy and robotic-assisted surgery create ethical and financial problems when combined. Financially speaking, especially in low-income areas, the large investment required for these technologies could cause variations in access. Strategic alliances, new funding concepts, and smart policy judgments all help to determine equitable distribution and affordability, most importantly. Still, one should also value the opportunity for long-term financial savings from reduced complications, shorter hospital stays, and improved patient outcomes resulting from less complexity. Ethically, reliance in more and more on AI in decision-making necessitates careful study of patient autonomy and informed permission. Clear policies for the moral use of AI, including openness in algorithmic processes and the elimination of any prejudices, are absolutely necessary. Furthermore, the collection and analysis of enormous medical data for tailored therapy and AI development demand strict data security rules to honor patient confidentiality and privacy. While telemedicine and remote procedures give access to specialist treatment and promise to promote accountability, patient safety, and the maintenance of the patient-clinician relationship, they also raise ethical issues about establishing clear policies and ethical guidelines for remote treatments is crucial to ensure that new technologies are used ethically and effectively, therefore balancing technology development with the fundamental concepts of patient-centered care.48,49
Figure 1 illustrates an intraoperative collaboration between a visceral surgery team and a gastrointestinal endoscopy team. The endoscopist (left) performs a simultaneous endoscopic procedure, inspecting the internal lumen on a monitor and performing the intervention from inside. The surgeons (right) conduct a laparoscopic procedure, observing the abdominal cavity. This image illustrates the coordinated teamwork and complementary expertise required for advanced hybrid surgical-endoscopic interventions.
Figure 1.
Cooperation between endoscopist and visceral surgeon.
Conclusion
The cooperation between gastrointestinal endoscopy and visceral surgery offers new standards of treatment to patients with improved diagnostic accuracy, lower demand for invasive procedures, and better post-interventional outcomes. Emerging technologies in robotics, AI, and telemedicine enable efficient and individualized management, which opens the door to hybrid procedures. To apply these advanced technologies widely, we need to improve training, overcome budgetary constraints, and resolve ethical problems. Efficient and fair distribution of these cutting-edge technologies, as well as methods that minimize expenses, should be the primary goals of future studies. Globally, the application of interdisciplinary collaboration and the advancement of technology in gastrointestinal treatment can significantly improve patient outcomes. Finally, new regulations should be created to guarantee the secure and efficient application of hybrid treatments. Endoscopists, GI surgeons, and related disciplines need to work together tightly to enhance the gastrointestinal field and provide better patient care.
Acknowledgments
We are grateful to Drs. Carola Günther, Awsan Mohamed, and Violeta-Alina Duma from the 4th Medical Department, Medical University Lausitz–Carl Thiem, for their valuable support and comments during the preparation of this manuscript.
Footnotes
ORCID iDs: Quang Trung Tran
https://orcid.org/0000-0001-8347-1614
Tobias Kleemann
https://orcid.org/0000-0003-3913-6821
Contributor Information
Quang Trung Tran, Department of Gastroenterology and Rheumatology, Medical University of Lausitz – Carl Thiem, Cottbus, Germany.
Dai Que Vu, Department of General and Visceral Surgery, Medical University of Lausitz – Carl Thiem, Cottbus, Germany.
Irka Wiedenhaupt, Department of Gastroenterology and Rheumatology, Medical University of Lausitz – Carl Thiem, Cottbus, Germany.
Ali Aghdassi, Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
Tobias Kleemann, Department of Gastroenterology and Rheumatology, Medical University of Lausitz – Carl Thiem, Thiemstraße 111, Cottbus BB 03048, Germany.
Declarations
Ethics approval and consent to participate: Not applicable.
Consent for publication: Not applicable.
Author contributions: Quang Trung Tran: Conceptualization; Methodology; Project administration; Resources; Validation; Writing – original draft; Writing – review & editing.
Dai Que Vu: Conceptualization; Methodology; Project administration; Resources; Validation; Writing – original draft; Writing – review & editing.
Irka Wiedenhaupt: Formal analysis; Visualization; Writing – review & editing.
Ali Aghdassi: Methodology; Supervision; Validation; Visualization; Writing – review & editing.
Tobias Kleemann: Conceptualization; Formal analysis; Methodology; Project administration; Resources; Supervision; Visualization; Writing – original draft; Writing – review & editing.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
The authors declare that there is no conflict of interest.
Availability of data and materials: Not applicable.
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