|Year : 2017 | Volume
| Issue : 2 | Page : 109-118
Telemedicine and tele-echocardiography in India
Krishnam P Raju1, SG Prasad2
1 Department of Cardiology, CARE Hospitals, Hyderabad, Telangana, India
2 Department of Telemedicine, CARE Foundation, CARE Hospital, Hyderabad, Telangana, India
|Date of Web Publication||28-Aug-2017|
Krishnam P Raju
CARE Hospital, Road No. 10, Banjara Hills, Hyderabad - 500 034
Source of Support: None, Conflict of Interest: None
India is a vast nation with almost 75% of their population living in rural and remote regions. The obvious challenge is in the health-care delivery mechanism because of the disparity in the availability of services and specialists across the region. Therefore, the technology that facilitates the delivery of this essential health care to these remote areas is the need of the hour today. Telemedicine which essentially encompasses exchange of clinical information through a communication media has provided a platform for the delivery of quality health care. Advances in Information and Communication Technology in the area of video-to-video communication have led to the growth of extending the reach of specialist services for diagnostic investigations to areas wherein specialists are unavailable. For a country of over one billion, the number of cardiologists available for even screening patients is abysmally low. Echocardiography is often used to diagnose and exclude important cardiac diagnoses in adults and children. The use of telemedicine in echocardiography is one way to alleviate this problem, wherein a diagnosis can be made through the transmitted images and an appropriate management plan suggested based on the findings before there is patient movement. With the right diagnosis, some of them do not need medical intervention in terms of a procedure or surgery, and they can just be managed by medicines. The convergence of science and technology in our dynamic digital era has resulted in the development of innovative digital health devices that allow easy and accurate characterization in health and disease. Internet of Things (IoT)-assisted medical devices have found immense potential in addressing some of the long-standing issues related to diagnostic tests such as electrocardiogram and echocardiography. These technological advancements and the miniaturization of diagnostic instruments have led to decreasing health-care costs and improving outcomes.
Keywords: Bandwidth, Information and Communication Technology, internet of things, remote patient monitoring, tele-echocardiography, telemedicine
|How to cite this article:|
Raju KP, Prasad S G. Telemedicine and tele-echocardiography in India. J Indian Acad Echocardiogr Cardiovasc Imaging 2017;1:109-18
|How to cite this URL:|
Raju KP, Prasad S G. Telemedicine and tele-echocardiography in India. J Indian Acad Echocardiogr Cardiovasc Imaging [serial online] 2017 [cited 2017 Nov 25];1:109-18. Available from: http://www.jiaecho.org/text.asp?2017/1/2/109/213680
| Introduction|| |
One of the major aspects in the progress of telemedicine is the ability to create cutting edge telehealth tools and technologies, thereby enhancing health-care delivery to medically underserved populations using the Information and Communication Technology (ICT) platform, to provide affordable and accessible medical specialty services, and to provide training of health-care providers, clinical trainees, and students in health-related fields. The advances in the field of ICT over the past decade have helped in balancing the supply and demand in the health-care services in quite an effective way. Telemedicine, in particular, has become a more viable and feasible model for health-care delivery with the advent of ICT platform. The emergence of Internet of Things (IoT) has further ensured that a continuum in care can be maintained, with patients having the opportunity to have wearable devices at their homes and using the telemedicine platform for transmission of medical data from these devices for consultations. The impact of social networking platforms and mobile technologies in the health-care domain needs further work, especially in their utility to serving the underserved and remote populations.
Health-care today involves multiple work centers and interdisciplinary work cooperation. Timely diagnosis has become a difficulty because of the increasing mobility of people and also the lack of monitoring the actual time span between health episodes. The lacunae in providing necessary infrastructure at secondary health centers like the district hospitals and the difficulty for patients in traveling for basic consultations have left us with no choice but to evolve systems in a manner that quality health-care services can be delivered with the use of the ICT platform.
We now stand at the threshold of a technological wave that promises not only to make health-care delivery simpler but also bridge the last mile gap; an issue that has found very few holistic solutions. Diffusion of mobile technology has been very quick even to the remote parts of this vast country. To empower the same device to be able to deliver health care would be the most economic and efficient solution today.
| Health Care of Patients - impact of Technology|| |
Theoretically speaking, technological innovation should bring better interprofessional cooperation, information sharing, decision support, and flexibility to the health-care system. However, it has been observed that societal and professional constraints have reduced the impact of such innovations, which includes legal, ethical, and data security. In general, health-care professionals can be resistant to innovations, particularly if the technologies are considered to be “solutions seeking a problem” and where the evidence for the impact on quality of care is seen as less than robust. Integrating new technologies into the health-care system often requires one to be adaptable to process “redesign or disruption” in the health-care delivery mode.
In any health-care system, the most important aspect still remains with the primary care of the patient and unfortunately this issue still remains unaddressed due to dearth of physicians and specialists at rural centers. With the predicted shortage of physicians across the United States and the world, we must think of new and effective ways of treating our patients including changes in our education model or our practice model.,, Recent article reviews the empirical evidence of telemedicine interventions in primary care. More than 2300 articles have been assessed between 2005 and 2015, and just 86 met the incorporation criteria for their investigation. This audit demonstrated a noteworthy change in adoption of telemedicine and that patient acceptance was more satisfactory than the healthcare providers. Despite the fact that telemedicine and telehealth have turned out to be essential parts of essential care around the world, the appropriation of telehealth still confronts challenges including approval of advancements and procedures.
While a lot of importance is given to facilitating medical practitioners to perform their tasks, an equally important issue to address is the health-care services provided to patients, as they are the end users who must feel comfortable receiving the treatment given. The provision of a technically feasible solution is not the only obstacle to deal with. Other important issues including patients' acceptance and accessibility need to be addressed. End users, particularly children and the elderly, may not be too keen on accepting technology as a tool for healing. Convincing patients of the benefits of information technology (IT) in health care may involve liability, security, and privacy issues. For example, in the case of monitoring or tracking a patient recovering at home, the patient must be assured that personal information is securely kept and no such information is accessed in any way without consent.
Population aging is becoming a significant concern in many countries, and it can be widely expected that more care and monitoring will be needed. A significant increase in the application of wireless communications in elderly care has been seen over the past few years as related technologies become more mature. The cost of service becomes more affordable, and portable devices become smaller and more user-friendly. As pervasive computing technology advances, more comprehensive and automated services will become available to the aging population in the years to come. The design of interconnected devices and sensors on the patients' side must ensure nonobtrusiveness and should be comfortably worn. It is important to ensure that user's movement is not restricted and the reliability of the device should not be hampered by the wearing conditions. User-friendliness is another important design factor, as absolutely minimal training should be necessary, especially for children and the elderly. These should be genuine “plug and play” devices. In this sense, the health-care system in the patient's home can be installed by a technician during initial deployment. Thereafter, almost everything should be fully automatic except for unavoidable scheduled maintenance such as battery replacement and calibration.
The rising prevalence of chronic illnesses in an aging population puts pressure on the supply side of health care. Clinicians are not being prepared sufficiently quickly to keep pace with the rate of administration request. What's more, given the increasing expense of care, new models for repaying health centers and different suppliers have started to underscore quality and proficiency as opposed to units of conveyed administrations. This has led to a competition wherein consumers look out for attractive health insurance policies that require significant deductibles and out-of-pocket expenses. Consequently, a flexible and transparent model for the delivery of health care is the need of the hour.
With the advances made in the field of ICT, telemedicine is now being a good health-care delivery model for people living remotely. One of the noticeable advantages of this technology is that it has ensured a reduction in the number of clinical visits, thereby increasing the convenience factor for the patient. The waiting time in clinics is no longer an issue as the patient can continue with other routine work or rest at home until the specialist is available. The advancement of faster computers and more efficient bandwidth usage has allowed more types of services to be extended to more users. For example, a few decades ago, a simple request for medical advice could be obtained by finding a fixed line telephone and dialing into the clinic where a physician was stationed. With the availability of mobile Voice over Internet Protocol technology, one can now simply pick up a mobile phone and place a video-enabled call to a physician, thereby providing the flexibility to the physician of not being restricted to stay at one clinic to provide medical advice.
India with its tremendous populace, of which 75% are poor and live in hard to achieve country, and unfriendly territory gets themselves out of reach to quality health care principally because of the colossal imbalance in the distribution of health-care services. It should be noted that more than 75% of Indian doctors cater to the urban sector whereas more than 75% of the population live in rural villages. Telemedicine can be an ideal mechanism wherein experts from the urban cities can establish connectivity with people living in these regions.
| Dynamics of Telehealth|| |
The growing demands in health care suggest that a holistic approach is essential which would require a slight paradigm shift from individual-centered care to community-centered care. It is important to differentiate here that community-centered care focuses on the health needs and expectations of communities and not on diseases while individual-centered care focuses more on the individual. The broad spectrum that is covered through community-centered care facilitates in shaping health policy and health services for the community, thereby serving a larger population base. Henve, from just being a diagnostic – cure model of health care, it has become imperative that we focus toward prevention and wellness. Hence, the new model approach should be more like the “wellness-prevention-diagnostic-cure.” It is, therefore, imperative that one has an interdisciplinary approach so that people receive a continuum of health promotion, diagnosis, treatment, disease prevention and management, rehabilitation, and palliative care services, in a comprehensive manner according to their needs throughout the course of their life. In today's world, telehealth encompasses five distinct domains of applications [Figure 1]. These are commonly known as:
- Real time: This is a synchronous activity which involves live, two-way interaction between a person and a provider using audiovisual telecommunications technology
- Store-and-forward: This is an asynchronous activity wherein the patient's clinical history which includes both data and images are archived and transmitted through the ICT platform to a practitioner, usually a specialist, who evaluates the case and gives his opinion outside of a real-time or live interaction
- Remote patient monitoring: This usually includes transmission of data on a real-time basis such as having a wearable sensor attached to a patient capturing the vitals and transmitting the same to a cloud server wherein specialists can view the data on a real-time basis and give their opinion/advice
- Mobile health: Health services and general well-being practice and training are bolstered by versatile specialized gadgets, for example, phones, tablet personal computers, and personal digital assistants (PDAs). Various applications ranging from sending alerts to patients in terms of monitoring of vitals, diet, medication, and lab results make the health-care delivery process easier for the patient
- Health education can also be delivered in a similar manner and includes a broad range of activities such as classes, patient portals and online discussion forums for patients, and training programs for all levels of health professionals. These services can be live interactive video with multiple users communicating in real time or prerecorded on-demand video streaming that can be downloaded to computers or digital devices.
The first four applications are essentially related to delivery of health care to the patients and can be called as telemedicine activity. The fifth application involves delivery of health education to nurses, paramedics, and medical professional using the same platform. This activity is not directly linked to the delivery of health care to the patient but helps in skilling, upskilling, and reskilling all personnel related to health-care delivery with newer techniques and helps in keeping them abreast with latest technologies.
In today's world with the increasing awareness through the universal social connectivity medium, telemedicine can find its application for diagnosing patients remotely. More than 94% of the world population (approximately 6.8 billion subscribers) use cell phone, of which 2.7 billion subscribers use internet. Subscription to cell phones is increasing quite rapidly and is estimated to be close to 8.5 billion by 2016 with almost 70% of smartphone users from developing countries. A number of applications are inbuilt in these smartphones such as location tracking, short message service, and access of wireless local area network/general packet radio service GPRS/3G enabling global connectivity at any given point of time. A number of studies have been conducted to measure the effectiveness of survival of aged patients with fragilities using inbuilt applications on mobiles.,,,
| Tele-Echocardiography|| |
Developing countries like India face the dual burden of high rates of cardiovascular disease (CVD) and barriers in accessing diagnostic and referral programs, especially in the rural communities.,,,,, A number of studies and data have suggested the rapidly rising burdens of CVDs, with the reported prevalence of coronary heart disease having doubled over the past 30 years. CVD is now the leading cause of death in India. A study conducted in 45 villages in 2004 revealed that 32% of all deaths in India were due to CVD, outranking infectious diseases, which were responsible for 13%. India is already considered to be the diabetes capital of the world, with 32 million persons affected. This number is projected to rise to 69.8 million in 2025. The number of hypertensive individuals is expected to rise from 118 million in 2000 to 214 million in 2025. Exacerbating this epidemic is a huge inequality in health-care distribution. Although nearly 75% of Indians live in rural villages, more than 75% of Indian doctors are based in cities.
There is a growing demand for having telemedicine connected centers across the country with the technological advancements in the ICT platform. The increased connectedness to internet through laptops, smartphones, and tablet computers has now enabled accessibility for the specialist with clinical information of the patients and also imaging information such as X-ray, echocardiography, and other images from other modalities. Telecardiology which essentially involves consultation with cardiologists and transmission of electrocardiogram (ECG) has been in operation since the 1980s. The transmission of ECG has been in practice for quite some time, and with IoT-based medical devices, the portability concerns and the ease of capture have more or less become less of an issue. The ability to transmit a patient's ECG is a good example of the benefits of telecardiology can bring and it has impacted greatly on the treatment of acute heart attacks. For example, ambulance staff can perform and transmit ECGs to remote cardiologists who can diagnose and direct staff to start immediate reperfusion treatment intravenously. This has proven to be a life- and time-saving treatment option that prevents further myocardial damage and improves the quality of life for the patient, when compared with diagnosis and treatment being delayed until the patient arrives at hospital. The continuous and rapid growth of echocardiography as the mainstream cardiac imaging modality (40%) and the use of portable ultrasound devices are stimulating this request for tele-echocardiography. The diagnostic quality of the tablet computer screens has now made it possible for having high-resolution echocardiographic images being viewed on these screens and provide diagnosis and advise for treatment. Previous difficulties included transmitting image data and, in particular, cardiac image data, as the heart is a dynamic organ and high image quality is required for a proper diagnosis. Large amounts of data need to be transmitted, but this is only possible by applying image compression, which can cause a deterioration of the quality. In the early days of tele-echocardiography, the images of the analog ultrasound console were digitized by computer first, applying so-called frame grabbers, and were then compressed before transmission, to avoid transmit times of several hours and reducing the need to send images overnight. The images were then stored locally and forwarded to the remote site where they were stored again before viewing and discussion.
Rapid advances in the computational capabilities of modern processors and their affordability have significantly sped up the development of novel technologies in cardiovascular imaging. Users are slowly moving away from expensive, large, stationary, and complex systems to smaller, easier to use, and more accessible technology. The availability of higher bandwidth and imaging algorithms has enabled transmission of echocardiographic images without losing resolution, thereby making online tele-echocardiography much more feasible and practical than earlier. Parallel to today's smartphones and wireless technology, the medical field has seen the emergence of miniaturized pocket-sized echocardiography systems that can be used in conjunction with telecommunications and IT to provide health care from a distance. Echocardiography has now become a natural application for telemedicine, as handheld ultrasound devices and cloud-based transmission solutions make it possible to perform a test at a remote location and have consultation, in real time, by expert thousands of miles away.
Smart phone technology has driven the demand of tele-echocardiography more strongly in the short term to become commercially available., These devices can connect to both wireless computer networks as well as to wireless telephone networks, enabling independent access to patient data irrespective of their location. Mobile phone-based tele-echocardiography can further expand the application of services to prehospital care as well as to home care. In this current 21st century, there is a great demand for a common telecardiology platform with shared access nationwide or even worldwide. This would enable sharing of data and patient clinical records across a wide spectrum of networking health-care workers.
Tele-echocardiography also finds an important role in pediatric cardiology. Congenital heart disease (CHD) may be diagnosed during routine echocardiographic screening in babies and fetuses with risk factors for CHD. [Table 1] shows how tele-echocardiography can play a significant role in the screening of patients with potential risk of CHD.
Telemedicine has a very distinct and unique role which can benefit in a significant manner in the discipline of fetal cardiology. Some attractive features that make telemedicine an attractive proposition are:
- Fewer specialists are available in fetal cardiology as compared to pediatric cardiology, so this technology can help in bringing together the limited expertise available. The vast majority of fetuses with CHD are born from pregnancies without a recognizable antenatal risk factor. Obviously, formal evaluation by a fetal cardiologist cannot be offered to every single pregnancy. Therefore, to maximize antenatal detection of CHD, greater proficiency, from the nonspecialist, is required at confirming normality and identifying any abnormal pathology.
- The summary of fetal cardiology literature demonstrates that timely, antenatal diagnosis of CHD is important for improving outcomes for fetus and family by facilitating: parental counseling, elective delivery at an appropriate center, parental choice in terms of termination and permitting fetal intervention in terms of pharmacotherapy for dysrhythmias, and catheter intervention for severe complex lesions (Bonnet et al., 1999; Allan, 2000; Tworetzky et al., 2001; and Gardiner, 2008).
| Studies of Tele-Echocardiography|| |
With the continuous development and democratization of the internet and other information technologies, tele-echocardiography has the potential to assist in the provision of specialist services to remote locations as shown in [Table 2]. In addition to typical teleultrasonography applications in routine clinical practice, reviewing patients in intensive care units has also become a possibility with this technology. The routine use of these and other innovations should result in overall improvements in patient care in remote and isolated regions.
| Our Experience|| |
CARE has been involved in telemedicine since 2001 and was one of the early institutes to establish connectivity with district hospital at Mahabubnagar under the public-private partnership model, with the Andhra Pradesh Vaidya Vidhana Parishad (APVVP) on behalf of the Government of Andhra Pradesh. The APVVP provided a facility at the district hospital with a fully operational computed tomography (CT), X-ray, ECG, and echocardiography units. Care Foundation was in-charge of providing in-house developed software, dissemination of training to a local field project executive, proving timely diagnosis with the help of the specialists at CARE Hospitals, and daily maintenance of the communication and IT network [Figure 2].
|Figure 2: Public-private partnership model, with the Andhra Pradesh Vaidya Vidhana Parishad on behalf of the Government of Andhra Pradesh. The Andhra Pradesh Vaidya Vidhana Parishad provided a facility at the district hospital with a fully operational computed tomography, X-ray, electrocardiogram, and echocardiography units|
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An ECG was taken for all the patients for whom an echocardiography investigation was suggested. A paramedic who was a resident of Mahabubnagar was trained at our hub center for a duration of 1 month on providing the echocardiographic views. As part of the process of telemedicine, the specialist would first have a face-to-face interaction with the patient to understand the condition and complaints of the patient all of which were recorded through the application software. A two-way interactive video conferencing (VC) system was provided for the live interaction, and the output of the echocardiographic machine was given as an input to the VC which enabled all echocardiographic images to be streamed live as the case was being done. The paramedic provided the necessary views through the established ICT platform for the specialist at the hub center to diagnose. The findings of the investigation were explained to the patient by the specialist before handing over the report.
A total of 3188 cases were diagnosed using this ICT platform which operated on a 256 Kbps bandwidth terrestrial network [Table 3].
ECG was taken for all the patients who underwent an echocardiography test. Of the 3188 patients who underwent echocardiography between the period January 2002 to July 2010, 1435 (45%) were classified as normal and the remaining 1753 (55%) were diagnosed with abnormality needing either further evaluation or intervention. Of the 1753 cases, it was found that 1402 (80%) of them could be medically managed whereas 141 (8%) of them needed further evaluation to be performed for a conclusive diagnosis/treatment suggestion and 210 (12%) of them needed interventional procedures as their treatment. A benefit of 73% was established through this technology against the costs involved in getting the same tests done at any private center in the city.
Case examples of tele-echocardiography:
- Case 1 – Dilated LV with noncompaction of LV apex [Figure 3]
- Case 2 – Fetal echocardiography [Figure 4]
- Case 3 – CHD with large PDA and atrial septal aneurysm [Figure 5]
- Case 4 – Organic TV disease with severe mitral stenosis [Figure 6]
- Case 5 – RV dysplasia [Figure 7].
|Figure 3: Case 1 – Dilated left ventricle with noncompaction of left ventricle apex|
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|Figure 5: Case 3 – Congenital heart disease with large Patent Ductus Arteriosus and atrial septal aneurysm|
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Our experience with teleradiology has been on a greater scale mostly because it involves more of a store and forward methodology of operation. Our scope of work involved reporting of X-rays, CT, and magnetic resonance imaging. All of these imaging modalities were Digital Imaging and Communication in Medicine (DICOM) enabled and so the acquisition of these images by our application software was seamless. Provision of history taking was provided in the application along with setting a flag on the urgency of the report. Essentially, flags for reporting are defined as routine flag (4-6 hours) and short turnaround time (STAT) flag (less than 1 hour). The reporting of cases is done based on this flag status. [Table 4] shows our teleradiology experience which caters to both the national and international regions.
| Challenges and the Future|| |
Telemedicine has evolved in a significant manner over the past 15 years and there has been much more attention to this technology for the last couple of years in India. While there has been satisfactory acceptance to the store and forward methodology which essentially is considered as an offline activity wherein the patient and the radiologist reporting seldom have an interaction, the real-time activities which include teleconsultation or live tele-echocardiography still face some challenges. A number of issues such as interface of medical equipment with application software have all become less of a problem now with DICOM standards being followed, especially with imaging modalities. Although communication technology has increased manifold, the throughput of reliable bandwidth from Internet Service Providers still causes concern more so at remote locations. Another issue that crops up time and again is the skill of the people involved in remote locations to handle technology and has a seamless activity. There are no set rules based on qualifications of the type of people involved, but in our experience, we have seen that the level of interest and willingness to adopt newer technologies and changes has some resistance. Telemedicine is visualized more as an application software, thereby making the entry barrier for software companies or health-care companies becoming low, but the challenge is that the effectiveness of the technology is only when there is an integrated approach adopted which includes software, hardware, health-care workers, and more importantly doctors all working in unison. One stiff challenge that we continue to face with the telemedicine technology is the mechanism of having a follow-up on patients who have availed treatment. Although mechanisms of retrieving data and analyzing the follow-up are well established, ensuring that patients come for a regular follow-up in spite of addressing accessibility issues still is not solved completely. With lot of miniaturization of medical devices and the advent of IoT-based medical devices (IOT-MD), integrating of these with application software needs constant monitoring and upgradations of the technology platform. These devices have now enabled remote monitoring of patients, thereby reducing the need for patients, especially chronic patients such as congestive heart failure to visit hospitals. Health care is now becoming more home centric and methodologies to provide chronic patients; the convenience of consultations and basic diagnostics at home is going to be the future. In this regard, the increasing usage of telemedicine technology looks promising and if a cost-effective ecosystem to cater to these needs is met, this platform can be the solution for ensuring accessible and affordable health care to the larger sections of the society. Needless to say this reach to people will provide us with all the data which can be help us build on an epidemiological database. The analysis of this data can help us understand the prevalence patterns across various sections of the society and prevention as well as wellness programs can be adopted to make communities healthier. With the evolution of digital capacity, more and more data are produced and stored in the digital space. The world of Big Data is so huge that we will need artificial intelligence (AI) to be able to keep track of it. AI in health care and medicine could organize patient routes or treatment plans better and also provide physicians with literally all the information they need to make a good decision.
| Conclusion|| |
Telemedicine has graduated as an operational technology and has made it possible to have patients always networked irrespective of their location, thereby maintaining a continuum of care. ICT has empowered telemedicine as a powerful model for health-care delivery in an effective manner. Patients have been provided, independent of their area, for remote checking and timely diagnosis with this innovation. While we know the distance decay effects, i.e. distance in terms of cost and distance acting as a deterrent to people consulting, this technology helps us overcome this factor. Telemedicine cannot bring about cure to all the problems existent in the rural areas, but sure will help in addressing the vast range of problems which otherwise go unrecognized and unattended. The evolution in communication technology and available bandwidths has made it possible to have data sent in quick time and also have enabled real-time interaction and reads on diagnostic examinations such as echocardiography. Tele-echocardiography has become a reality by having trained technicians providing the views to specialists on a real-time basis, thereby facilitating such examinations at remote locations. The implementation of tele-echocardiography in remote or needy places allows for more timely detection of problems, facilitates the obtaining of a second opinion, and reduces the costs of moving. Educational strategies for health agents in remote or needy locations must be continuously researched and developed with the purpose of standardizing training protocols and providing quality assistance to these populations. Miniaturization of medical devices and the advent of IOT-MD will only compliment and facilitate telemedicine technology as an effective health-care delivery system and provide the convenience to patients in terms of accessibility to specialists and timely diagnosis.
We like to thank the management of CARE Hospital for the support provided for the execution of the telemedicine project. The contribution of Dr. C Sridevi, Dr. Nitin K Rao, Dr. V Karani, Dr. AV Anjaneyulu, Dr. K Raghu, and Dr. Gokul Reddy, Consultant Cardiologists, who advised patients using this platform is well recognized and duly appreciated. The efforts put in by the technical team of Mr. M Bhavan Kumar and Mr. Subhash on field and the technical team at the hub center is recognized and appreciated. Prof. Arun K Tiwari, Director, CARE Foundation who was instrumental in initiating and providing technical guidance to the telemedicine project is very much appreciated and acknowledged.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4]