|Year : 2019 | Volume
| Issue : 3 | Page : 162-170
Introduction to translational research in vascular surgery/medicine
Thushan Dhananja Gooneratne1, Gnaneswar Atturu2
1 Vascular Surgery, Registrar Department of Vascular Surgery, Leeds General Infirmary, Leeds, UK
2 Consultant Surgeon, Department of Vascular and Endovascular Surgery, CARE Hospitals, Hyderabad, Telangana, India
|Date of Web Publication||29-Aug-2019|
Dr. Gnaneswar Atturu
Consultant Surgeon, Department of Vascular and Endovascular Surgery, CARE Hospitals, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
Translational research is the process of applying the knowledge gained from basic research to clinical practice. Over the past three decades, translational research has transformed from a simple bi-directional flow from basic science to clinical care to a multifaceted, translational research spectrum that has the patient as the centerpiece. Globally, the vascular diseases spectrum has also been continuously changing with the aging population, change in lifestyle, and diabetic epidemic. This review aims to introduce new and exciting translation research concepts in the field of vascular surgery and medicine in general that could transform the management of patients with vascular diseases. An overview of contemporary translational research in the management of atherosclerosis, aneurysmal disease, and peripheral arterial disease is also highlighted.
Keywords: Aneurysm, atherosclerosis, peripheral arterial disease, translational research, vascular surgery
|How to cite this article:|
Gooneratne TD, Atturu G. Introduction to translational research in vascular surgery/medicine. Indian J Vasc Endovasc Surg 2019;6:162-70
| Introduction|| |
Opening a bottle of paracetamol and popping in a few pills when you are having a headache is easy to take for granted. This apparently simple act is only possible due to decades of research performed by laboratory-based scientists and clinician investigators. The history of how drugs, devices, and diagnostics were discovered is not always stories of easy success. These are stories of discovery preceded by countless failures, stories of determination, and perseverance.
Conventionally, research is divided into two main types, namely basic and applied research. Basic (or fundamental) research is driven by the curiosity of scientists. It may or may not aim to create, invent, or solve something, but aims to expand our knowledge base, and to find why things happen, i.e., what makes our hair color different? Applied research is designed to solve a specific, practical problem of an individual or a group of people, rather than simply to acquire knowledge for the sake of knowledge. It aims to improve the human condition, i.e., how can we find out if a disease a mother carries, can be carried down to her fetus?
Owing to a successful human genome project, we know the molecular basis of over 10,000 diseases, yet we have treatment only for about 500 of them. With modern technology, one would think that it would not be too hard to “bridge the gap” between, “what is known from basics science” and “applying that knowledge to find a treatment.” In reality, there is not a “bridge;” and the “gap” is more akin to the “valley of death.” Translational research is a jump across this “valley” in the hope to land on the other side. Most will fail, but one may succeed and redefine the boundaries of knowledge. Among over 10,000 compounds that begin this journey, only 4 or 5 make it to a clinical trial. Moreover, one lucky drug may reach the Food and Drug Administration (FDA) approval. On average, this process takes 14.7 years and at the cost of over 2.6 billion USD.,
Translational research, as defined by the National Institute of Health, USA, is the “process of applying ideas, insights, and discoveries generated from the basic sciences, to the treatment or prevention of human disease.” Unlike applied sciences, translational research is specifically designed to improve health outcomes. The goal is to convert basic science discoveries more quickly and efficiently into clinical practice, without compromising the quality and opportunity for basic research.
When the concept of translational research was developed, researchers quickly recognized the need for a two-way-flow of information between the bench and the bedside. Improving feedback between basic researchers and front-line clinicians resulted in more targeted research. Translational research in the modern day has evolved beyond just simply a bi-directional flow into a “translational research spectrum.” The latest framework for translational research as shown in [Figure 1] considers a more holistic view of the translational research process. It involves the bench, the bedside as well as the population. Rather than a linear process with the bi-directional flow, each stage on the spectrum builds on each other to form an interwoven network of shared knowledge. Patient involvement is a critical feature and remains at the centerpiece of translational research.
|Figure 1: Diagrammatic representation of the translational research spectrum|
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Translation research in vascular research
The vascular disease has changed immensely over the past few decades. An aging population, change in lifestyle, and a diabetic epidemic have resulted in a global shift in the pattern of vascular disease. There is now a greater need for a better understanding of the new disease paradigm than ever before to design novel therapeutic drugs and devices to treat the modern-day patient. Much of what we know in vascular disease has been extrapolated from the translational research in cardiovascular medicine. While this is applicable in most instances, we have also realized that the coronary arteries and peripheral arteries have different biological behavior. In this review, we aim to highlight some new and exciting concepts in the pipeline for the management of atherosclerosis, aneurysmal, and peripheral arterial disease (PAD), which may transform the future of vascular surgery/medicine.
| Translational Research in Atherosclerosis|| |
Atherosclerosis, a generalized chronic inflammatory process, affects all vasculature including the coronary, cerebral, renal, mesenteric, and extremity vessels resulting in the highest morbidity and mortality. The development of a fatty streak lesion and its transformation to a highly hazardous rupture-prone plaque involves many cellular and molecular events. Modifying this inflammatory/immunological response has been a crucial area in translational therapeutics.
Initially, research on the pathophysiology of atherosclerosis eluded to the presence of a “bad cholesterol” that is inherently related to the disease. Low-density lipoprotein cholesterol (LDL-C) was discovered as the main culprit, while high-density lipoprotein (HDL) was identified as the “good” cholesterol. The discovery of statins, inhibitors of cholesterol ester transfer protein, inhibitors of intestinal cholesterol absorption (ezetimibe) to control the “bad cholesterol” LDL remained the mainstay of treatment. Limitations on targeting the LDL-C alone are coming to alight with epidemiological studies suggesting that optimal LDL-C levels are achieved in only 35%–50% of the population.
Fundamental research has identified that the atherosclerotic pathway is much more complex than once thought. A multitude of novel pathways are being discovered. Translational research attempts to identify new targets for therapeutic manipulation through these pathways.
Proprotein convertase subtilisin-Kexin type 9 (PCSK9) is a protein that mediates the degradation of the LDL receptor. It is by far the most researched therapeutic strategy, with strong evidence that modulation of PCSK9 allows control of cholesterol levels. A number of clinical trials are being conducted to test PCSK9 inhibitors. Monoclonal antibodies developed against PCSK9 such as Alirocumab (ODYSSEY), Evolocumab (FOURIER, GLAGOV9), and Inclisiran (ORION-1) are in the phase III trials. They have demonstrated up to 70% more efficacy in lowering LDL-C when compared to statins. One hopes that PCSK9 therapeutics would soon cross the “valley of death” for a clinically effective treatment.
Atheroprotective properties of high-density lipoprotein and apolipoproteins
Theoretically improving levels of HDL-cholesterol (HDL-C) should allow for control of the atherosclerotic process. Unfortunately, initial clinical trials on the elevation of HDL-C levels were frustratingly disappointing, and interest on HDL-C was subsequently lost. There is now renowned interest in targeting HDL metabolism and functionality to treat or prevent atherosclerosis. It has become clearer that rather than the HDL-C levels per se, it is the functionality that is important toward atheroprotection. HDL functionality is dependent on its apolipoprotein composition. ApoA-I and Apo-E3 have emerged as key players in this process and being clinically researched. Translational scientists are developing reconstituted HDL particles-containing ApoA-1 and ApoE. Effective atheroprotective functions of reconstituted high-density lipoprotein (rHDL) particles have been demonstrated in preclinical models. Among them, CSL-112 (plasma derived apoA-1(Human), CSL Behring company, PA, USA) has transcended the clinical barrier and demonstrated efficacy with potential for therapeutic clinical use. With the application of novel targeted proteomics and metabolomics, there is further interest in investigating the role of other apolipoproteins. ApoA-4 and ApoC-3 have demonstrated therapeutic potential, and translational research in future may define the role of various apo isoforms in this complex pathogenesis.
Vascular smooth muscle proliferation as a potential target
The role of endothelial cells and vascular smooth muscle cell (VSMC) interaction in plaque formation and plaque remodeling is also being investigated. Current therapeutic strategies in atherosclerosis primarily focus on controlling circulating lipids. Future therapeutics may attempt to control vascular cell interactions and smooth muscle proliferation. Epigenetic modulations have been tested in anticancer treatment with success. There is research into understanding the potential epigenetic pathways and inhibitors at different stages of plaque progression. Bromodomain and extra-terminal motif inhibitors and nucleoside DNA methyltransferases inhibitors have shown promise in reducing atherosclerosis progression in early research.
Non-coding ribonucleic acids
Non-coding ribonucleic acid (RNA) is a group of RNAs that are not involved in encoding proteins. They include long intergenic non-coding RNA (lincRNA), microRNA (miRNA), circular RNA, and PIWI-interacting RNA. With the advent of newer gene-editing technology such as clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) and a global shift toward “omics,” the role these lincRNA's play in atherosclerosis is being investigated. Metastasis-associated lung adenocarcinoma transcript-1 has shown promise in its role in vascular functions. Similarly, macrophage expressed LXR-induced sequence and liver-expressed LXR-induced sequence have also shown promise in managing lipid metabolism. miRNA 125a and 758 have been implicated in increased lipogenesis. Results from preclinical models are quite promising; however, we are still far from their therapeutic use. Translational research in future will unravel their therapeutic potential.
The concept of atherosclerosis regression seems implausible, at least at first. However, regression of advanced, complex atherosclerotic plaques has been confirmed in animal models. It is not merely a rewinding of the disease, but a complex, coordinated, dynamic remodeling process. Genetic and epigenetic manipulation, specific induction of pro-emigrant molecules to provoke foam cells to leave the arterial wall, viral therapy, and nanotechnology to deliver cholesterol removing fibers to plaques are being trialed with exciting potential for future therapeutic use.
| Translational Research in Peripheral Arterial Disease|| |
PAD is a progressive disease characterized by gradual stenosis of the peripheral arteries and reduced neo-angiogenesis, ultimately leading to tissue loss. In patients with patent distal target vessels, open or endovascular revascularization options could be used to salvage the limb. However, in patients with no distal target vessel, progression of disease after revascularization or with primarily small vessel disease, translational research with novel therapies remains the only hope. Apart from the above-mentioned progress in managing atherosclerosis, therapeutic angiogenesis using protein/gene/cell therapy is being explored.
The long-held belief that, differentiation of mesodermal cells into angioblasts and endothelial cells occurs only during embryonic development was challenged both by clinical and basic research findings. In 1997, Asahara et al. reported the first successful isolation of endothelial progenitor cells (EPC) from human peripheral blood. Since then there has been an exponential research culminating in evidence for existence of EPC in adults that could be utilized for therapeutic purposes., Studies from tumor proliferation and angiogenesis has identified several target genes and pro-angiogenic growth factors that could also be utilized in the management of PAD. These basic research findings have opened a new era of therapeutic angiogenesis in PAD. Broadly, these therapeutic strategies can be divided into protein/gene therapy based, cell based or other unconventional therapies.
Several endothelial growth factors have been shown to stimulate angiogenesis in animal models but only few were translated into clinical practice., Out of many, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF) are the most commonly studied endothelial growth factors in clinical trials. Transcription factors such as hypoxia-inducible factor-1, chemokines like stromal cell-derived factor-1, and extracellular matrix (ECM) proteins like developmental endothelial locus-1 were also explored in clinical trials. The initial animal trials involving direct injection of growth factors intramuscularly were unsuccessful due to the shorter half-life and lack of control on dosing. Novel techniques to control the dosing and transfer to the target lesion facilitated the translation of basic research into clinical practice.
Out of the five members and several isoforms of the human VEGF family of genes, VEGF-165 and VEGF-121 are the only VEGF isoforms that were used in clinical trials. In 1996, Isner et al. published their first clinical experience of arterial gene transfer of plasmid VEGF165 using hydrogel polymer coated angioplasty balloon in a 71-year-old female with ischemic leg. This was followed by the first FDA approved ischemic limb clinical trial using plasmid-encoding VEGF-A165 and cytomegalovirus promoter. In 2002, Mäkinen et al. showed that intra-arterial administration of naked-plasmid/adenovirus VEGF 165 gene transfer in patients with PAD increased the vascular density compared to placebo in a randomized controlled trial. While all studies reported increased vascularity, apart from Mäkinen et al., no other phase III clinical trial on VEGF gene therapy in PAD has shown significant benefit in primary outcomes of limb salvage. Reversible, moderate-to-severe edema was a consistent adverse event in all these trials.
Out of the 22 members of FGF family, the therapeutic angiogenesis potential of FGF-1, FGF-2, FGF-4, and FGF-5 has been tested in clinical trials. Initial Phase I and Phase II trials using intramuscular administration of a human naked plasmid DNA encoding FGF-1 (NV1FGF) into the ischemic thigh and calf of patients with non-reconstructable PAD showed promising results. In the Phase II trial (TALISMAN 201), eight intramuscular injections of 16 mg of NVIFGF to patients with non-reconstructable critical limb ischemia significantly reduced the amputation risk at 12 months compared to placebo. However, similar clinical benefits were not reproduced in a larger multicentric Phase III study (TAMARIS). Since then, there has been no further trials on FGF-1 usage in PAD. A study using FGF-4 also failed to show clinical efficacy. So far, a Phase I/IIa, clinical trial using new gene transfer vector recombinant Sendai virus (rSeV)/human fibroblast growth factor -2 df-h(FGF-2), performed on 12 patients with nonoptional critical limb ischemia showed good improvement in walking distance. A Phase IIb clinical trial is ongoing and the results are expected in 2020.
HGF is another growth factor investigated in clinical trials. Unlike VEGF and FGF, it has anti-inflammatory and anti-oxidant properties that reduces the risk of vascular permeability and edema. So far, five clinical trials have assessed the efficacy of HGF in PAD. A Phase I/II study using 2 mg or 4 mg of naked HGF plasmid in patients with critical limb ischemia showed reduced rest pain and improvement in ulcers without any evidence of leg edema or serious edema. These benefits were sustained at 2-year follow-up. Two Phase II trials and Phase III trials have also confirmed the beneficial effect of hepatocyte growth factor (HGF) in improving rest pain and reducing ulcer size without significant adverse events.,,,
Despite hundreds of preclinical studies, none of the human clinical trials have shown promising and sustained results. This lack of translation from basic research and animal models to clinical outcomes could be due to several reasons including patient selection, selection of protein/gene, vector for gene delivery, method of delivery, quantity, and duration of treatment. Problems also exist in measuring successful gene transfer and therapeutic effect.
Theoretically, stem cells that can reach the ischemic tissue and differentiate into various types of cells required for angiogenesis could overcome several inherent problems associated with protein/gene therapy. Cell-based therapy for therapeutic angiogenesis has become a reality after Asahara et al.'s first successful isolation of EPC from human peripheral blood. Their findings have opened a new era of cell-based therapies for therapeutic angiogenesis in PAD.
Broadly, there are three types of stem cells that could be used for cell-based therapy: Embryonic stem cells (ES), inducible pluripotent stem cells (iPS), and adult stem cells. However, due to ethical concerns, ES are not currently being used in clinical trials and basic research is still going on to find clinical application for iPS. Adult stem cells can be broadly divided into three groups based on their origin: bone marrow stem cells, circulating pool of stem cells, and tissue resident stem cells. Majority of the clinical trials use adult stem cells that can be harvested from either bone marrow, peripheral blood, or adipose tissue.
Unselected mononuclear cells (MNC), harvested from the bone marrow or the peripheral blood, represent a mixture of cells including EPC, mesenchymal stem cells, and monocytes. In 2002, Tateishi-Yuyama et al. in their landmark trial called therapeutic angiogenesis using cell transplantation study showed that intramuscular injection of autologous bone marrow MNC (BMMNC) into the legs of patients with critical limb ischemia (CLI) is safe and can increase the vascularity, walking distance, and reduce rest pain. The clinical benefits were sustained even at 3-year follow-up.
This was followed by several small and large multicentric randomized trials and many more in pipeline.,,,,,,,, To summarize, several techniques were used to harvest the BMMNCs and majority of the trials evaluated intramuscular injection of BMMNC into the affected leg. In the RESTORE-CLI trial, a commercial kit called Ixmyelocel-T was used to harvest BMMNC and showed significant benefit in wound healing and delay in the progression of disease. Only one randomized control trial (PROVAS trial) evaluated the benefit of intra-arterial injection of BMMNC compared to placebo and did not find significant benefit in the primary end points. Meta-analysis of these studies showed improvement in both subjective and objective endpoints. However, when only placebo-controlled randomized control trials were analyzed, no improvement in amputation rates, survival or amputation free survival was noted.
The risks associated with bone marrow aspiration and the ease with which peripheral blood can be collected has generated interest in the clinical application of peripheral blood MNC (PBMNC) in the treatment of PAD. Although, the initial Tateishi-Yuyama et al. study showed better results with BMMNC compared to nonmobilized PBMNC, studies using granulocyte-colony stimulating factor (G-CSF)-mobilized PBMNC showed significant clinical benefit in terms of improved the ankle-branchial index and wound healing both in diabetic and nondiabetic patients.,,, Randomized controlled trial (RCT) comparing the two modalities also showed similar results with more practical value and benefit with G-CSF-mobilized PBMNC.,
Very few studies have assessed the therapeutic potential of EPC in the management of PAD. Kawamoto et al. studied the benefit of intramuscular injection of G-CSF-mobilized peripheral blood-derived CD34+ cells in patient with CLI. In the 12-week observation period, pain-free walking distance, ulcer size, and transcutaneous partial oxygen pressure improved. An RCT comparing the same with placebo also showed significant reduction in amputation rates in patients with PAD. Recently, a phase II trial evaluating the safety and efficacy of G-CSF-mobilized peripheral blood-derived CD34+ cells in hemodialysis patients with CLI also confirmed improvement in the toe skin perfusion pressure and absolute claudication distance.
| Translational Research in Aortic Aneurysmal Disease|| |
Aortic aneurysms have gained a lot of interest in the recent past. Unlike other vascular diseases, current therapeutic options are restricted to surgical repair. Although surgical treatments are becoming increasingly sophisticated and less invasive, there remains an urgent need to understand pathways in its pathogenesis toward identifying pharmaceutical treatments to prevent aneurysm growth or rupture.
Beta-blockers.,, Angiotensin-converting enzyme inhibitors (ACEI), Ticagrelor and supervised exercise therapy, were extensively studied based on their role in atherosclerotic risk modification. Macrolides were studied based on their anti-chlamydial action;, doxycycline gained much interest owing to its anti-matrix metalloproteinases (MMP) activity;,, canakinumab, an interleukin-1 monoclonal antibody was trialed based on its immune-modulating action; and pemirolast was studied based on its mast cell inhibitory action. Despite successful preclinical and early human trials, none of these agents have succeeded to demonstrate a therapeutic efficacy in randomized clinical trials.
However, these “apparent” failures have allowed for a better understanding of the disease pathogenesis. Contrary to previous understanding we now know that that aneurysm formation is different pathogenically to atherosclerosis and is secondary to a localized nonatherosclerotic inflammation. Current translational research attempts to elaborate these mechanisms toward developing novel therapeutic strategies.
Translational research has demonstrated increased activity of a variety of inflammatory cells/mediators that could lead to aneurysm expansion. Macrophages and lymphocytes are the predominant cell type with mast cells and neutrophils migrating to a lesser extent. A multitude of inflammatory mediators, such as tumor necrosis factor-alpha, tissue growth factor (TGF), prostaglandins, leukotrienes, and peroxisome proliferator-activated receptor G have been implicated.
Harada et al. demonstrated that pharmacological inhibition of focal adhesion kinase, an important signaling pathway in macrophage-induced inflammation, blocked CaCl2-induced abdominal aortic aneurysm (AAA) progression. miRNA (non-coding RNA) have recently been discovered as key regulators of AAA formation and genetic deficiency of miR-33 displayed reduced AAA formation in mice models. Exaggeration of CD4+ T-cells and neutrophils have also been demonstrated in animal aneurysm models and modulation of their functions have allowed to attenuate AAA formation and expansion.,
Mechanisms related to disruption of the aortic wall integrity
The inflammatory response triggers an imbalance between active MMP's and their inhibitors, generation of reactive oxygen species, smooth muscle apoptosis, etc., resulting in a disruption of the structural integrity of the aortic wall.
MMP isoforms 1, 2, 3, 13, 12, 19 have been found to be expressed in human AAA. In murine AAA models, these MMPs perform a crucial role in the direct degradation of the ECM in the tunica media and adventitia leading to AAA formation. Systemic treatments of MMP inhibitors have not yet shown efficacy in clinical trials. However, findings from Nosoudi et al.'s published model of using targeted nanoparticle-based delivery of MMP inhibitors to the aneurysm site may lead to a different clinical strategy. Other researchers have used a proteomics approach. Fava et al. studied the effect of metalloproteinase ADAMTS-5 and Angelov et al. studied the effect of TGF-beta on AAA formation.
The precise role of luminal thrombus in AAA formation is not clearly defined, but there is suggestion that the thrombus provides a substrate for platelet recruitment/and activation, activation of plasminogen and other proteolytic enzymes, and generation of reactive oxygen species, all of which contribute to AAA development and rupture. Antagonists of P2Y1, a G-protein coupled receptor that regulates platelet activation has reduced thrombus development, as well as leukocyte infiltration, MMP9 expression, and elastin degradation in a rat aneurysm model.
Diabetes and abdominal aortic aneurysm
Epidemiological studies and RCT's have identified an inverse association between diabetes and both AAA and thoracic aortic aneurysm., This compelling clinical data have led to resurgence of interest to understand the role of diabetes and find a possible crucial pathogenetic mechanism that continues to elude us.
Diabetes mellitus is able to modulate several pathways that we now know are key to aneurysm development. These include ECM remodeling,, (through deposition of increased amounts of basement membrane components); inflammation, (via modulation of MMP activity), VSMCs homeostasis, aortic mural neoangiogenesis, (via inhibition of ischemia-induced neovascularization), and intraluminal thrombus formation (via an increased clot density and reduced porosity).
It is still not clear whether the diabetes itself or the pharmacological intervention for diabetes that affects the pathophysiological process in AAA. Studies by Hsu et al. and Fujimura et al. have suggested a protective role of metformin, with preservation of VSMCs, aortic medial elastin, and decreased inflammatory cell infiltration., Studies on pioglitazone and fenofibrate demonstrated reduced aortic diameter in angiotensin-induced mice aneurysm models. Similarly, beneficial effects have also been demonstrated through the incretin effects of GLP-1 agonists and DPP-4 inhibitors., Interestingly, insulin therapy has demonstrated mixed effects on AA formation with negative effects and possible protective effects.
VSMCs in the distal abdominal aorta have different embryological origin compared to thoracic aorta and arch. Ongoing genomic and metabolomic studies are hoping to identify potential targets for therapeutic intervention and may revolutionize diagnostic, screening, and therapeutic management of aneurysms.,
What is in future?
The future will define the role of inflammation, infection, autoimmunity, genetics, etc., in understanding better triggers for aneurysm formation, expansion, and rupture. We may establish biomarkers to predict aneurysm expansion or rupture risk. With understanding that each aneurysm is different to each other, we may develop personalized therapeutic strategies for individual aneurysms based on aneurysm location, geography, and size. New trials on statins and ACEI may pave way for better evidence for routine use in AAA. Diabetes, the curse of vascular disease, may yet return as its savior. The future of translational research in aneurysm disease continues to be challenging and exciting.
| Conclusion|| |
The translational research paradigm has undergone many changes over the past three decades and progress in translational research has opened up new horizons in the management of vascular diseases such as atherosclerosis, aneurysms, and PAD. However, experience from initial clinical trials has revealed several lacunas in our understanding of the pathophysiology of vascular disease and their management. The biggest hurdle to translational research, by far, is the behavioral and cultural differences between the basic scientist and the clinical investigator. There is a need to ensure that the future vascular trainee has the right attitude, mentorship, and training to adopt a translation-centered research perspective. These barriers need to be overcome through a multidirectional and patient-centered translational approach for better outcomes.
The future of translational research remains exciting. Many drugs that were previously shelved are now being revisited and being re-purposed with our increased understanding of disease pathogenesis. The concept of “thinking out of the box” with a “pragmatic” approach to translation by conducting research in real-life settings is gaining interest. With the human genome project completed and the “human metabolome” project now underway, we may be stepping into an era of individualized healthcare. New concepts such as developing a virtual physiological human, humanized tissue models may shift a “one-size-fits-for-all-approach” to a personalized/precision treatment.
The future of medicine will likely be shaped by how translational research evolves. It is important that we remain abreast with this explosion of knowledge and translational research and not get left behind to ensure that the optimum patient care is delivered.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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