|Year : 2022 | Volume
| Issue : 3 | Page : 215-222
Recognition of those at risk of lymphedema, benefits of subclinical detection, and the importance of targeted treatment and management
Neil B Piller
Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University and Medical Centre, Bedford Park, South Australia
|Date of Submission||05-Jun-2022|
|Date of Acceptance||05-Jun-2022|
|Date of Web Publication||21-Aug-2022|
Neil B Piller
Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University and Medical Centre, Bedford Park
Source of Support: None, Conflict of Interest: None
Primary and secondary lymphedemas, irrespective of their cause, remain a significant issue around the world, impacting physical, functional, and psychological well-being, family relationships, and the ability of the affected person to undertake work and household tasks. Often, an accurate, objective differential diagnosis is not (or cannot) be made, sometimes resulting in treatment, which is suboptimal, or which does not achieve expected outcomes due to the impact of a range of comorbidities on lymphatic load or functioning. Diagnosis, Management, and targeted treatment of these comorbidities such as chronic edema, lipedema, and phlebedema will allow improved outcomes for the lymphedemas. To treat and manage lymphedemas well, there is a lifelong cost both to the affected individual, the family, and the health-care system. However, for those with lymphedemas irrespective of its stage, there are significant leverage points for obtaining a good outcome through an accurate differential diagnosis, but it is the group who are at risk of lymphedema where we can have the greatest impact with respect to optimizing their health and well-being. The solution is multifaceted involving three major components: (1) the recognition of those at elevated risk of developing lymphedema and the reduction or management of those risks; (2) the early detection of the subclinical stages of lymphedema; and (3) appropriately targeted and sequenced treatment delivered in a holistic sense within a compassionate caring community environment with appropriate integrated and continuing health professional support. We also need to be aware that high-level technology and equipment is not always needed for an accurate assessment of the lymphedema or its risk, with simple tape measurements and associated volume calculations along with the use of the pitting test and the Stemmer sign being acknowledged as dependable and informative. While the evidence is increasing that lymphovenous or lympho-lymphatic anastomoses, and lymph node transfers are of benefit when created in the earlier stages of lymphedema (and perhaps in those detected as being at a high risk of developing it), complex and invasive treatments are most often not needed when the lymphedema is detected early. In these stages, simple management strategies work well when we employ our knowledge of the importance of weight control, self-management through exercise and activity programs (which can include yoga and tai chi breathing techniques) and skin care, massage with compression provided by bandaging, garments, or wraps, in an environment of integrated professional functioning and advice. In today's COVID environment and when services are not available nearby or what the patient cannot travel, when it is not possible to physically see a therapist or other health professional, telemedicine and its associated information and interactive education programs are of increasing importance. We must together ensure that the information about lymphedema, its risk factors, treatments, and management is made available in clinics and community health facilities, so everyone has access to it and is aware of who to approach for continuous and integrated holistic care.
Keywords: Bioimpedance spectroscopy, detection, differential diagnosis, fibronometry, lymphedemas, perometry, sharing global knowledge, staging, targeted treatment, tissue dielectric constants
|How to cite this article:|
Piller NB. Recognition of those at risk of lymphedema, benefits of subclinical detection, and the importance of targeted treatment and management. Indian J Vasc Endovasc Surg 2022;9:215-22
|How to cite this URL:|
Piller NB. Recognition of those at risk of lymphedema, benefits of subclinical detection, and the importance of targeted treatment and management. Indian J Vasc Endovasc Surg [serial online] 2022 [cited 2022 Sep 24];9:215-22. Available from: https://www.indjvascsurg.org/text.asp?2022/9/3/215/354074
| Underlying Issues: Genetics|| |
While the majority of lymphedemas in Western populations are related to cancers, their treatments, and preexisting risk factors, even when all are of a similar base cause, there is a wide variation in the development, progression, and severity of them. While less is known about filarial-related lymphedemas, there are likely to be similar variabilities.
Some, but not all, of the reasons for this can be attributed to inherited genetic susceptibility.
Advances in genetic techniques such as genome-wide association studies, whole-genome sequencing, and whole-exome sequencing are improving our ability to discover the impact of genetic variations linked to lymphedema and how each influence and determines the characteristics of heritable forms of lymphedema. Kapellas in a systematic review reported significant genetic variations in 23 genes in patients with breast cancer related lymphoedema (BCRL). While much more research is needed, their findings highlight the importance of genetic susceptibility recognition in the development of not only breast, but other forms of cancer-related lymphedemas. Witte et al. created a human chromosome map of lymphedema-lymph angiogenesis genes involved in primary lymphedemas, which may underlie many secondary lymphedemas. It is clear, however, that genetic testing is likely to have future importance in our ability to predict likely development of lymphatic system-related swellings and their treatments.
| The Development of Lymphedema – Physiological and Pathophysiological Changes and Their Links|| |
Identifying subclinical lymphedema facilitates early, conservative intervention and will reduce the chances that the condition will progress to a chronic advanced stage. Identifying and treating lymphedema at an early stage offers greater treatment success and potential cost savings with conservative management programs including compression garments, wraps education for self-care, self-manual lymphatic drainage (MLD) (and/or partner/care giver-MLD), psychosocial support, and exercise.
Early identification may also offer the opportunity for lymphatic-venous shunts or other surgical approaches in appropriate situations to offer a potential life-long avoidance of further treatment.
We all are aware that there is nothing simple about lymphedema, its etiology, comorbidities, identification, conservative and surgical treatments, patient and carer management, and the way in which we all need to team up to get the best outcomes. Critical in it all is what the patient has in terms of needs and seeks in terms of outcomes. These should be requested and responded to as indicated by Bareham and Speirs in their article on the patient perspective with the very important question of “what about us?”
The patient, clinicians, and therapists (in fact the whole team) need to know more about lymphatic dysfunction and its causes. As indicated above, lymphedemas can have an underlying genetic factor and that lymphatic gene dysfunction can also affect immune function, leading to enhanced infection risk; it can influence cancer development and spread, and it may even influence fat transport so impacting nutrition and obesity. We are certainly aware that obesity is one of the major risk factors for lymphedemas and its progression and often its severity.
We know for those lymphedemas associated with cancers that radiation, the extent and location of any axillary/groin dissection, and neoadjuvant medical therapy are associated with an increased risk of lymphedema. Oncoplastic reconstruction is not a risk factor at least for arm lymphedema. This surgery which rebuilds the breast after breast cancer surgery, with the aim of reducing scarring and preserving existing breast tissue, seems a good way to go. Nevertheless, we are clearly aware that the more conservative the surgery is, the more targeted the radiotherapy, the less risk of developing lymphedemas. This is only possible when the cancers are detected early, and it relies on patients to be knowledgeable in terms of early signs of cancer or quality screening programs.
Many countries are faced with lymphatic damage and dysfunction related to filarial, and in these cases, the early detection of their presence using antigen detection tests is a good solution. This type of test is now commonly used in the detection of COVID. In conjunction with these tests is the important need to compress the timeline between triple-drug therapy (for instance) developments and delivery.
The effect of other comorbidities associated with lymphedema remains elusive. Morfoisse et al. suggested more information and direction is needed regarding estrogen receptor antagonists or aromatase inhibitors. Further, they indicated that the role of sex hormones and gender has been poorly investigated in the etiology of the pathology of lymphedema, so there is still much to do to gain understanding of their impact.
Our knowledge regarding pathologies involving morphological or functional lymphatic changes is improving. Examples of these are atherosclerosis and dyslipidemia, hypertension (and other cardiovascular diseases), inflammation and inflammatory bowel disease, glaucoma, and neurodegenerative disease. Rockson emphasized that the disparate nature of these suggests that the presence (or absence) of the resulting structural/functional lymphatic changes could have an often-unrecognized influence on the maintenance of the patient's health and the promotion/exacerbation of those diseases and the lymphedema.
The clear message is we need to look widely with an open mind as to what may be underlying the lymphedema we see in the patient presenting to us.
| When a Patient Presents|| |
We must collect a clear family history of swellings and the patient's lifetime surgical and medical history, so we can better know and understand and have others treat or manage other underlying diseases or issues before we focus on the lymphatic issues and their failure.
| The Measurements and Assessment We Can Make|| |
The signs of lymphatic failure
Irrespective of the cause, the objective details of the lymphedema and other issues we collect can be shared with other members of the health-care team, and this represents a key leverage point.
Regarding signs of lymphatic failure, we know that their early detection is of critical importance as prompt targeted treatment gives better outcomes. The major signs are fluid and fibrous tissue changes, locally and often over the whole limb or area affected.
Changes in tissue fluids
Bioimpedance spectroscopy (BIS) is a potential tool with demonstrated benefits of early diagnosis of lymphedema and that it can provide an economic benefit in terms of the future cost of treatment., There are also other early detection strategies utilizing tissue dielectric constants (TDC), which can give information about fluids at specific sites such as an individual lymphatic territory and at varying depths., However, there are limitations of both. Keeley showed that limb volume measurements performed better than BIS in the early detection of BCRL and emphasized that pre- and postoperative monitoring of limb volume measurements is useful in the early detection of it and for prediction of those likely to develop, BCRL and so allow the important early intervention. Lahtinen et al. reported that differences between TDC and BIS and that these were linked to the techniques, but indicated that TDC was more sensitive than BIS in early-stage lymphedemas since the fluids are mainly superficially located. The clear message here is we have to already have some idea of the lymphedema stage in front of us and then select the right measurement technique. Sometimes simple can be better as Keeley indicated.
Does it matter then what we do as long as something is done and it helps inform us of the condition and guides us to the appropriate targeting and sequencing of treatments.
The objective assessment of fluid in a whole limb or part of it or an individual lymphatic territory as described above is great when you have the equipment. If not, the simplest means of getting a feeling of fluid content is using the pitting test. It is simple and effective and achieves best replicatable results when pressure is applied to an area for at least 30 s (according to most recommendations). The grade of pitting can then be given usually on a 1-4 scale.
Changes in fibrous tissues
Apart from the accumulation of fluids in lymphedema when the lymphatic system fails for whatever reason, there is progressive fibrotic induration of the tissues. Induration can be measured in many ways ranging from magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) CT, ultrasound, to tonometers, indurometers,, or fibronometers to the simple basic Stemmer sign. While the latter is very useful, we do have to be mindful that there may be other reasons for the presence of the sign.
There is a huge spectrum of these tools, and I can only cover each briefly but in doing so I hope an indication of their benefit can be seen. Some are complex and expensive and will only be found in large clinics and hospitals, while others such as tonometers, indurometers, and fibrinometers are basic and widely accessible in therapist and community-based clinics. Focusing now on just ultrasound, Ricci et al. acknowledge that a patient's medical history and physical examination should be coupled with anthropometric measurements to ensure a quality differential diagnosis and targeted management of patients with lymphatic diseases. Given the current progress and improvements in ultrasound imaging to now more accurately assess the superficial soft tissues of the human body they suggest additional ultrasound examination has the potential to improve the accuracy of the diagnosis. Certainly, though this combined information collection, no matter what the cause of the lymphedema we will gain a more accurate assessment of its presentation.
A study of quantitative ultrasound by Omura et al. to evaluate lymphedema severity compared to what is regarded as gold standard method (the International Society of Lymphology staging map) they reported the combinations of ESD and EAC in the dermis, HK parameters in the hypodermis and typical features (dermal thickness and echogenic regions in the hypodermis) improved classification performance between ISL stages 0 and ≥I so this represents an increasing objectivity of assessment.
Interestingly, ultrasound has also the potential to show the “dance” of the living adult worms in lymphatic filariasis, but its main use is in highlighting tissue alterations and allowing comparison with nonaffected limbs or areas and indication how compositional changes progress as lymphedema develops.
| Functional Imaging|| |
Indo cyanine green
Indocynanine green is increasingly used in the functional assessment of the lymphatics at least as far as the superficial system is concerned. It has a number of advantages over indocyanine green (ICG) lymphography, but it must be acknowledged that the latter is still the major way to evaluate the functional status of the deep lymphatics.
Historically and currently for lymphatic imaging of the lower limb tracers are injected into the interdigital spaces. Shinoaka et al. indicated that due to the fact that there are four independent lymphatic vessel groups (anteromedial, anterolateral, posteromedial, and posterolateral) in the lower limb single site injection cannot present us with the whole picture of lymphatic failure. Their study using the three additional injection sites for lymphatic imaging of the entire lower limb showed that defects detected in the posteromedial and posterolateral groups through their imaging should be introduced as further criterion for judging lymphedema severity and perhaps leading to a new lymphedema severity classification, but as good as this might be. Oh et al. indicated that dermal backflow (DBF), which refers to lymphatic reflux due to lymphatic valve insufficiency, is a diagnostic finding in lymphedema. However, the three-dimensional structure of DBF remains unknown. Photoacoustic lymphangiography is a new technique that enables the visualization of the distribution of light-absorbing molecules, such as hemoglobin or ICG, and can provide three-dimensional images of superficial lymphatic vessels and the venous system.
When Lymphoscintigraphy (LAS) is combined with SPECT CT, much higher resolution sequential three-dimensional (3D) images are displayed with greater sensitivity and improved spatial localization.
Newer diagnostic, investigational, and potentially interventional tools used to elucidate lymph angiodysplasia/lymphedema syndromes (including in newborns and children) and structural alteration in the lymphatic system include magnetic resonance imaging (MRI). The MR repertoire encompasses MR lymphography and MR angiography techniques both with (peripheral and intranodal injections) and noninvasively without contrast. These are continually being refined and utilized-9-increasingly in specialized centers around the world. These techniques and protocols provide images with high spatial resolution including structures deep in the body (thoracic duct). Other techniques utilized include CT, CT lymphograms, 3D oil contrast lymphography, ultrasonography. Dual-energy X-ray absorptiometry or biphotonic absorptiometry) can also help in the staging and classification of lymphedemas however, perhaps its best use is to assess the composition of the lymphedematous area or limb. This applies particularly to changes in epifascial fat and subfascial muscle.
Limitations of the measurements
No matter its location or the reasons for its presence, the incidence of lymphedema vary widely in part due to its dependence on criteria which define it (despite the fact we have the ISL consensus and other documentation, a lack of information about pretreatment baseline starting points and about comorbidities such as cardiac, thyroid, liver, kidney issues which may affect fluid levels and associated interstitial and fluid changes. The clear message again is we must perform a clear and accurate differential diagnosis and consider and manage any comorbidity before we can get to the core issue– the lymphedema.
As I've presented above there are a range of methods available for the noninvasive quantitative assessment of all forms of lymphedema, but most are relevant to BCRL in terms of investigations of their reliability. Lahtinen et al. indicated that TDC has a greater sensitivity at detecting early localized lymphedema and that it seemed best for local area assessment and in conjunction with volume assessment. They emphasized its advantages including the fact that it is not contraindicated in those with pacemakers or metal implants and that it can be used even if the person being measured is in contact with a metal surface. Other findings from their critical review of the literature search also indicated that both BIS and semiautomated and automated circumference measurement approaches also are beneficial especially in larger clinics with a high-volume throughput. However, acknowledge from a cost-benefit view that tape measurement with volume calculations using input into XLS or similar files and limb volume measurements using water displacement work well when the situation or economy do not allow for other equipment.
Reliability of the measurements
But what do we know of the reliability between all these measurements? Campanholi et al. compared circumferential girth measurements of the upper limbs using a tape measure and volume calculations based on a truncated cone, together with the opto-electronic perometer measurements and concluded that there is a good agreement between perometry and circumferential girth measurements when patients were classified as having a difference between arm volumes or more than 200 mL or 10% - the widely accepted criteria for the beginnings of clinically discernible stage 1 lymphedema.
Ridner et al. using a >10% arm volume change from baseline compared the use of BIS and tape measurements as triggers for an intervention in what was originally a subclinical lymphedema (again BCRL). They showed that compared to tape measurement, BIS provided a more precise identification of patients likely to benefit from an early compression intervention.
While not as recent, but still indicative of the situation faced by us all, Hidding et al. in a systematic review found that the measurement instruments with evidence for the best reliability and validity were (not in any particular order) BIS, volumetry, tape measurement, and perometry.
They noted that BIS could detect changes in the ECF in stage 1 (ISL classification) and that the other measurement instruments could detect volume changes from stage 2. Interestingly, it was indicated that water volumetry was regarded as a reference test for measuring at least in the upper extremities.
Perhaps, the clear message here is decide on a measurement technique and use it throughout all assessments and across the clinic or health center area so we can better compare and communicate to other members of the team.
Qualitative measures lymphedema quality of life questionnaire
As well as objective measures. Assessing the quality of life of the patient is vital. When done before treatment commencement, it can help target subsequent treatments, so they can remediate some of the quality-of-life (QOL) issues and when used during or following treatment, it can help present a holistic picture of the benefits of the treatment program and indicate where changes might be made.
There are a range of validated QOL instruments in use around the world for arm, leg, and recently head and neck lymphedemas. The most commonly used one has stemmed from the original lymphedema QOL questionnaire instrument designed and validated by Keeley et al. There have been a range of translated versions into Dutch, German, Turkish, Italian, and recently Chinese.
Bringing it together
Taken together this and other information particularly the introduction of ICG lymphography and its use in guiding personalized conservative management plans, can be translated into clinical practice and can help us change our research and educational priorities and training programs.
All up its clear that we not only have to embrace and apply our new knowledge and incorporate this into our training programs but also we must work as a team, integrate our treatment, care programs, and provide education for those in at-risk patient groups as well as for those with lymphedema. Because we are a tight-knit multidisciplinary community already its well within all our means.
For the patients, its knowledge, empowerment, and ability to better self-manage, and our patient groups around the world are making sure this is promoted and supported.
| Early Recognition and Intervention|| |
Prospective surveillance model
Our lymphedema and lymphatic failure detection tools are wide ranging and have good reliability and accuracy as described above. But, when they are used to assess the early stages of lymphedema we can be missing out on a key factor. That is what the limb(s) were like before the intervention which may have contributed to the lymphedema and what they were like before any clinically detectable lymphedema by these tools. Further, for those patients who are about to go through the cancer treatment program, prehabilitation may provide improved functional outcomes and through improved awareness may allow earlier recognition and management of lymphedema risk factors and subclinical changes.
Compression delivered by bandages, garments, wraps, and pumps is the core of lymphedema treatment and management once its developed, but we also need to be aware of its potential prophylactic benefits. Paramanandam et al. showed a reduced and delayed occurrence of arm swelling in those indicated to be at elevated risk for lymphedema in the 1st year after their surgery following 3 months of compression. Similar studies are required for those at risk of leg lymphedemas, but there is enough evidence already in the literature to indicate a benefit also in this group as well. Can the information from these studies be translated also to the early and subclinical phases of lymphedema associated with filarial infections? The answer seems to be “yes” but again we must undertake further research.
| Continuity of Care|| |
No matter the type of lymphedema for the best outcomes for the patient and the satisfaction of the professional (gained from seeing a good outcome) continuity of care is a core necessity.
| What the Patient Can Do|| |
There is a plethora of information on the web which patients and health professionals can access, but unfortunately, not all of it is accurate or appropriate to the individual. What this indicates is there is always a need for the patient to be well informed by medical or health professionals when searching as they may be inadvertently taken down the wrong treatment or management pathway thus achieving far from optimal outcomes and thus a tendency to become dis engaged with the appropriate plans devised or recommended to that person.
However, there are good strategies and programs available. Fu et al. conducted a trial on how web-based information can be used with respect to pain and symptomatic management and impact on limb volumes. The web-based intervention program focused on improving lymph flow in a general sense and showed significant improvements in the ability to manage chronic pain, soreness, general bodily pain, arm/hand swelling, heaviness, and impaired limb mobility.
| Conservative Treatments|| |
There are a huge range of conservative treatments, which are selected and in which sequence will be determined by the assessment of the professional. There is not the space here to deal with them all in any detail I strongly emphasize again that the treatments and their type and timing and sequencing and targeting should be made on as much information and objective evidence as possible.
The treatments range from compression delivered by bandaging, garments, wraps, IPC's; negative pressure creating units, Kinesio taping, Low-level Laser and light, Yoga TaI Chi and Chu Gong and medications to name a few.
| Exercise and Activity|| |
Perhaps one of the most important involvements of a patient at risk of or with lymphedema can be exercise and activities. We know that activity of any form can help lymphatic flow and reduce lymphedema quantitatively in terms of volumes and qualitatively. Basha et al. showed a significant benefit of exercise on function and quality of life.
Caru et al. in their scoping review showed that physical activity interventions were feasible and acceptable in the cancer survivors. It was noted that the interventions were individualized and mainly aerobic in nature. Further supporting the benefits of aerobic exercise Abe et al. studied the impact of cycling in a supine position when the patients were wearing elastic compression stockings and found using perometry a greater volume a greater decrease after supine AECT than after CT alone. Nelson et al. in their systematic review that patients with arm lymphedema at least could participate even in high-intensity exercise without worsening it.
Hayes et al. undertook a systematic review of exercise for the prevention and treatment of cancer-related lymphedema and found that there was strong support for the inclusion of exercise guidelines for the wider cancer population for those at risk of cancer-related lymphedemas. The exercise statement applied to aerobic and resistance exercises and not just resistance type of programs. Hence, the key message is for the patient to get involved in activity and exercise of almost any type (ideally though under the guidance of a health professional.
| What a Health Professional Can Do|| |
Laurence indicated the benefits of a professionally controlled and monitored program involving weight management and psychological well-being and indicated that most often patients are aware of the benefits of healthy eating and its relationship to their wish to lose weight but that unfortunately they frequently self-sabotage, associated with a range of external influences impacting on their weight-loss. Her program focused on the knowledge that if a patient's psychological health could be improved then weight management would be more likely to occur and that further there would be likely positive effects on their adherence to their particular lymphedema treatments.
The Yildiz et al. review also emphasized that it is very important to identify patients' needs and expectations. Further to this, they should be referred for treatment according to their needs and crucially treatment or management effectiveness should be objectively evaluated which is a continuing theme over many reports.
They like other indicate patient education must be considered an integral part of any treatment program and that a clear diagnosis and access to treatment is critical. I would also urge that education of their partner or carer is included so again the whole package is well integrated.
| Health-care Practitioners' Knowledge of Lymphedema|| |
Knowledge of how to differentially diagnose, swellings, and have those other reasons for swelling (such as associated with cardiac failure, lipedema, liver or kidney issues, thyroid issues, etc.) dealt with by others expert in these areas before targeting the lymphatic failure and subsequent lymphedema is poor across almost all health-care educational and CPD programs.
Yarmohammadi et al. undertook a systematic review of articles relating to knowledge in breast and other cancer-related lymphedemas filariasis, and podoconiosis. They found overall knowledge was low or only average in five and 11 of the included articles, respectively. They concluded that “Structured education of lymphedema is needed to increase the knowledge of HCPs and to enhance their collaboration in multidisciplinary care teams.”
| COVID and Lymphedemas|| |
We should consider the impact of COVID on lymphedema, not only due to the increased viral load on the lymphatic system, associated inflammatory events, etc., but also on the ability of the patient to interact optimally with the health professional expert in treatment and management of the lymphedemas Borman et al. evaluated the concerns and problems and concerns of lymphedema patients. They included issues about access to care and provision of management and control follow-ups and the presence of psychological symptoms. They concluded that the COVID-19 lockdown has a significant impact on the patients' health and health care. Many were not able to receive recommended treatment or get new garments when needed. These issues need further exploration, but certainly, in order to meet the needs of the patients, the lymphedema services must be prepared to make available and deliver information and directions virtually to enable effective care.
| Global Knowledge and Its Sharing|| |
Gibson et al. indicated that there is a market-led biomedical hierarchization focusing often on high levels of intervention and high-cost approaches. These are often imposed on areas of low income and socioeconomic settings. They indicated that low-cost and relatively well evidence-based studies and knowledge from low-or middle-income countries is neither recognized nor valued. They concluded “that unpacking these dynamics is a necessary route to providing a more equitable health delivery accessible for the many rather than the few.” Witter et al. found that we need to recognize more the influence of local groups and the importance of developing national and subnational institutions for gathering, filtering, and sharing evidence globally.
| Consensus and Expert Opinion Documents|| |
There are several consensus and expert opinion documents which are ideally read in conjunction with this article. They are a general summary of our knowledge and opinion regarding all aspects of lymphedema from diagnosis to treatment and maintenance; some have an international relevance while others are more suited to the needs of individual countries. As examples are those from International Society of Lymphology, The International Lymphedema Framework, and the American Vein and Lymphatic Societies.
But almost every society and national group around the world has some type of documentation, often they necessarily differ but perhaps its time to look at an even more integrated world approach so we can all better assess the status of lymphedemas and of the impact of our treatment and management programs.
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Conflicts of interest
There are no conflicts of interest.
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