Key learning objectives

These practical recommendations aim to provide information and assistance to paediatricians and healthcare professionals treating childhood cancer survivors

• with general background regarding the risk and extent of cardiovascular diseases.

• recommended diagnostic methods for surveillance and early detection of cardiovascular diseases.

• how to motivate survivors to be physically active and engage in a healthy lifestyle to reduce the risk of cardiovascular late effects.

Childhood cancer treatment has radically changed in the last few years. Since 1990, there have been attempts to reduce the intensity of treatment among children with relatively good prognosis neoplasms, with the aim of reducing the risk of treatment-related morbidity and mortality. Previous research identified that thoracic radiotherapy and specific types of chemotherapy, especially anthracycline, introduced in the late 1970s, increase the risk of heart disease among childhood cancer survivors. The survival of children with cancer has risen considerably over the last decades with 5-year survival rates exceeding 80%. ^{Reference Gatta, Botta and Rossi1} However, the long-term health effects in the growing population of childhood cancer survivors are of significant concern. Adverse cardiovascular events (e.g., chronic cardiomyopathy, valvular dysfunction, arrhythmias, peripheral vascular disease, pericardial disease, early coronary artery diseases, and stroke) are one of the leading causes of morbidity and mortality for cancer patients and constitute a significant health problem, considering the prevalence with a previous diagnosis of cancer. ^{Reference Leerink, de and Feijen2,Reference Armenian, Armstrong and Aune3} In this scenario, cardio-oncology, a discipline aimed at the diagnosis, prevention, and treatment of cardiovascular diseases as complications of anticancer therapies, is constantly evolving. Not only in terms of clinical activity and scientific research but also regarding the development of organisational models and training courses. For this reason, the multidisciplinary Working Group Sports Cardiology, Physical Activity and Prevention, the Working Group Adult Congenital Heart Disease, the Working Group Imaging, and the Working Group Heart Failure of the Association of European Paediatric and Congenital Cardiology aimed to state the art, risk prediction, surveillance, and treatment but also the establishment about the role of physical activity in the prevention of future cardiovascular diseases.

Cardiovascular diseases in childhood cancer survivors

Survival after childhood cancer continues to improve but second malignant neoplasia and cardiovascular diseases remain among the risk of premature mortality in childhood and adolescent cancer survivors. The risk of death related to cardiovascular diseases is most common after a long survival period. Long-term survivors of childhood cancer are five to seven times more likely to develop cardiovascular diseases compared to the healthy population due to the treatments they were exposed to at a young age. ^{Reference Mertens, Liu and Neglia4–Reference Nathan, Amir and Abdel-Qadir8} This primarily includes anthracyclines and radiation therapy targeting the chest. Over time, survivors may additionally acquire conventional risk factors for cardiovascular diseases as the general population. Certain cancers have been independently linked to the development of cardiovascular diseases, and many oncological patients have pre-existing risk factors or a genetic predisposition. Kidney cancers (Wilms tumour), bone sarcoma, lymphoma (especially non-Hodgkin lymphoma), and leukaemia are associated with a higher cardiovascular risk because of the more significant cardiotoxicity of their treatments or their association with cardiovascular risk factors ^{Reference Mertens, Liu and Neglia4,Reference Fidler, Reulen and Henson9} compared to other malignant diseases like some tumours of the central nervous system and some soft-tissue sarcomas not being treated with anthracyclines. However, most patients receive cardiotoxic treatment of varying doses. Oncological therapy should be considered an independent risk factor for potentially cardiotoxic events, critical after anthracycline therapy exceeding 250 mg/m² or after radiotherapy of > 30 Grays (or after combined therapies).

Cardiovascular diseases, which appear among long-term survivors of childhood cancer, may manifest in different ways as summarised in Table 1. ^{Reference Leerink, de and Feijen2,Reference Armenian, Armstrong and Aune3} Adequate control of cardiovascular risk factors in people diagnosed with cancer during childhood is a priority during follow-up.

Table 1.

Most common cardiovascular diseases in paediatric cancer and underlying causes

DCM = dilated cardiomyopathy; RT = radiation therapy; QTc = corrected QT interval; CV = cardiovascular.

Adapted from Armenian et al. ^{Reference Armenian, Armstrong and Aune3}

Key message: cardiovascular diseases in childhood cancer survivors

• Children and adolescents treated for cancer are at a higher risk of developing cardiovascular pathology in long-term survival.

• Certain cancers are associated with a higher cardiovascular risk due to the necessary application of cardiotoxic treatment.

• Cardiovascular diseases can manifest in various ways in long-term survivors of childhood cancer. Therefore, adequate control of cardiovascular risk factors is essential during follow-up.

Key messages: primary and secondary prevention of cardiotoxicity

• To reduce the risk of cardiotoxic late effects, it is important to integrate primary and secondary prevention into cancer treatment regimens.

• For primary prevention, dexrazoxane, liposomal anthracyclines, and elongated infusion time (up to six hours) appear to have cardioprotective effects and are well tolerated. ^{Reference de, van Dalen and Mulder20}

• Secondary prevention aims at evading and managing occurring problems following application of cardiotoxic treatment and reducing risk factors for cardiovascular diseases on multiple levels, including cardioprotective medication and promoting a healthy lifestyle.

Screening for cardiovascular disease in long-term childhood cancer survivors

Long-term childhood cancer survivors are at risk of the following cardiovascular diseases:

• Myocardial damage: cardiomyopathy, heart failure

• Arterial hypertension

• Metabolic syndrome

• Valvular disease, pericardial constriction, and premature coronary artery disease (caused by mediastinal radiation).

The risk of developing cardiovascular diseases depends on the cumulative dosage of anthracycline or mediastinal irradiation administrated. A useful risk score according to Erhardt et al. ^{Reference Ehrhardt, Leerink and Mulder24} is shown in Table 2.

Table 2.

Definition of cardiovascular disease risk groups and surveillance recommendations ^{Reference Ehrhardt, Leerink and Mulder24}

Gy = gray; NA = not applicable.

It is recommended that childhood cancer survivors with high and moderate risk should have a lifelong surveillance for development of cardiomyopathy. The screening aims to detect subtle cardiovascular system dysfunction in asymptomatic childhood cancer survivors as early as possible.

Besides taking the history and performing the physical examination of childhood cancer survivors as usual, the examinations described below should be performed

• as baseline before starting cancer treatment and

• not later than two years after completion of cardiotoxic therapy and every two years thereafter. ^{Reference Ehrhardt, Leerink and Mulder24}

Detection of myocardial damage

Childhood cancer survivors have a risk of > 50% to develop subclinical cardiac dysfunction in later life.

In all childhood cancer survivors, as a basis, the following examinations summarised in Table 3 should be performed.

Table 3.

Summary of benefits and harms regarding primary surveillance by risk groups and modalities ^{Reference Ehrhardt, Leerink and Mulder24}

MRI = magnetic resonance imaging.

* see Table 2.

Echocardiography

Standard echocardiography must be performed including measurement of 2D or 3D left ventricular ejection fraction to investigate asymptomatic left ventricular systolic or diastolic dysfunction or heart failure as defined by the American Society of Echocardiography ^{Reference Lang, Badano and Mor-Avi26} and the European Association of Cardiovascular Imaging recommendations ^{Reference Nagueh, Smiseth and Appleton27} as previously published ^{Reference Ehrhardt, Leerink and Mulder24} (Table 3).

It is agreed that left ventricular ejection fraction is reduced when there is a decrease by > 10 percentage points with a final value of < 53%. ^{Reference Plana, Galderisi and Barac28} Additional determination of diastolic left ventricular function is thought to be a marker of early myocardial damage in asymptomatic childhood cancer survivors. For this purpose, the following measurements should be performed:

• Left atrial size (area or volume)

• Peak mitral valve diastolic velocity (E- and A-wave)

• Mitral valve septal and lateral diastolic velocity (tissue Doppler with E/E´).

Recently, it has been shown that measuring global longitudinal strain with speckle tracking might detect myocardial dysfunction before a decrease in left ventricular ejection fraction is seen. A reduction of global longitudinal strain > 15% over baseline is thought to be potentially pathological. Usually, a global longitudinal strain < −18% is considered reduced. ^{Reference Plana, Galderisi and Barac28–Reference Dobson, Ghosh and Ky30}

Electrocardiogram

Electrocardiogram is recommended when patients enter survivorship. Further testing is conducted if needed based on clinical indicators. Screening electrocardiogram is strongly recommended for heart rhythm, ST segment changes and all sorts of arrhythmia. Special attention should be paid to prolonged QT interval corrected for heart rate interval and reduced variation in circadian heart rate.

Cardiac biomarkers

Serial measurements of blood biomarkers (natriuretic peptides and troponins) are not recommended but strongly suggested as strategy for cardiomyopathy surveillance. It is generally recommended to monitor the course of asymptomatic left ventricular systolic or diastolic dysfunction or heart failure. ^{Reference Ehrhardt, Leerink and Mulder24}

Cardiopulmonary exercise testing

Cardiopulmonary exercise testing can detect cardiorespiratory dysfunction, which is not seen in routine resting studies. Maximal oxygen consumption (VO₂ max) is one of the most useful parameters for assessing physical capacity. Age- and sex-adjusted measurements < 80% of normal are considered pathological. Studies have shown that patients treated with median anthracycline doses of 240 mg/m² (range 100–490) are at significant risk of subclinical cardiac dysfunction. De Caro et al. reported that post-exercise subclinical cardiac dysfunction could be identified in up to one-third of patients, such as reduced left ventricular posterior wall dimension or percentage thickening or increased left ventricular end-systolic wall stress. ^{Reference De Caro, Smeraldi, Trocchio, Calevo, Hanau and Pongiglione31}

Cardiac magnetic resonance imaging

Cardiac MRI is the gold standard for evaluating left ventricular ejection fraction. MRI should be done if the echocardiography fails to give sufficient information on myocardial performance. Furthermore, cardiac MRI can measure myocardial fibrosis associated with myocardial damage via late gadolinium enhancement and T1 mapping sequences. Cardiac MRI is therefore increasingly used in cardiac surveillance. ^{Reference De Caro, Smeraldi, Trocchio, Calevo, Hanau and Pongiglione31,Reference De Caro, Smeraldi, Trocchio, Calevo, Hanau and Pongiglione31–Reference Foulkes, Costello and Howden36} One paediatric study reported that the end-systolic volume index increased, and the left and right ventricle ejection fraction decreased during anthracycline therapy without any clinical signs of dysfunction. ^{Reference Oberholzer, Kunz, Dittrich and Thelen32} Exercise cardiac MRI is also increasingly used to detect subclinical changes in cardiac function. ^{Reference Foulkes, Costello and Howden36}

Comorbidities of myocardial damage

Arterial hypertension

Hypertension is the most prevalent cardiovascular risk factor in childhood cancer survivors. In the study by Chow et al., ^{Reference Chow, Chen and Armstrong37} hypertension occurred among 18% of childhood cancer survivors. The prevalence is 2.6-fold (95% CI 1.6–4.7) higher than expected, based on age-, gender-, race-, and body mass index-specific rates in the general population. ^{Reference Gibson, Li and Green38} Arterial hypertension in children under 16 years of age can easily be determined following blood pressure reference values for height percentile, age, and gender. ^{Reference Flynn, Kaelber and Baker-Smith39} In adolescents aged 16 years or older and adults, high normal blood pressure is defined as a blood pressure ≥ 130/85 mmHg and hypertension as ≥ 140/90 mmHg, respectively. ^{Reference de, Mancusi and Hanssen40,Reference Lurbe, Agabiti-Rosei and Cruickshank41} As high-quality and moderate-quality evidence supported the association between hypertension and asymptomatic left ventricular systolic or diastolic dysfunction and heart failure, care providers must remain vigilant for hypertension in childhood cancer survivors.

Metabolic syndrome

In the study by Chow et al., the prevalence of metabolic syndrome in young adult survivors in different studies is 6.9–33.6%. ^{Reference Chow, Chen and Armstrong37,Reference Pluimakers, van Waas, Neggers and van den Heuvel-Eibrink42} It is recommended that in all follow-up examinations, at least every two years, blood has to be taken to determine the cardiovascular risk factors, such as total cholesterol, high-density lipoprotein, low-density lipoprotein, fasting glucose and glycosylated haemoglobin.

Cardiovascular diseases after mediastinal irradiation

Accelerated atherosclerosis and vascular events are significantly more likely in patients treated with radiotherapy. In childhood cancer survivors, these risks are increased 5- to 29-fold for cardiovascular mortality and 2.4- to 3.6-fold for acute myocardial infarction. Mediastinal radiotherapy has been found to increase the relative risk of death in childhood cancer survivors. ^{Reference Nielsen, Offersen, Nielsen, Vaage-Nilsen and Yusuf43} Mediastinal irradiation may induce fibrosis and subsequent insufficiency of the cardiac valves ^{Reference Shrestha, Bates and Liu44,Reference Zamorano, Lancellotti and Rodriguez Muñoz45} and may result in pericarditis and pericardial constriction. Echocardiography is the method of choice to detect and monitor these changes. Additionally, cardiac MRI will add further information that is difficult to receive by echocardiography, such as in childhood cancer survivors with constrictive pericarditis. There are no specific diagnostic tools for the detection of premature coronary artery disease in this population. The usual examinations to rule out or to confirm myocardial ischaemia should include: Electrocardiogram at rest and under exercise, measurement of the biomarker high-sensitive troponin, and looking for regional wall motion abnormalities on echocardiography. ^{Reference Leerink, Feijen and van der Pal46}

Key message: screening for cardiovascular disease in long-term childhood cancer survivors

• Childhood cancer survivors need a lifelong screening for cardiovascular diseases with a frequency depending on the number of cardiotoxic drugs and mediastinal irradiation administered.

• Echocardiography is favourable for detecting cardiomyopathy early by assessing 2D or 3D left ventricular ejection fraction (recommended additional measurements: diastolic left ventricular function and global longitudinal strain). If the information on myocardial performance is insufficient, cardiac MRI should be done additionally.

• Cardiopulmonary exercise testing can detect cardiopulmonary changes, which are not apparent at rest. Regular testing intervals of 2–3 years are recommended.

Monitoring and treatment

Frequency of performing cardiovascular monitoring

The Children’s Oncology Group and the Scottish Intercollegiate Guidelines Network have provided guidelines for the long-term follow-up of childhood cancer survivors. ^47,48 The Children’s Oncology Group suggested a monitoring timeframe dependent on patient age, anthracycline dosage or exposure to radiation doses. ⁴⁷ The Scottish Intercollegiate Guidelines Network group recommended repeated echocardiograms during treatment and every three years after treatment in their guideline or naturally increasing the frequency of follow-up in those situations where cardiac dysfunction occurs. ⁴⁸ Concordances and discordances among cardiomyopathy surveillance recommendations between different groups are summarised in Table 4 according to Armenian et al. ^{Reference Armenian, Hudson and Mulder49}

Table 4.

Concordances and discordances among cardiomyopathy surveillance recommendations (cited from Armenian et al.) ^{Reference Armenian, Hudson and Mulder49}

ACE = angiotensin-converting enzyme; CV = cardiovascular; Dx = diagnosis; Gy = gray; Hx = History; RT = radiation therapy; yrs = years.

* Radiation therapy involving the heart: mediastinal, thoracic, left or whole upper abdominal, or total body irradiation.

Concordance and discordance are shown across the guidelines from the Children’s Oncology Group (COG), the Dutch Childhood Oncology Group (DCOG), the Scottish Intercollegiate Guidelines Network (SIGN) and the United Kingdom Children’s Cancer and Leukemia Group (UKCCLG).

Treatment

The most common complications after cardiotoxic therapy are: (1) dilated or restrictive cardiomyopathy, (2) arrhythmias, (3) valve disease, and (4) pericardial dysfunction. Moreover, a combination of these is not uncommon. Medical therapy is then initiated (Table 5). Late dilated cardiomyopathy is considered a progressive disease, and the medical treatment initiation seems still too late. Elevated biomarkers, progressive exercise intolerance, and deep echocardiographic phenotyping of myocardial muscle function (standard echocardiographic measurements, tissue Doppler, strain and strain rate analysis) could be used as a marker to start medical therapy. In this setting, angiotensin-converting enzyme inhibitors, beta-blockers, statins, and spironolactone have been tried. ^{Reference Yancy, Jessup and Bozkurt50–Reference Akpek, Ozdogru and Sahin54} Medical treatment is initiated according to the current heart failure guidelines. ^{Reference McDonagh, Metra and Adamo55,Reference Lyon, López-Fernández and Couch56}

Table 5.

Medical therapy for late complications in cardio-oncology patients

SGLT-2 = sodium-glucose cotransporter-2.

For restrictive cardiomyopathy or constrictive pericarditis, medical therapy is mainly initiated to suppress symptoms and clinical signs of heart failure. ^{Reference McDonagh, Metra and Adamo55} It involves using loop diuretics and sodium-glucose cotransporter-2 inhibitors that might improve outcomes. Therapeutic strategies are adapted from standard cardiology treatment. ^{Reference McDonagh, Metra and Adamo55}

When drug therapy fails, fenestration of the interatrial septum, mechanical support to decompress the left atrium, pericardiectomy, or heart transplantation (if in remission) may be considered as alternative therapeutic choices.

Arrhythmias can be either bradycardia or tachycardia. For the approach, reference is made to the existing guidelines for treating arrhythmias. ^{Reference Brugada, Katritsis and Arbelo57–Reference Zeppenfeld, Tfelt-Hansen, Riva and de59} Besides medication, ablations and implantation of devices may also be necessary.

Finally, managing valve disease due to past oncological treatment is no different from managing degenerative valve disease. Both valve pathologies are progressive and require timely intervention. As it involves damaged valve tissue, valve replacement rather than valve-sparing therapy will be preferred. Also here, valve guidelines can be referred to existing guidelines. ^{Reference Vahanian, Beyersdorf and Praz60}

Key message: monitoring and treatment of cardiovascular diseases in long-term childhood cancer survivors

• Treatment of the wide range of cardiovascular diseases in long-term childhood cancer survivors should start as early as possible to minimise their progression and limit late effects.

• Elevated biomarkers, progressive exercise intolerance, and deep echocardiographic phenotyping of myocardial muscle function are valuable markers for early initiation of medical therapy.

• Guidelines provide long-term follow-up monitoring and treatment recommendations, including medical and surgical interventions tailored individually to the survivor.

Physical activity and lifestyle changes

All previously described recommendations and methods to reduce the risk of cardiovascular diseases in childhood cancer survivors are passive actions from the survivors’ perspective. Beyond that, there is a spectrum of influencing factors that have not received enough attention yet, however, with a promising potential: modifiable lifestyle risk factors. These factors include physical activity, body weight, and nutrition. Lack of physical inactivity, unhealthy nutrition, and most commonly associated obesity increase the risk of cardiovascular diseases in the generally healthy population. ^{Reference Zhang, Pan and Chen61}

Physical activity

Physical and cardiorespiratory fitness are usually used as a measurable surrogate marker for physical activity behaviour and one of the most important predictors of overall health. An active and healthy lifestyle can reduce the risk of developing cardiovascular diseases in the group of survivors, ^{Reference Armstrong, Oeffinger and Chen62} and encouraging physical activity may even positively reduce overall mortality. ^{Reference Slater, Ross and Kelly63} Meta-analytic evidence supports the effectiveness of physical exercise to improve cardiorespiratory fitness and highlights the effectiveness of the cardiovascular system in childhood cancer survivors. ^{Reference Bourdon, Grandy and Keats64,Reference Morales, Valenzuela and Herrera-Olivares65} Schindera et al. ^{Reference Schindera, Zürcher and Jung66} recently showed that increased physical fitness is also associated with fewer cardiovascular risk factors. This potential cardioprotective effect, or at least the increase in physical capacity, should convince childhood cancer survivors to engage in a long-term active lifestyle. However, a high number of this population is physically inactive compared to healthy controls. Innovative strategies (Table 6) tailored to the survivors’ physical limitations and preferences to encourage physical activity are needed. ^{Reference Antwi, Jayawardene, Lohrmann and Mueller67,Reference Sloof, Hendershot, Griffin, Anderson and Marjerrison68} Although knowledge of chemotherapy-related cardiotoxicity and exercise interventions is at an early stage, ^{Reference Caru and Curnier69} the importance of engagement in exercise for childhood cancer survivors to mitigate and manage treatment-related cardiovascular dysfunction is obvious. ^{Reference Kendall, Langley and Aghdam70}

Table 6.

Practical implications for physicians to address the topic of physical activity with childhood cancer survivors

Body weight

Body weight significantly impacts oncogenesis, the outcome of cancer therapy, the patient’s different lifespan, and their quality of life. Although there is no data available for paediatric patients, it is recognized that an increased body mass index in childhood raises the risk of several malignancies in adulthood. ^{Reference Weihe, Spielmann, Kielstein, Henning-Klusmann and Weihrauch-Blüher71} There are 430 million children with excessively high body weight worldwide. ^{Reference Abarca-Gómez, Abdeen and Hamid72} After stabilisation on a high level, increases are obvious due to global events like the COVID-19 pandemic. ^{73,Reference Schienkiewitz, Brettschneider, Damerow and Rosario74} Body weight is crucial already in diagnosing cancer in children since being overweight, obese, and even underweight increases the risk of morbidity and mortality during therapy and beyond. ^{Reference Barr and Stevens75,Reference Ladas, Sacks and Meacham76}

Furthermore, if the patient is considered a normal weight at the beginning of treatment, unwanted weight gain is often caused by certain therapies such as higher cranial radiation dose, abdominal radiation, total body radiation, surgery in suprasellar region, corticosteroids or being younger age at treatment (age < 4 years), and female sex. Conversely, weight loss is also a common consequence of the oncotherapy. More than 50% of cancer patients suffer from cachexia, which impairs quality of life, responsiveness to cancer therapy, and survival. ^{Reference Sadeghi, Keshavarz-Fathi, Baracos, Arends, Mahmoudi and Rezaei77} Consequently, successful primary prevention of increased body mass index is pivotal in children in general, moreover it is highly recommended to perform a precise follow-up of the patient’s body weight and composition during and after cancer therapy, to minimise the overall morbidity and mortality among childhood cancer survivors.

Nutrition

Adequate nutrition plays an important role both in prevention and treatment of childhood cancer. Besides its known positive impact on the cardiovascular system, it may contribute to the reduction of overweight and obesity, which are associated with reduced disease-free survival and overall survival in cancer. ^{Reference Protani, Coory and Martin78–Reference Kroenke, Chen, Rosner and Holmes83} In adults, a high intake of vegetables/fruits and whole grains has been shown to be associated with reduced mortality and cancer recurrence when compared with a high intake of refined grains, processed and red meats, and high-fat dairy products. ^{Reference Kwan, Weltzien, Kushi, Castillo, Slattery and Caan84–Reference Kroenke, Fung, Hu and Holmes86} Successful personalised nutrition must be based on the patients’ and parents’ knowledge of the long-term impact of the child’s nutritional status. This includes proper counselling regarding avoidance of restrictive or alternative nutrition. ^{Reference Fabozzi, Trovato and Diamanti87}

Besides usual nutrition recommendations, the link between nutrition and physical activity behaviour should not be overlooked. Physical activity is positively associated with healthier eating habits as shown in healthy adults in Brazil during the COVID-19 pandemic. ^{Reference Christofaro, Werneck and Tebar88} Furthermore, interventions must target multiple health behaviours as healthy adolescents often show risk behaviour patterns and fail to meet dietary and physical activity guidelines. ^{Reference Sanchez, Norman, Sallis, Calfas, Cella and Patrick89}

Apart from an unhealthy diet, alcohol, drug abuse, and smoking habits might increase the risk of late effects and other health problems in childhood cancer survivors. ^{Reference Marjerrison, Hendershot, Empringham and Smoking90} Therefore, advice regarding this risk-taking behaviour should be provided for survivors by their treating physician and other healthcare professionals and specialists.

The risk factors mentioned above are modifiable and probably a cost-effective measure to reduce long-term sequelae concerning cardiovascular health. The most apparent problem in interventions aiming at lifestyle changes in childhood cancer survivors is the lack of sustainability, due to the complexity of behaviour change. Future research focusing on targeted and effective interventions should be supported by advice from treating physicians (e.g., oncologist, cardiologist) as a different approach to encouraging an active and healthy lifestyle in childhood cancer survivors. Exercise professionals should further assist survivors in maintaining and consolidating this behaviour and, most importantly, avoiding physical inactivity. Practical implications for treating physicians are summarised in Table 6.

Key messages: physical activity and lifestyle changes

• Physical activity, adequate nutrition, and body weight management are promising and actively modifiable factors to reduce the risk of cardiovascular diseases associated with childhood cancer.

• Personalised strategies to incorporate an active and healthy lifestyle during treatment and follow-up are needed.

• Treating physicians and exercise professionals should assist survivors in maintaining an active and healthy lifestyle by explaining the importance, giving advice, and helping to detect potential barriers in realisation.