Selected health problems of a child with juvenile idiopathic arthritis – nursing care based on scientific evidence

INTRODUCTION

Juvenile idiopathic arthritis (JIA) is one of the most common arthropathies. This heterogeneous group of diseases includes in its definition all forms of inflammatory conditions of the joint system of unknown aetiology, which have their onset before the age of 16 years and last no less than 6 weeks. A significant proportion of these conditions are au-toimmune in nature [1]. The primary pathological process of JIA includes inflammatory changes originating in the synovial membrane, then involving periarticular tissues, tendon and muscle attachments, and tendon sheaths up to the bone root [2]. Studies conducted in selected treatment centres in Poland have shown that the incidence rate of juvenile idiopathic arthritis is between 5 and 6.5 cases per 100,000 children, while in the studies conducted by American re-searchers, the scale of the phenomenon varied between 2 and 20 people per 100,000. The morbidity rate among girls is almost twice as high [3].
The main mechanism of JIA is a prolonged, chronic inflammatory process that results in damage to joints and bone epiphyses and the onset of extra-articular symptoms [2].
The classification of JIA has been unified thanks to the work of a paediatric task team that is part of the International League of Associations for Rheumatology (ILAR) [3]. The disease can manifest in the following forms: with generalised onset; with predominant systemic symptoms; with predominant joint symptoms; with non-multi-joint onset (chronic or expanding inflammation involving one to four joints); with multi-joint onset without the presence of rheumatological factor RF (–); with inflammation involving 5 or more joints during the first 6 months; with multi-joint onset with the presence of the rheumatologic agent RF (+); psoriatic arthritis; enthesis related arthritis (ERA), arthritis with tendonitis; and undifferentiated arthritis [3, 4].
The pathogenesis of juvenile idiopathic arthritis remains unknown. Genetic, autoimmune, and immunological factors play a significant role in its development [5, 6]. Among the genetic factors, the ones that deserve special attention are female gender and the functioning of the HLA system that allows for identification of one’s own cells. The impact of immunological factors is understood as a disruption of immune mechanisms resulting from impaired metabolism and excretion of products formed during the inflammation process, as well as an abnormal response of T lymphocytes to the intrusion of an unknown antigen. An important role of pro-inflammatory factors that influence the development and persistence of the JIA disease process, such as tumour necrosis factor α (TNF-α), interleukin (IL)-1, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, as well as granulocyte and macrophage colony-stimulating factors (GM-CSF) [6-8], is also indicated. In addition, significant importance is attributed to environmental factors such as bacterial and viral infections, as well as physical and psychological trauma in children, which impair the immune barrier, particularly in patients with a genetic predisposition [9].
In the course of JIA, both general and area-specific developmental disorders are observed [10]. The experience of the disease adversely affects the psychosocial development of children and the quality of life of both the child and their family, determining the fulfilment of social roles by having to cope with the requirements of pharmacotherapy, frequent hospitalisations, specific dietary needs, changes in hygiene habits, or restriction of physical activity [11, 12].
In view of the above information, the medical team, especially the nursing team taking care of the child suffering from JIA, should take into account not only the disease process itself with its consequences, but also the developmental stage with the associated anatomophysiological differences such as lower density of growing bones and their weaker saturation with components (greater bone elasticity), shrinking of the epiphyseal cartilage as the ossification process progresses, the end of bone ossification when reaching puberty, as well as the susceptibility of growth cartilage cells to the effects of growth hormone and oestrogen [13].
The aim of the report is to present the leading health problems of a child suffering from juvenile idiopathic arthritis, including possible nursing solutions specific to the child’s developmental stage, formulated based on scientific evidence.
The research method was literature analysis.

SELECTED HEALTH PROBLEMS IN A CHILD SUFFERING FROM JUVENILE IDIOPATHIC ARTHRITIS

CHRONIC PAIN AND MORNING STIFFNESS BECAUSE OF AN ONGOING AUTOIMMUNE INFLAMMATORY PROCESS

Chronic pain has its origin in disturbed processes of a biological nature characteristic of the condition (see above), psychological factors (e.g. anxiety, emotional disorders of a depressive nature), the process of diagnosis and treatment, as well as cultural and social factors [14, 15].
Universal and specific actions of nursing staff being members of the interdisciplinary team:
• Quantitative and qualitative pain assessment using pain assessment scales optimally adapted to the child’s age and intellectual capacity. Pain assessment for newborns/infants is based on standardised scales: NFCS (Neonatal Facial Coding System), IBCS (Infant Body Coding System), Baby FACS (Facial Action Coding System), NIPS (Neonatal Infant Pain Scale), as well as the FLACC Scale (Face, Legs, Activity, Cry, Consolability). For toddlers and pre-school children, it is recommended to use pictorial scales such as the modified VAS scale (Visual Analogue Scale). In paediatric school-age patients, the NRS (Numerical Rating Scale) can be used [16, 17]. Also, less common scales such as the SUPER-KIDZ (Standardised Universal Pain Evaluation for Paediatric Rheumatology Providers) scale, dedicated specifically to children with JIA, can be used to assess pain. The SUPER-KIDZ scale takes into account 3 age variants of patients and can also be used in a group of children with impaired verbal communication. The McGill Pain Questionnaire (MPQ), on the other hand, is used for both quantitative and qualitative assessment of the pain experienced, taking into account the emotions that accompany it. Thus, it allows for a complementary assessment of the patient, including their psycho-emotional state [17, 18].
• Assessment of the incidence of factors that lower the pain threshold (fever, noise, bright lights, etc.) and an attempt to identify their sources (fear of diagnostic tests, disturbed family relationships, etc.) [19].
• Assessment of the duration and severity of morning stiffness.
The duration of morning stiffness has an impact on the patient’s overall functioning. Morning stiffness is a good reference for assessing the aggressiveness of ongoing disease. The assessment of morning stiffness and its outcome should determine the planning of nursing and other interventions (e.g. physiotherapy, education) so as not to overburden the patient during its occurrence/exacerbation.
• Documentation of the severity of pain and factors affecting it (time of day, subsidence under medication, selection of the best route of administration for the child, child’s behaviour during an acute pain episode, non-pharmacological measures to reduce pain intensity, e.g. changing the position of the limb, distraction by conversation [17, 19-21].
• Taking measures to increase the pain threshold, such as the administration of painkillers, classical disease-modifying medicines (csDMARDs), and coanalgesics (adjuvants), according to the individual medical order sheet.
The multiplicity of JIA forms and its inhomogeneous course make it difficult to select a uniform effective treatment for all patients [22, 23]. The aim of JIA treatment is to minimise or eliminate the active inflammatory and immunological processes of the disease, to slow down or completely stop the progression of joint pathologies, to eliminate pain, to stop developmental disorders and prevent short stature, to prevent the development of osteoporosis or limit its con-sequences, to prevent dysfunction of internal organs and eyesight, to limit disability and complications, and to allow the child to return to life activities.
The American College of Rheumatology (ACR) has published recommendations containing guidelines for JIA treatment, considering prognostic factors, indices of the disease course, and biomarkers [24, 25]. The treatment guidelines for various forms of JIA according to the ACR have been constantly changing over the years due to newer and newer research findings. Such modifications were issued in 2011, 2013, 2019, and 2022. The basis of each recommendation invariably remains the Treat to Target strategy (a therapeutic regimen aimed at achieving remission or reducing disease severity), whereas what changes is the order in which individual medication groups are administered or moved from primary treatment groups to adjunct or bridging therapy components. In light of the latest 2019 and 2022 reports, the ACR’s treatment regimen for individual forms of JIA continues to place special emphasis on early introduction of biological medication into therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticosteroids (GCSs), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biological DMARDs, i.e. classic biological disease-modifying medications, continue to be used in the treatment regimen. The order in which they are introduced into therapy and the routes of administration depend on the form of the disease and, as the ACR emphasises, on the patient’s individual preferences and predispositions. The preferred drug of the csDMARDs group invariably remains methotrexate, giving better therapeutic effects than sulfasalazine or leflunomide [22-27].
Juvenile idiopathic arthritis patients suffer from chronic pain, often taking the form of nociceptive pain (irritation of nerve endings via inflammatory mediators of ongoing inflammation) or neuropathic pain, which is associated with the patient’s decreased sensitivity/resistance to most NSAIDs. To eliminate the patient’s pain, treatment according to the analgesic ladder and multimodal analgesia is implemented, often with the use of adjuvants. Adjuvants (coanalgesics) are medicines that have no analgesic effect but influence pain sensations by raising the pain threshold. These include sleeping pills, anti-anxiety drugs, antidepressants, and antiepileptic medicines. Gabapentin or pregabalin have antiepileptic effects; however, they have applications in the treatment of neuralgia and neuropathic pain [15, 28-30]. Complementation of medicinal treatment is extensive musculoskeletal rehabilitation. In paediatric patients, procedures of a corrective-reconstructive nature on both bony elements and joints are performed relatively infrequently due to the risk of damaging both the growth cartilage and the vessels of the growing bony epiphysis [30].
• Improving the quality of sleep, minimising fatigue by introducing sleep hygiene habits, such as regular bed times, adjusting the duration and occurrence of naps during the day to the child’s age, needs, and health [19, 21], taking into account child’s preferences in preparing the room for sleep, reducing or eliminating sources of noise, and using blackout in the child’s bedroom (with particular attention to eliminating sources of blue light, such as cell phones).
• Regular assessment of the patient’s body temperature and, in a febrile child, taking pharmacological measures to lower it – see: Fever problem.
• Physical and mental preparation of the child for diagnostic tests to diagnose the disease, evaluate the effectiveness of therapy or possible complications associated with the disease or its treatment. The diagnostic process includes participation in the following research:
– Laboratory confirmation of JIA (specific), such as disease-specific indicators, which include anti-granulocyte cytoplasmic antibodies (ANCA), anti-CCP antibodies, rheumatoid factor (RF), HLA-B27 and HLA-DR4 antigens, and ANA antinuclear antibodies. Patients in whom ANA antinuclear antibodies were detected, despite belonging to different subtypes according to the ILAR classification, clinically share many of the same features not characteristic of ANA (–) patients. These include female gender, onset of disease at a younger age, asymmetry of inflamed joints, and anterior uveitis.
– Non-specific laboratory tests, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (usually elevated values), blood count (especially erythrocyte count, thrombocyte count, leukocyte count), ferritin level, albumin concentration, aminotransferase, and lactate dehydrogenase activity [31].
– Laboratory tests differentiating JIA from other diseases, among which we distinguish the level of antistreptolysin (ASO), antibodies against Gram (–) bacilli and antigens of Lyme, HBs, HIV, EBV, and CMV. They allow for the differentiation of JIA from diseases with a similar clinical picture, such as: reactive arthritis, allergic and toxic arthritis, arthropathy in the proliferative course, metabolic and other immunological diseases, fibromyalgia, and psychogenic rheumatism.
– Biopsies: bone marrow biopsy to exclude proliferative disease in patients without RF (–); biopsy of the synovial membrane of the inflamed joint and joint fluid during the ongoing inflammatory process to verify the presence of RF factor and the nature of the inflammatory material collected [32].
– Imaging tests: X-rays (radiographs), included in the standards for assessing inflammatory processes during JIA, ultrasound (USG) and magnetic resonance imaging (MRI).
Due to their nature, X-rays do not allow early detection of inflammatory changes. They show imaging abnormalities at late stages of inflammation, frequently already with progressive tissue destruction.
MRI and ultrasound are examinations with greater sensitivity compared to X-ray, allowing relatively early diagnosis of an arthropathy such as FMS, which is particularly important in the situation of involvement of the cervical spine (resulting in stiffness in children) and peripheral joints, including the temporomandibular joints, which can lead to deformities in the craniofacial area [33].
• Attempt to improve the child’s mental state – balancing the child’s emotional state, lowering anxiety, strengthening the child’s self-esteem.
Improvement in the child’s emotional state can be achieved by actively involving the family in the implementation of the care plan, pain prevention in the case of invasive procedures, rehabilitation or planned diagnostic tests, as well as children’s participation in various forms of therapy, such as story therapy, music therapy, choreotherapy, dance therapy, horticulture therapy, or canine-assisted therapy. Participation in therapy can have a significant impact on reducing the level of perceived anxiety in a group of paediatric patients, as well as on the development of their social skills, including empathy. Benefits for children in terms of suppressing aggressive and self-aggressive behaviour are also indicated [34-36]. The care of JIA patients should take into account the risk of developing anxiety and depressive disorders in this group, determined not only by the consequences of the disease and treatment, but also generated by the difficulties of adolescence [37].
• Assessment of patient’s functioning (quality of life) based on available questionnaires, e.g. CHQ, CHAQ, JAQQ [38], or in the absence of their availability based on a targeted interview.
• Assessment of the child’s and parents’ knowledge and educational needs regarding the condition, the importance of systematic treatment, regular physical activity, coping with pain and negative emotional states.
• Educational activities aimed both at the child as a subject of care, with adaptation to their age and perceptual capabilities, and at their family.
To reduce the sense of helplessness, educational activities should be tailored to the results of the knowledge assessment and the needs of the child and parents. Activities aimed at parents and, above all, adolescents should include the ability to use analgesics, systematic treatment of the disease, the principles of proper nutrition, strengthening self-esteem, self-confidence, and responsibility for one’s health [19-21, 29, 39-42].

FEVER INCLUDING HECTIC FEVER BEING A CONSEQUENCE OF AN UNDERLYING DISEASE OR INFECTION FOLLOWING IMMUNE DISORDERS

The incidence of a temperature above 38-38.5°C is followed by several positive and negative consequences. An increase in body temperature results in an enhanced T-cell and B-lymphocyte defence response, as well as an increase in the antiviral and antitumour activity of interferons. However, the burden on the child’s organism as a result of fever is associated with heat shock proteins, an increase in fluid intake requirements of 15%/1°C above optimal body temperature, as well as an increase in energy requirements with a concomitant appetite loss and impairment of nutritional processes [43].
Nursing activities, both universal and specific to the age of the patient:
• Regular measurement of body temperature with evaluation of the effectiveness of measures to reduce fever, documentation of the results of the measurement and the measures taken and their effects.
• Therapy of the underlying disease, pharmacological and non-pharmacological lowering of body temperature. Reduced tolerance to lower temperatures, such as in children with Reynaud syndrome and systemic scleroderma, should also be considered [44].
• Considering the child’s varying caloric requirements due to the greater energy losses in the course of fever, amounting to about 12% for each additional degree of temperature. In the nutrition of febrile children, particular emphasis is placed on replenishing fluids and avoiding forcing the child to eat. Meals given in small quantities should be rich in protein, vitamins (especially C and D3), zinc, omega3 acids, and fibre [45].
• Supply of fluids as required by oral and/or intravenous route according to the child’s age, considering losses due to increased temperature [46]. The child’s basic daily fluid requirements should be calculated according to the Holliday-Segar rule (1-10 kg – 100 ml/kg, 11-20 kg – 1000 ml + 50 ml/kg for each kilogram of body weight, over 10 kg > 20 kg – 1500 ml + 20 ml/kg for each kilogram of body weight over 20 kg) [2, 43, 44, 46-51].
• Taking into account the risk of febrile convulsions in younger children (febrile convulsions in patients over 6 months of age until about 5 years of age are considered to be physiological symptoms, unless they occur in the course of central nervous system (CNS) infections, electrolyte disturbances, and meet the criteria for other symptomatic convulsions) [46, 48-51].
• Selection of the route of a temperature-lowering drug administration depending on the age and the child’s clinical condition (tolerance of the drug administered by the oral route, tolerance and acceptance of the intrarectal administration of the drug – especially recommended in young children, but approached with caution when administering immunosuppressive drugs!, possibility of inserting an intravenous cannula – child in the course of hospitalisation).
• Educational activities aimed at parents/guardians involving the following:
– regular temperature measurements, documentation of results, the treatment applied and its effectiveness – these measures are aimed at observing trends in the occurrence of fever, selecting more efficient methods of lowering the temperature, as well as their faster implementation and preventing complications arising from prolonged persistence of high body temperature [46, 48-50];
– recognition of febrile convulsions and taking appropriate action when they occur. In case of a febrile seizure, the first thing to do is to keep the child safe by placing him or her in a safe position, which prevents aspiration of fluid and injury, loosening their clothes, assessing their vital functions, calling an ambulance team if the seizure persists for more than 2-3 minutes, possible rectal administration of diazepam as indicated and in the dose ordered by the child’s doctor, as well as administering antipyretics. The application of physical cooling should be considered after prior administration of an antipyretic. It is important to assess the nature and duration of seizures and the occurrence of postictal symptoms, such as excessive drowsiness, and involuntary urination or defecation.

DIFFICULTY IN MAINTAINING BASIC PHYSICAL ACTIVITY BECAUSE OF PAIN, FEVER, AND DEGENERATIVE CHANGES IN THE JOINTS

Pathologies such as bone disruption, chronic inflammatory processes, proliferative diseases, or long-term glucocorticosteroid therapy can cause bone growth disorders due to mechanical and chemical damage. Such disorders include limb shortening and/or closure of bone epiphyses, resulting in impaired growth of the affected bone or stunted growth of all long bones, leading to low stature [13].
Universal and specific nursing activities:
• Assessing the musculoskeletal system in terms of its capacity, meeting the child’s needs according to his/her deficits/limitations.
• Motivating the child to be active at any stage of the disease, adjusting the nature and intensity of exercise according to the period of acute illness or remission.
It is important to adapt the attractiveness of the chosen activities according to age. In the case of younger children, for whom special attention should be paid to the development of fine motor skills (fingers and hands), it is advisable to paint, colour, shape plasticine, and play with a ball. For the correct development of the articulatory apparatus and the masticatory organ, singing songs and reciting rhymes can be beneficial. In older children, on the other hand, we focus mainly on further development of large motor skills by offering activities involving the whole body. An important goal of the activity is also to prevent the regression of achievements and formation of contractures. The best form of rehabilitation, in addition to the standard ones, is to do sports that the child likes, such as swimming or cycling. However, the child’s participation in contact sports should be approached with great caution, and both children and their parents should be constantly reminded about it. In the hospital environment, it is necessary to pay attention to keeping the child physically active, taking into account the course of the disease, the level of pain and morning stiffness, and fever (frequent change of position, passive gymnastics, walking with assistance if possible, keeping the hands active by, for example, drawing, painting, crumpling paper, plasticine, or putting blocks together).
• Cooperation with a physiotherapist/rehabilitation specialist who is part of the interdisciplinary team which is aimed at joint assessment of the child’s fitness and development.
The nursing staff have a greater opportunity to observe the child during natural daily activities. Assessment of the child’s development can be carried out using, among other things, the Child Development Inventory scale, which identifies speech and motor deficits, which will serve to select further physiotherapy and optimise the holistic care of the patient. The nursing team’s activities also include ensuring continuity in the deformity treatment through the use of bedside rehabilitation under the guidance of a physiotherapist and encouraging/reminding the patient to perform daily exercise prescribed by the physiotherapist, assessment of pain prior to planned physiotherapy including appropriate pharmacotherapy, and checking rehabilitation equipment for safety [52].
• Participation in pharmacological pain treatment according to individual medical recommendations (see diagnosis: Pain).
• Educational activities aimed at the child and parents in the field of pro-health habits (keeping correct posture, safety during physical activity), principles of pharmacotherapy, correct and safe use of rehabilitation equipment, the possibility of purchasing rehabilitation equipment and the use of subsidies for its purchase.
Rehabilitation equipment, understood as devices and equipment recommended by a doctor and necessary for home rehabilitation, are not subject to the same rules of sale as medical equipment – there is no unified list of reimbursed items. Parents of children with a recognised degree of disability who meet the necessary income criteria can apply for a grant from PEFRON funds. Parents/guardians of a child suffering from JIA should pay particular attention to the need to keep the child physically active to avoid/minimise the risk of disability in adulthood [36, 52-56].

THE RISK OF NUTRITIONAL DEFICIENCIES AND IMPAIRED CHILD DEVELOPMENT BECAUSE OF PROBLEMS IN BITING AND CHEWING FOOD, IMPAIRED GASTRIC SECRETORY FUNCTION, LIVER DETOXIFICATION FUNCTION, PANCREATIC DYSFUNCTION, AND ANAEMIA, AS CONSEQUENCES OF JIA OR ITS COMPLICATIONS

Liver cell dysfunction has an influence on impaired secretion of the so-called insulin-like growth factor leading to stunted growth, and changes in the gastrointestinal tract led to impaired absorption of nutrients impairing child development.
Activities of nursing staff as members of the interdisciplinary team:
• Participation in pharmacotherapy of the underlying disease and/or reducing the consequences of pharmacological treatment (vitamin/mineral supplements, proton pump inhibitors), administration of preparations improving the functioning of the gastrointestinal (liver cell-protective) and haematopoietic systems (e.g. folic acid) according to individual medical recommendations.
• Assessment of the child’s ability to chew and bite – cooperation with a dietitian who is part of the interdisciplinary team and joint selection of the appropriate consistency and timing of the meals served; proper selection of methods of heat treatment of food products, taking into account the impairment of the functions of the digestive system organs (cooking, baking vs. frying); optimisation of the scheduling and distribution of analgesic drugs before meals.
• Supervising the correct and regular use of the relaxation splint (for children above one year of age); drawing the child’s and parents’ attention to maintaining oral hygiene before the splint is fitted and keeping it clean (it reduces the risk of oral infection, especially because the chemical composition of saliva is altered in this condition and stimulates the build-up of plaque) [57].
• Reducing acute disease relapses by treating the underlying disease, implementing healthy habits (ensuring good quality of sleep), and preventing infections.
• Considering the need to implement speech therapy for younger children – pain in the temporomandibular joints can negatively affect the development of the speech apparatus.
• Education of children/parents/guardians regarding their participation in the care plan, as well as explanation of its various aspects.
It is important to emphasise the need for home documentation of the child’s health and development, including monitoring of centile grids and results of vital signs measurements. While educating parents/guardians, they should be made aware of any possible complications resulting from both the underlying disease and the treatment administered (according to nursing competence). Chronic disease is a stressful factor for both the child suffering from it and his or her loved ones. In some way, it permanently or periodically disrupts the performance of social roles by the patient and family members, especially the primary caregiver involved in the hospitalisation process. Consequently, it can be the cause of generating anger, rebellion, and disappointment. Acceptance of the disease and the changes it implies is particularly difficult for children who remember the period before the disease. The restrictions suddenly imposed by the disease, as well as the altered self-image – both physical, related to complications of the disease and pharmacotherapy, and emotional, resulting from feelings of isolation, lack of group membership, and a sense of being different – adversely affect the patient’s daily functioning. Sources of suffering for the child may include the development of post-steroidal obesity, increased hairiness over the entire body surface, complications of the underlying disease requiring the use of assistive equipment such as orthoses or crutches, and the onset of comorbidities such as post-steroidal diabetes requiring insulin therapy [58].
Making children aware of the nature of individual symptoms and the risk of undesirable behaviours, especially in adolescents with JIA, provides an opportunity for early detection of abnormalities and immediate implementation of corrective measures, whether in terms of pharmacotherapy, diet, rehabilitation and surgery, or psychological support [57, 59-63]. Attempts to educate children should be taken from an early age – knowledge passed on in the form of exercises and workshops on, for example, snack selection, menu planning, or safe sporting activities, can serve to develop healthy habits for life.
Problems resulting from the chronicity of the disease, which are often underestimated and yet determine the effectiveness of treatment, independence, and even the survival of the patient, are of great importance. These include exacerbations of the disease, frequent hospitalisations and diagnoses (iatrogenesis, jatrosomatopathy), progressive disability and invalidity, the possibility of the disease progressing to an adult form, prolonged pharmacotherapy – often highly destructive, limitations resulting from disability and treatment, emotional disturbances, impact on the economic situation of the family, disruption of social functions, limitation of social contacts, impact on school achievement and choice of profession, as well as the problem of sexuality and procreation. However, this list may not encompass all the difficulties faced by the child and his or her family. It is worth noting that for each patient the hierarchy of these problems will be different, depending on the form of the condition, the presence of comorbidities and/or complications of JIA, the type of therapy used, the developmental period and developmental challenges, as well as the sources of the support available and applied coping strategies.

CONCLUSIONS

Juvenile idiopathic arthritis is a disease that burdens the patient, their family, and the health care system, in which holistic nursing care based on scientific evidence plays an important role.
Addressing the complexity of health problems and developing models of care for patients with JIA will improve the effectiveness of therapy and the quality of nursing care, reducing the risk of complications and disability for patients, thereby reducing the social costs of treatment.

Disclosures

This research received no external funding.
Institutional review board statement: Not applicable.
The authors declare no conflict of interest.

References