Parkinson's Disease Nursing CE Course for RNs and LPNs

More specifically, the neurotransmitter dopamine is responsible for movement. Dopamine binds to G-protein-coupled receptors to promote motor control, cognitive function, motivation, and reward. Imbalances in dopamine impact muscle coordination (Klein et al., 2019).  

Pathophysiology 

In individuals experiencing PD, the basal ganglia deteriorate, and dopamine levels are low (Norris, 2019). Specifically, a drop in circulating dopamine is a result of the destruction of neuronal cells in the substantia nigra located in the basal ganglia of the brain (Honan, 2019; MacMahon et al., 2021). The dopaminergic nigrostriatal pathway degenerates, causing an imbalance of neurotransmitters in the corpus striatum (Norris, 2019).  

Typically, the neurotransmitters acetylcholine (excitatory) and dopamine (inhibitory) counterbalance each other when relaying impulses to the higher motor centers of the brain. As a result, motor movement is controlled and refined (Hinkle & Cheever, 2018; Honan, 2019). When there is a loss of neuronal cells in the substantia nigra of the basal ganglia, dopamine storage is depleted. This provokes a predominance of the excitatory neurotransmitter acetylcholine over the inhibitory neurotransmitter dopamine. The ability to fall and stay asleep is affected by increased acetylcholine levels, and muscle rigidity makes changing positions during sleep difficult (Bauldoff et al., 2020). Clinical manifestations of PD become apparent when approximately 60% of the neuronal cells in the substantia nigra are destroyed, and the dopamine level is decreased by 80% (Hinkle & Cheever, 2018; Honan, 2019). 

Risk Factors and Protective Features 

Men are diagnosed with PD more often than women. Advancing age, genetics, head trauma, and exposure to toxins are also risk factors for an individual to develop PD (Norris, 2019). Oxidative stress caused by toxins promotes protein aggregation, neuroinflammation, microglial cell activation, and mitochondrial dysfunction, all of which promote neuronal death (Agnihotri & Aruoma, 2020). 

Signs and Symptoms 

The clinical manifestations of PD progress slowly (Hinkle & Cheever, 2018; Honan, 2019). Cardinal signs of PD can be recalled through the mnemonic TRAP, which stands for:  

• tremor 

• rigidity of muscles 

• akinesia/bradykinesia 

• postural disturbances (Honan, 2019) 

Tremor 

Most patients present with a slow, unilateral, resting tremor at the time of diagnosis. A resting tremor occurs while the extremity is motionless and disappears with purposeful movement (Hinkle & Cheever, 2018; Honan, 2019). This tremor can involve a rhythmic, slow-turning motion of the forearm and hand (pronation to supination) accompanied by movement of the thumb against the other fingers as if rolling a pill (Honan, 2019). As the disease progresses, the tremor may become bilateral and affect the patient's ability to perform activities that require dexterity, such as eating and writing (Bauldoff et al., 2020). 

Rigidity 

Rigidity manifests as passive resistance to limb movement. The passive range of motion of an extremity can result in a jerky movement known as cogwheel rigidity. An early manifestation of rigidity is cramping in the hands or toes or shoulder pain. Patients may also report stiffness, heaviness, or muscle aches due to rigidity (Bauldoff et al., 2020; Honan, 2019). 

Akinesia and Bradykinesia 

Akinesia is a lack of movement, while bradykinesia is a delay in the execution of movement (Honan, 2019). Patients may have difficulty initiating actions such as rising from a chair or changing positions in bed (Hinkle & Cheever, 2018). 

Postural Disturbances 

Patients with PD experience a loss of postural reflexes (Honan, 2019). An involuntary flexion of the head and shoulders results in an inability to maintain the trunk in an upright position while sitting or standing (Bauldoff et al., 2020). As the patient attempts to move their feet under the body's center of gravity, they demonstrate a shuffling gait with decreased arm swing (Honan, 2019). Additionally, patients with PD have difficulty with pivoting, which can impair balance and result in falls (Bauldoff et al., 2020). 

Other Signs and Symptoms 

Some symptoms of PD result from a loss of functions controlled by the autonomic nervous system (Bauldoff et al., 2020). This includes excessive and uncontrolled sweating, paroxysmal flushing, elimination problems (e.g., constipation and urinary hesitancy or frequency), orthostatic hypotension, and sexual dysfunction, including erectile dysfunction, decreased libido, vaginal dryness, and anorgasmia (Bauldoff et al., 2020; Honan, 2019; Wright, 2019). Due to increased sweat gland activity, patients may experience eczematous skin changes and seborrhea (Bauldoff et al., 2020). 

In many instances, PD patients will also develop dysphagia, posing a risk for aspiration. Dysphonia (a soft, low-pitched, nasal-sounding voice) can also occur in response to muscle weakness associated with speech and paralysis of the soft palate. As dexterity declines, patients develop micrographia (small, shrinking handwriting; Honan, 2019). The face also appears mask-like (i.e., expressionless), and blinking decreases (Hinkle & Cheever, 2018; Honan, 2019). 

Patients with PD also report sleep disturbances, along with cognitive and psychiatric changes. Cognitive changes may be evident in the patient's judgment, reasoning, and decision-making abilities. Depression and anxiety are common, followed by acute confusion, dementia, and visual and auditory hallucinations (Hinkle & Cheever, 2018; Honan, 2019). 

Diagnosis 

PD is diagnosed by a neurologist after a thorough neurological examination with disease staging. Careful assessment is needed, as PD signs and symptoms mimic other disease processes (National Institute on Aging, 2022). The gold-standard staging assessment uses the 4-part Movement Disorder Society – Unified PD Rating Scale (MDS-UPDRS), which examines non-motor aspects experiences of daily living, motor aspects experiences of daily living, motor function, and motor complications—specifically, motor complications that are specific to parkinsonism symptoms, such as bradykinesia, a resting tremor, and muscle rigidity (Goetz et al., 2008; Postuma et al., 2015).  

In addition, neurologists can use various imaging and diagnostic tests to assist in diagnosing an individual with PD, such as computerized tomography (CT) scanning, genetic testing, magnetic resonance imaging (MRI), and positron emission tomography (PET; Belloli et al., 2020; Pagano et al., 2016). Other studies include a sleep study and dopamine transporter scanning (DaTscan). The sleep study identifies whether an individual acts out their dreams, while the DaTscan examines changes in dopamine levels in the brain via a gamma camera (Oregon Health & Science University Brain Institute, 2022).  

Treatment and Management

Pharmacological Agents      

Healthcare providers (HCPs) will initiate pharmacological management when PD is identified, and quality of life begins to decline. The decision to incorporate medication is mediated by a discussion between a neurologist and their patient. The goal of pharmacological therapy is to control the client's symptoms to the greatest possible extent (Bauldoff et al., 2020; Hoffman & Sullivan, 2017; Spindler & Tarsy, 2021). The medications discussed below are administered orally.  

Dopamine Precursors   

Levodopa is converted to dopamine in the central nervous system. Carbidopa, a decarboxylase inhibitor, prevents the premature breakdown of levodopa to dopamine in the peripheral tissues. Levodopa/carbidopa (Parcopa, Sinemet) can relieve tremors and rigidity; it is considered the most effective treatment for PD symptoms (American Parkinson Disease Association, 2022a; Bauldoff et al., 2020; Vallerand, 2017). Side effects of levodopa/carbidopa (Parcopa, Sinemet) include nausea, vomiting, constipation, decreased appetite, orthostatic hypotension, darkening of urine and sweat, and dyskinesias (Hinkle & Cheever, 2018; Vallerand, 2017). Patients who take levodopa/carbidopa (Parcopa, Sinemet) may experience an "on-off syndrome," which is characterized by periods of immobility (off effect) followed by a sudden return of mobility (on effect). Changing the dosing regimen or switching to another medication may help minimize this syndrome (Hinkle & Cheever, 2018). Contraindications to administration include angle-closure glaucoma and malignant melanoma (Vallerand, 2017).  

When educating patients and families, the nurse should discuss rising slowly from a supine or seated position due to the risk for orthostatic hypotension; dividing daily protein intake among all meals, as high-protein meals can impair the medication's effectiveness; and adhering to HCP instructions for laboratory testing (liver function studies, renal function studies, and complete blood count with differential; Vallerand, 2017).  

Dopamine Agonists      

Dopamine agonists—such as bromocriptine (Parlodel), pramipexole (Mirapex), pergolide (Permax), and ropinirole hydrochloride (Requip)—are useful in postponing the use of levodopa/carbidopa (Parcopa, Sinemet) therapy, or they can be used concurrently (Bauldoff et al., 2020; Honan, 2019). Dopamine agonists mimic the role of dopamine in the brain and consequently decrease tremor and rigidity (Bauldoff et al., 2020; Vallerand, 2017). Side effects consist of orthostatic hypotension, nausea, and psychologic disturbances (Bauldoff et al., 2020). Contraindications for dopamine agonists include psychotic disorders (Vallerand, 2017).      

When educating patients and families, the nurse should discuss rising slowly from a supine or seated position due to the risk for orthostatic hypotension and notifying the HCP of any new or increased gambling, sexual or other intense urges, or psychotic-like behavior (Vallerand, 2017).   

Antiviral Therapy   

Amantadine hydrochloride (Symmetrel) is often used in early PD to manage symptoms related to akinesia and tremors (Bauldoff et al., 2020; Honan, 2019). The incidence of side effects is low but can include mood changes, confusion, depression, hallucinations, orthostatic hypotension, heart failure, edema of the lower extremities, nausea, urinary retention, headaches, and visual changes (Hinkle & Cheever, 2018; Honan, 2019).      

When educating patients and families, the nurse should discuss rising slowly from a supine or seated position due to the risk for orthostatic hypotension; monitoring for signs and symptoms of heart failure, such as sudden weight gain, edema, or difficulty breathing; and notifying the HCP if incomplete bladder emptying is suspected.  

Monoamine Oxidase-B (MAO-B) Inhibitors  

MAO-B inhibitors, such as rasagiline (Azilect) and selegiline (Eldepryl), inhibit dopamine breakdown (Hinkle & Cheever, 2018). They can be combined with dopamine agonists to delay the use of levodopa/carbidopa (Parcopa, Sinemet) therapy (Bauldoff et al., 2020). Side effects include dizziness, orthostatic hypotension, insomnia, nausea, dry mouth, headaches, and serotonin syndrome (Hinkle & Cheever, 2018; Vallerand, 2017). Selegiline (Eldepryl) is available as a transdermal patch in addition to an oral formulation (Vallerand, 2017).  

When educating patients and families, the nurse should discuss rising slowly from a supine or seated position due to the risk of orthostatic hypotension and avoiding consumption of tyramine-containing foods (e.g., aged cheeses, fermented meats, beer, and ale) due to the risk for hypertensive crisis. In addition, patients should notify their HCP if they develop any signs of serotonin syndrome, such as mental status changes, autonomic instability, neuromuscular changes, and/or gastrointestinal symptoms (Vallerand, 2017).  

Catechol-O-Methyltransferase (COMT) Inhibitors   

COMT inhibitors block the function of catechol-O-methyltransferase, which is the enzyme responsible for metabolizing dopamine. Entacapone (Comtan) or tolcapone (Tasmar) can be given in combination with levodopa/carbidopa (Parcopa, Sinemet), allowing for more levodopa to be converted to dopamine in the brain (Honan, 2019). Side effects include nausea, constipation, diarrhea, abdominal pain, hepatotoxicity, back pain, blood in the urine, and orthostatic hypotension (Hinkle & Cheever, 2018; Vallerand, 2017).  

When educating patients and families, the nurse should discuss rising slowly from a supine or seated position due to the risk for orthostatic hypotension; avoiding intake of alcohol; and adhering to HCP instructions for laboratory testing, such as liver function studies (Bauldoff et al., 2020; Vallerand, 2017).  

Anticholinergics  

Anticholinergic agents control tremors by counteracting the action of the neurotransmitter acetylcholine (Honan, 2019). Trihexyphenidyl hydrochloride (Artane) and benztropine mesylate (Cogentin) are examples of anticholinergics used to treat PD. Anticholinergics reduce tremors but have almost no impact on bradykinesia or gait disturbances. Side effects include blurred vision, flushing, constipation, a dry mouth, hypotension, and urinary retention (Hinkle & Cheever, 2018; Vallerand, 2017). Anticholinergics are contraindicated in patients with angle-closure glaucoma, and they should be used cautiously in patients with benign prostatic hypertrophy. In addition to the oral form, benztropine mesylate (Cogentin) is available for intramuscular and intravenous administration for acute dystonia and drug-induced extrapyramidal reactions (Vallerand, 2017).  

When educating patients and families, the nurse should discuss rinsing the mouth frequently and using sugarless gum or candy to decrease dry mouth and rising slowly from a supine or seated position due to the risk for orthostatic hypotension (Vallerand, 2017).  

Nonpharmacological Management

Interdisciplinary Collaboration 

A physical therapist, an occupational therapist, a speech therapist, and a social worker should all be part of the interdisciplinary care team. Physical therapy can provide individualized exercises and activities to promote strength, flexibility, and mobility (Hoffman & Sullivan, 2017). Examples of beneficial exercises may include stretching (stretch-hold-release), range-of-motion exercises, and postural exercises. Physical therapists should also work with patients on safe walking techniques, such as walking erect with the feet separated (creating a wide base of support) and looking straight at the horizon (Hinkle & Cheever, 2018; Honan, 2019).  

Occupational therapy provides strategies to promote maximal independence and optimize mental functioning (Hoffman & Sullivan, 2017). The therapist can recommend available adaptive or assistive devices to help with daily function. Occupational therapists can also evaluate each patient's needs in their home environment and suggest modifications (Honan, 2019).  

Speech therapy should include a swallow evaluation, as swallowing difficulties are common in patients with PD. Swallowing problems can be due to poor head control, tongue tremor, delayed swallowing, an inability to form a food bolus, or disturbances in pharyngeal motility. A speech therapist can identify the specific swallowing issues and make appropriate dietary recommendations. The speech therapist can also design speech improvement exercises, as PD patients tend to have soft, monotonous speech (Honan, 2019). Patients should be encouraged to speak slowly, exaggerate their pronunciation of words, face the listener, and use short sentences (Hinkle & Cheever, 2018; Honan, 2019).  

A social worker can connect patients and caregivers with support groups and helpful resources such as the American Parkinson Disease Association and the Parkinson's Foundation (Bauldoff et al., 2020).  

Surgical Management  

For carefully selected patients who may have advanced tremors that are no longer responsive to medications or are impaired by dyskinesias associated with long-term use of levodopa/carbidopa (Parcopa, Sinemet), deep brain stimulation (DBS) may be considered (Bauldoff et al., 2020; Hinkle & Cheever, 2018). According to the AANS (2022b), candidates for DBS must have a decreased quality of life, symptoms despite medication, and adverse effects from the medication regimen. In addition to medications, non-surgical treatments should be utilized before surgical intervention (AANS, 2022b). 

DBS involves the delivery of high-frequency electrical stimulation to targeted areas of the brain identified through a CT scan or an MRI (Honan, 2019). One or more electrodes are placed in either the globus pallidus or subthalamic nucleus and connected to a pulse generator via an extended wire. The battery-powered pacemaker is placed beneath the collarbone (AANS, 2022b; Hinkle & Cheever, 2018; Honan, 2019). 

Stimulation to these areas may increase dopamine release, leading to a reduction in tremors and rigidity. The goal is for medication doses to decrease after the insertion of this device (Hinkle & Cheever, 2018). Individuals who have DBS may have the surgery bilaterally and experience continuous symptom management. The risks of surgery are as follows:  

• brain hemorrhage (e.g., cerebral vascular accident) 

• infection 

• device malfunction 

• headaches 

• persisting disease symptoms 

• worsening emotional or mental status (AANS, 2022b) 

Long-Term Outcomes for Surgical Management 

Overall, DBS has demonstrated positive long-term outcomes in PD surgical candidates (Bove et al., 2021). Studying PD patients at the 3- and 5-year marks, Shin and colleagues (2020) found that levodopa medication dosages were decreased in all 49 patients who underwent DBS. Hitti and colleagues (2019) demonstrated that DBS was effective for long-term symptom management, highlighting a 51% survival rate at a 10-year telephone follow-up for 200 patients. The retrospective study included 320 patients who had DBS from 1999–2007. Similarly, Bove and colleagues (2021) found statistically significant improvement in 51 patients at a 15-year follow-up after DBS placement (p<0.001); these patients required fewer dopamine-replacement medications, reported greater quality of life, and experienced fewer dyskinesias.  

Evidence-Based Nursing Practice 

Improving Mobility  

Changes in mobility reportedly decline within the first 5 years of PD diagnosis (Johansson et al., 2020). Therefore, educating patients on fall prevention and sustaining muscle strength is important. Daily exercise will help increase muscle strength, improve coordination, decrease muscle rigidity, and prevent contractures (Hinkle & Cheever, 2018). Walking, riding a stationary bicycle, and swimming can help maintain joint mobility (Honan, 2019). Using a treadmill or an elliptical machine can enhance gait, stride length, and speed (International Parkinson and Movement Disorder Society, 2018). Warm baths and massage help facilitate range-of-motion exercises (Hinkle & Cheever, 2018). Because patients with PD often lack a normal arm swing, nurses should remind patients to make a conscious effort to swing their arms and pick up their feet while walking (e.g., by practicing walking to marching music; Honan, 2019).  

Beneficial Non-Traditional Forms of Exercise 

Besides walking, using traditional workout equipment, and swimming, non-traditional forms of exercise can help prevent falls in the PD population. Nurses can introduce these during patient education encounters. Tai chi improves posture control and balance, preventing falls (International Parkinson and Movement Disorder Society, 2018). Research by Li and colleagues (2020) on 500 individuals with early PD found that incorporating tai chi with traditional forms of exercise prevented falls and limited levodopa dosages more than traditional exercise alone (p<0.0001, q=38.512).  

Pereira and colleagues (2019) examined 40 studies and 5 reviews on music and dance therapy for individuals with PD, finding that music and dance therapy enhanced motor ability, cognition, and quality of life. 

More specifically, the tango enhanced spatial awareness, the ability to focus, and coordination (Guettard et al., 2018; International Parkinson and Movement Disorder Society, 2018; Rabinovich et al., 2021). Nurses can recommend classes at a dance studio, senior center, or home-based programs.  

Improving Nutrition 

Many individuals with PD experience weight loss and malnutrition (Ma et al., 2018). Each patient's weight should be monitored weekly to identify concerns (Hinkle & Cheever, 2018). Eating requires extra concentration due to chewing and swallowing difficulties, as well as the medication-related side effect of dry mouth (Hinkle & Cheever, 2018; Honan, 2019). Patients should sit in an upright position when eating to facilitate the swallow reflex and decrease the risk of aspiration (Hoffman & Sullivan, 2017). Suction equipment should be readily available at the bedside in the event of aspiration and to assist with handling oral secretions (Hoffman & Sullivan, 2017).      

A semisolid diet with thickened liquids is easier to swallow, so recommendations from speech therapists may include avoiding thin liquids. The patient should place food on their tongue, close their lips and teeth, and lift the tongue up and then back to swallow. Patients should be encouraged to chew food first on one side and then the other before swallowing (Hinkle & Cheever, 2018; Honan, 2019).  

To assist with eating and promote independence, a plate stabilizer, a no-spill cup, and built-up handles for utensils can be of value. Nurses may need to collaborate with occupational therapists to secure these devices if applicable. As PD progresses, patients may need a percutaneous endoscopic gastrostomy (PEG) tube to maintain adequate nutritional intake (Honan, 2019).  

Improving Communication  

Cognitive-linguistic impairments are frequently overlooked in the clinical care of patients with PD (Smith & Caplan, 2018). Patients with PD may benefit from speaking slowly and deliberately and taking a few deep breaths (Hinkle & Cheever, 2018). An electronic amplifier may be useful if family members, caregivers, or providers are having difficulty hearing the patient (Honan, 2019).  

Patients with PD are at risk for social isolation due to a decline in abilities to communicate clearly (Theodoros et al., 2019). Nurses can advocate by encouraging speech and language therapy for the patient and their caregivers. In addition, nurses should also be mindful of patients' altered self-confidence and self-perception as their communication abilities change (Johansson et al., 2020). 

Improving Bowel Elimination 

PD may cause severe constipation from several factors. Weakening of the muscles used for defecation, immobility, decreased fluid intake due to impaired swallowing, decreased autonomic nervous system activity, and adverse effects of medications can all contribute to constipation. The following measures should be incorporated into the plan of care: setting a regular schedule for defecation, consuming foods with moderate fiber content, and increasing fluid intake. A raised toilet seat and allowing ample time for bowel movements may also be of benefit (Hinkle & Cheever, 2018). If nonpharmacological techniques are ineffective in managing constipation, providers can suggest various pharmacological agents, such as bulking agents, osmotic and stimulant laxatives, chloride channel activators, ghrelin agonists, 5-HT4 receptor agonists, and probiotics (Mozaffari et al., 2020).  

Promoting Self-Care Activities      

Modifications to the patient's environment can compensate for diminished abilities and promote safety and independence. Nurses should counsel patients to remove throw rugs, ensure sufficient lighting throughout the home, and install handrails in all bathrooms and stairwells (Honan, 2019). Occupational therapists can determine the best assistive devices for each patient. Additionally, nurses should encourage patients and caregivers to manage their medication regimen carefully to promote balance and limit side effects.  

Promoting Sleep  

Medications that treat PD can often contribute to sleep pattern disturbances. For example, levodopa (Parcopa, Sinemet) can lead to vivid dreams. In addition, many individuals experience insomnia, daytime sleepiness, and restless leg syndrome (Stefani & Högl, 2020). Sleep pattern hygiene basics include going to bed and waking around the same time every day, avoiding naps too close to bedtime, limiting caffeine intake, darkening the bedroom, and decreasing any ambient noise (American Academy of Sleep Medicine, 2020; Bauldoff et al., 2020). Patients with PD may require a video-polysomnography to identify changes in sleep patterns and guide other recommendations (Stefani & Högl, 2020). 

Supporting Coping Abilities  

Patients with PD often experience apathy, loneliness, and embarrassment about their external symptoms. These feelings can lead to depression and anxiety. Nurses can offer some strategies when appropriate to combat depression, such as achievable goals, physiotherapy, support group participation, medication therapy, and psychotherapy (Honan, 2019). Patients with PD have demonstrated positive results with cognitive behavioral therapy, including when provided over the telephone (Dobkin et al., 2020; Reynolds et al., 2020). If a patient expresses an interest in medication therapy for mood stabilization, nurses should encourage providers to offer additional information. As always, nurses should be watchful for any worsening mood symptoms or suicidality. 

Future Research 

Future research includes looking at the presence of Lewy bodies, using stem-cell-based treatments, and understanding the impact of neuroinflammation on PD individuals. 

Lewy Bodies 

Although there is no indication that Lewy bodies cause PD, researchers have noted their presence in brains affected by PD (Norris, 2019). Lewy bodies are alpha-synuclein proteins that clump in association with changes in cognition and motor function (American Parkinson Disease Association, 2022b). Most notably, Lewy bodies can contribute to the onset of dementia within ten years of PD diagnosis due to neuronal death and changes in dopamine levels (Alzheimer's Association, 2022; Davis Phinney Foundation for Parkinson's, 2018). While a correlation is present, researchers are seeking to understand better the greater association between Lewy bodies and PD. 

Stem Cells 

Harvard Stem Cell Institute (2022) is currently examining how modifying skin cells from a patient with PD can induce pluripotent stem cells to differentiate into dopaminergic neurons. UCI Health (2022) is conducting stem cell research on individuals with advanced-stage PD for whom medications are no longer effective. The trial involves surgically implanting differentiated dopamine-producing stem cells into the brain, based on a hypothesis that dopamine-cell replacement therapy may enhance an individual's quality of life and reduce dependence on medication (UCI Health, 2022). 

Other Experimental Treatments 

In addition to stem cell therapy, neuron-repair treatments, gene therapy, and gene-targeted treatments are being examined for PD (Ntetsika et al., 2021). Neuron-repair treatments are currently being investigated in mice; specifically, re-programming astrocytes has increased new dopaminergic neurons (Wei & Shetty, 2021). Gene therapy and gene-targeted treatments are currently being investigated as disease-modifying and non-disease-modifying options: disease-modifying treatments focus on preventing neuron death or regenerating new neurons, whereas non-disease-modifying therapies focus on symptom management (Axelson & Woldbye, 2018).  

Neuroinflammation 

MacMahon Copas and colleagues (2021) identified a possible link between inflammation and PD that requires more research. More specifically, the presence of T lymphocytes in patients with PD may signify inflammation. Baird and colleagues (2019) observed T cells in the substantia nigra of PD individuals. Bhatia and colleagues (2021) found that T lymphocyte levels correlated with advanced-stage PD. This research has the potential to impact the direction of the treatment and understanding of PD progression (Baird et al., 2019).  

References 

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