CE 2.

Continuing Education

HOURS

Depression in Older Adults

A nurses guide to recognition and treatment.
t is a misconception that depression is a normal,inevitable part of aging; it is not. The illness, which the writer William Styron has called darkness visible, is defined by Stedmans Electronic Medical Dictionary as a temporary mentalstate or chronic mental disorder characterized by feelings of sadness, loneliness, despair, low selfesteem, and self-reproach. Depression is prevalent among older adults: an estimated 15% to 19% of Americans ages 65 and older suffer from depressive symptoms.1, 2 Depression has significant adverse effects on quality of life, and its a known risk factor for suicide. In 2007 (the most recent year for which data are available), suicide accounted for about 14deaths per 100,000 in people ages 65 and older, compared with 11 deaths per 100,000 in the general population.3 Among non-Hispanic white men ages 85 and older, 47 deaths per 100,000 were due to suicidethe highest rate of any population subgroup. Such figures probably dont begin to tell the whole story. Experts agree that depression in older adults often goes unrecognized and untreated.4, 5 Yet there is abundant evidence that depression in older adults is treatable, perhaps in as high as 65% to 75% of cases.6 Depression can affect older adults living in any setting. Among those in long-term care facilities, the prevalence of some level of depressive symptomatology has been estimated at anywhere from 6% to 44%.7-9 The prevalence of depression is also very high in patients receiving home health care services. Studies have indicated that one in seven such patients meet the diagnostic criteria for major depression, and as many as one in three have some level of clinically significant
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Mourning Old Man by Vincent van Gogh; akg-images / Newscom.

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By Cynthia G. Cahoon, MS, DNP, PMHNP-BC, APRN

OVERVIEW: Depression affects an estimated 15% to 19% of Americans ages 65 and older living in a variety of settings, yet the illness often goes unrecognized and untreated. Known risk factors for older adults include having chronic medical conditions, physical or cognitive functional decline, polypharmacy, experiencing multiple losses, and social isolation. There are brief screening tools that have proven effective in this population, and once recognized, depression is highly treatable. This article describes the signs and symptoms common in older adults, outlines several types of depressive disorders, discusses screening tools, describes treatment modalities, and addresses nursing implications. Keywords: depression, dysthymia, older adults

depression.10, 11 One study found that, during the first two weeks following admission to home care, the hospitalization rate for depressed patients was more than twice that of patients who werent depressed.12 Another study found that, even after one year of home care services, patients with depression had significantly lower scores for physical and mental quality of life and life satisfaction than did patients who werent depressed.13 There is also a significant burden on the family caregivers of older adults with depression. A 2004 study found that depressive symptoms in older adults were independently associated with higher levels of informal caregiving, even after adjusting for major chronic comorbidities.14 The researchers stated that the additional caregiving hours associated with depression represented a significant time commitment for family members and, therefore, a significant societal economic cost. A more recent study found that improvement in patient depression was associated with significantly reduced depression-specific caregiver burden.15 The researchers concluded that treating latelife depression benefits both patients and their family members. Depression and comorbidities. Many illnesses that are common in older adults are known to be associated with depressive symptoms. One frequently cited older study found that even older adults with few or no physical comorbidities had a significantly increased risk of developing a disability in activities of daily living when they developed depressive symptoms.16 However, its also worth noting that studies have found that depression can color self-perceptions and lead to overreporting of functional disability.17 Comorbidities require careful evaluation, since worsening of one condition often leads to worsening of another. Moreover, failure to detect all etiologies for symptoms
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leads to ineffective treatment, since important causes are left unaddressed. Cardiovascular disease was one of the first med icalconditions to be associated with depression.18 Depression is associated with reduced physical activity; one recent study found it was low levels of physical activity in depressed patients, rather than other depression symptoms, that increased their risk of cardiovascular mortality.19 Another recent study found that severe depression was associated with an unhealthy diet (die tary risk factors included comparatively low levels of polyunsaturated fatty acids, low fiber intake, and low carbohydrate intake) and other risk factors for acute myocardial infarction.20 Other conditions often associated with depression include diabetes, Parkinsons disease, and chronic pain. Astudy investigating health-related quality of life in adults with diabetes found that 31% had depressive symptomsand that by far the most significant negative impact on quality of life was due to those symptoms.21 A systematic review of studies of depression in people with Parkinsons disease found an average prevalence of 17% for major depression and a combined prevalence of 35% for depressive symptoms.22 Another review yielded comparable results and noted that depression reduces both subjective and objective quality of life independent of motor deficits.23 Chronic pain stemming from various etiologies has been associated with depression.24, 25 One large Canadian study found that 20% of people with chronic back pain experienced major depression, compared with 6% of those without back pain.24 Lastly, there is evidence that depression in people with dementia is seriously underrecognized and undertreated, in part because of difficulties in relying on self-report in this population, as well as symptom overlap.26
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As for whether many drugs commonly taken byolder adults (including antihypertensives, lipidlowering agents, corticosteroids, and sedatives or hypnotics) are also associated with depression, the evidence is contradictory.27 Its important to remember the difference between correlation and causality, and that its often not possible to determine whether agiven medication actually causes depression. That said, the authors of one review suggest that when new onset or worsening of depressive symptoms occurs, withdrawal of suspect medications should be considered.27 (The American Geriatrics Societys updated 2012 Beers Criteria [http://bit.ly/MuuHpD] lists drugs considered high risk in older adults.) Pathophysiology. The pathophysiology of depression is still not well understood. According to the American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR), the pathophysiology may involve a dysregulation of a number of neurotransmitter systems, including the serotonin, norepinephrine, dopamine, acetylcholine, and gamma-aminobutyric acid systems.28 Its hypothesized that the dysregulation may occur either through excessive presynaptic uptake or through stress-related downregulation of postsynaptic receptors.29 Some recent studies, generally using postmortem investigations or neuroimaging, have focused on the roles played by dopamine and by inflammatory cytokines. Dunlop and Nemeroff reviewed the evidence for the role of dopamine and found support for the hypothesis that major depression is associated with a state of reduced dopamine transmission.30 There is also strong evidence of an association between elevated levels of various cytokines and major depression in older adults.31, 32 Both dopamine circuit dysfunction and inflammatory cytokines have been suggested as areas for further research. If the pathophysiology of depression could be more exactly described, there would be possibilities for newer, more effective treatments. But as Krishnan and Nestler observe, there is a unique challenge in studying the pathophysiology of depression: Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models.33 Risk factors. The etiology of depression can be unclear, and its often difficult to determine which symptoms are caused by depression and which have other causes. That said, there are several known risk factors that increase an older persons chances of developing a depressive disorder. These include5 chronic medical conditions polypharmacy multiple losses functional decline (physical, cognitive, or both) personal or family history of depression
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IDENTIFYING DEPRESSION

social isolation substance abuse or dependence Cole and Dendukuri conducted a systematic review and meta-analysis of 20 prospective studies of risk factors for depression in community-dwelling older adults.34 They found that five factors (bereavement, sleep disturbance, disability, prior depression, and female gender) are significant risk factors for depression; they also noted that the first three factors are potentially modifiable. A study by Jones and colleagues found that 63% of visually impaired older adults reported depressive symptoms, indicating a strong association between visual impairment and depression.35 Older people do tend to experience more losses than do younger people. Often they struggle with numerous losses within relatively short periods of time. These might include the losses of friends and significant others, health, independence, home, livelihood, or a combination of these. Sadness and grief after loss are normal, but sadness that persists or leads to feelings of hopelessness demands further evaluation. Signs and symptoms. Depression in older adults can manifest in numerous ways, and many symptoms are also symptomatic of physical illnesses common inthis population, complicating recognition.2, 36 Physical signs and symptoms of depression may include weight loss, insomnia, slowed movement, and vague complaints of pain. Individuals may develop memory problems and begin to appear confused. They may either demand help from others or become socially withdrawn.2 Its also not unusual for an older person to deny feelings of sadness while exhibiting other signs of depression. Types of depressive disorders. Major depression is diagnosed and described using the DSM-IV-TR. A diagnosis of major depression requires that at least five of the following symptoms (including either depressed mood or anhedonia) have been present nearly every day for at least two weeks and represent a change from previous functioning28: depressed mood diminished interest or pleasure in most activities (anhedonia) significant weight loss or gain, or decrease or increase in appetite insomnia or hypersomnia psychomotor agitation or retardation fatigue or loss of energy feelings of worthlessness or inappropriate guilt diminished ability to think or concentrate, or indecisiveness recurrent thoughts of death or of suicide (with or without a specific plan) There are also a number of other depressive dis orders. Dysthymia is a chronic, less severe form of depression. Its characterized by depressed mood that occurs for most of the day more days than not for at
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least two years and two or more of the following symptoms28: poor appetite or overeating insomnia or hypersomnia low energy or fatigue low self-esteem poor concentration or difficulty making decisions feelings of hopelessness Adjustment disorder with depressed mood arises in response to a specific stressor, such as placement in a long-term care facility or the death of a spouse or 28 partner. Depressive disorder not otherwise specified can include depression secondary to another medical condition or to medication.28 Some experts recognize minor or subsyndromal depression, which is charac terized by depressive symptoms like those of major depression, but with fewer symptoms and less impairment.37 There are many evaluation instruments available to help clinicians in identifying depression. The Beck Depression Inventory,38, 39 the Hamilton Rating Scale for Depression,40 and the Patient Health Questionnaire-9 (PHQ-9)41, 42 have all been used effectively to assess depression in a variety of populations and settings. The Geriatric Depression Scale (GDS) Long Form is a 30-item questionnaire that was first developed in 198343 and has since been tested and used extensively. In 1986, a GDS Short Form was developed, using the 15 questions from the Long Form that had the highest correlation with depressive symptoms.44 The Short Form, which takes five to seven minutes to complete, is more easily used by patients with physical illnesses or mild-to-moderate dementia,45 and has been evaluated in various older populations (inpatient, outpatient, primary care, nursing home, and home health care).46 As Marc and colleagues have noted, both GDS forms purposely do not assess somatic symptoms in order to avoid attributing symptoms of medical illness to depression.46 But there is some risk that in excluding somatic symptoms, some cases of depression might be missed. That said, both forms have proven effective in screening for depression in older adults. Yet even a five-to-seven-minute screening may be too long for clinicians to incorporate readily into every patient encounter. At least two shorter instruments are available. The Patient Health Questionnaire-2 (PHQ-2) uses just the first two questions of the PHQ-9. These ask patients whether theyve felt down, depressed, or hopeless or taken little interest or pleasure in doing things within the past two weeks.47 The PHQ-2 also asks about the extent of symptoms: possible answers are not at all, several days, more than half the days, or nearly every day. Thus, the PHQ-2 functions as both a screening tool for depression and a measure of depression severity.48, 49
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The briefest validated depression screening tool, the Whooley Depression Screen, is quite similar to the PHQ-2 and also asks just two questions50: 1.  During the past month, have you often been bothered by feeling down, depressed, or hopeless? 2.  During the past month, have you often been bothered by little interest or pleasure in doing things? While the first question alone is 93% sensitive, adding the second question increases sensitivity further.50 A negative response to both questions makes depression highly unlikely. Depression in patients of any age can be treated with psychosocial interventions, psychotherapy, or psychopharmacology.

TREATMENT

SCREENING

Its essential to assess the patients mood regardless of presenting symptomatology.

Psychosocial interventions and psychotherapy. Depression may respond to nonspecific psychosocial interventions, such as physical activity and socialization.51-53 A study by Ciechanowski and colleagues in community-dwelling older adults with minor depression found that an intervention emphasizing increased physical and social activity led to signifi cantly lower severity and greater remission than did usual care.51 Another study found that providing such patients with social visits, with or without physical activity, led to improved quality-of-life measures of mood and mental health.52 However, for patients whose depression doesnt respond to such treatment, other interventions are needed. As Mackin and Arean have noted, in 1991 the National Institutes of Health consensus statement on the treatment of late-life depression ranked psychotherapy as third in a line of treatment options, with antidepressant medication first and electroconvulsive therapy second, indicating that there was insufficient evidence to recommend psychotherapy as a first-line treatment for older adults.54 Since then, there has been more research on the effectiveness of psychotherapy, both as a stand-alone intervention and in combination with medication. The two most widely investigated psychotherapies are cognitive behavioral therapy and interpersonal therapy. Cognitive behavioral therapy, a form of short-term psychotherapy, was first developed by Aaron Beck in the 1970s and is based on the premise that a persons mood and behavior are determined by how she or he
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perceives the world.55 Working together, the therapist and the client focus on identifying and changing the clients maladaptive thinking in order to influence behavior and mood. This therapy has been found to be effective in treating depression in older adults.56 Indeed, cognitive behavioral therapy has been studied in at least 15 randomized clinical trials in that population, and its efficacy has been compared to that of placebo, usual care, other brief therapies, and medication.57 Although several of these studies were conducted 15 or more years ago,58-60 they demonstrated the effectiveness of cognitive behavioral therapy, especially when treatment emphasized learning skills for coping with ongoing challenges.61 Interpersonal therapy has been described as a com posite of psychodynamically-informed strategies (exploration, clarification of affect) and cognitive- behavioral strategies (behavior change techniques, reality testing of perceptions).57 It seeks to address four areas of conflict: unresolved grief, role transitions, interpersonal role disputes, and interpersonal deficits.57 In a systematic literature review, Mackin and Arean evaluated 17 studies that investigated various forms of psychotherapy as treatment for late-life depression.54 They concluded that cognitive behavioral therapy, reminiscence therapy, brief psychodynamic therapy, and the combination of medication and interpersonal therapy are acutely efficacious in treating major depression in ambulatory older adults. They also recommended further investigation of certain psychotherapies and combinations of these with medication, and stated that although older adults can benefit from psychotherapy, many may be accessing treatments that havent been studied adequately.

Many illnesses that are common in olderadults are known to be associated withdepressive symptoms.
Regardless of the type of psychotherapy provided, there are special aspects to psychotherapy in this population.62 For example, significant family involvement in the patients daily life and care can make maintaining patient confidentiality challenging. Sensory or cognitive deficits must also be considered and adjusted for. Psychopharmacology. The use of antidepressant medications in older adults also involves certain considerations. For one, physiologic changes associated with the aging process affect pharmacokinetics, including drug absorption, distribution, metabolism, and excretion.63 The rate of gastric absorption may slow, delaying or otherwise altering response. Increased body fat and decreased lean muscle mass,
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decreased total body water, and decreased serum albumin each affect drug distribution, generally making drug effects more intense. The rate of hepatic drug metabolism decreases with age, and this can lengthen the half-lives of some drugs and prolong response. The rate of renal excretion decreases and results in drug accumulation, which Lehne notes is the most important cause of adverse drug reactions inthe elderly.63 Lehne also cautions that the extent of age-related pharmacokinetic change varies widely among individuals. Medication adherence is difficult for many patients, not just those who are older or depressed. One review of studies of medication adherence found that even in clinical trials, adherence was just 43% to 78%; among psychiatric patients with depression, the mean rate of adherence was 65%.64 There can be many reasons for nonadherence, including unwanted adverse effects, dosing complexity, and medication expense. Studies of adherence in both the general population65 and in older adults66 have found that simpler, less frequent dosing regimens are associated with improved adherence. Adverse effects are common with many antidepressants, and vary by category of medication. There are four commonly prescribed categories of anti depressants: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and atypical antidepressants that affect various neurotransmitters. While all have possible adverse effects, particularly at the start of therapy, SSRIs are usually the first-line choice for older adults because these drugs dont typically cause sedation, hypotension, anticholinergic effects, or cardiotoxicity.67, 68 One early study found that 28% of patients stopped taking their antidepressants within the first month of therapy and more than 40% stopped after three months; dislike of adverse effects was the most commonly given reason.69 Nausea and vomiting have been found to be the most common reasons for discontinuation.70 (For more on antidepressants and possible adverse effects, see Table 1.67, 71, 72) Clinical practice guidelines recommend continuous antidepressant therapy for six to 12 months.73, 74 Early discontinuation can result in ineffective treatment and recurrence. Interestingly, Katon and colleagues found that patients who were adherent to antidepressant therapy were significantly more likely to be adherent to therapy for comorbid conditions; improved adherence was also associated with reduced medical costs.75 Other modalities. While psychotherapy and psychopharmacology are the most common treatments for depression, two other treatments have been used successfully to treat depression in older adults. In electroconvulsive therapy (ECT), which is used to treat severe depression, the patients brain is electrically stimulated to produce a seizure. After repeated treatments this typically results in an improvement in
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depressive symptoms, although the mechanism of action is unknown. ECT eliminates concerns about drug adverse effects and interactions, but the need for general anesthesia may be problematic for some older patients. Still, research indicates that it is at least as effective in older patients as it is in younger ones.76 The newest treatment offered for treatment of depression is repetitive (or rapid-rate) transcranial magnetic stimulation (rTMS), which uses magnetic fields to stimulate the prefrontal cortex. As with ECT, repeated treatments can produce a reduction in depressive symptoms, although the mechanism of action is not well understood. But unlike ECT, rTMS produces no seizure activity, and there is no need for general anesthesia. Thus far the evidence regarding rTMS for elderly patients has been inconclusive. An early study found increased responsiveness to rTMS in patients ages 65 and younger, compared with older patients.77 But two later studies suggest that rTMS effectively reduces depressive symptoms in older patients.78, 79 The evidence isnt clear enough to allow rTMS to be considered a first-line treatment, and both access and affordability are barriers to this treatment. The majority of older adults with depression will present for treatment of physical conditions, rather than for evaluation for a mood disorder. But its essential to assess the patients mood regardless of presenting symptomatology, because mood independently affects daily functioning and can impede treatment for medical comorbidities. Every nurse can ask older patients the two questions in the Whooley Depression Screen; this takes very little time, and the screens sensitivity is high. (Some outpatient facilities include this screen on their electronic medical record.) Because the Whooley screen has established sensitivity of over 90% (and despite specificity under 60%),50 if nurses used this tool with every older patient, we could identify over 90% of those who might benefit from treatment for depression. A recent study explored the use of a nursefacilitated depression screening program in a busy primary care clinic for military families.80 The researchers found that a majority of clinicians felt that this program was a quality component of clinical practice that benefited the population served. Although this study screened family members over the age of 18,rather than older patients, the concept of nursefacilitated screening is applicable to any population. After an initial screening, further evaluation and referral will depend on the practice setting. Sometimes the nurse will convey the results to the patients primary care provider, who then conducts a more extensive evaluation. In some settings, the practice protocol might call for the nurse to proceed with the next level of evaluation, perhaps the PHQ-9. Sometimes patients will be referred to mental health specialists.
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Table 1. Some Antidepressants Commonly Prescribed for Older Adults 67, 71, 72
Drug class Selective serotonin reuptake inhibitors Citalopram (Celexa) Escitalopram (Lexapro) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Tricyclic antidepressants Amitriptyline (Elavil) Desipramine (Norpramin) Doxepin (Sinequan) Nortriptyline (Pamelor) Atypical antidepressants Bupropion (Wellbutrin) Duloxetine (Cymbalta) Mirtazapine (Remeron) Trazodone (Desyrel) Venlafaxine (Effexor) Monoamine oxidase inhibitors Phenelzine (Nardil) Selegiline (Eldepryl; Emsam) Tranylcypromine (Parnate) Some possible adverse effects Headache Gastrointestinal disturbance Sexual dysfunction

Sedation Anticholinergic effects Orthostatic hypotension Cardiac toxicity Varies by drug

NURSING IMPLICATIONS

Agitation Restlessness Insomnia Anticholinergic effects Orthostatic hypotension

Helping patients to manage psychiatric medications is an important nursing function. Patients need to understand that it can take several weeks for antidepressant medications to take effect; they shouldnt stop taking a prescribed drug prematurely. Furthermore, sometimes several different dosages or different antidepressants must be tried before an effective treatment is found. This period can be confusing and frustrating for patients, and some may be tempted togive up. It helps to remind them there is no one right medicine thats effective in all people, and that there are many possible medications to try. Its also important for nurses to assess older patients for both positive and adverse effects of psychotropic drugs. As Lindsey notes, older adults are highly vulnerable to such adverse effects; those older than age 70 are 3.5 times more likely than those younger to be admitted to a hospital because of adverse drug reactions to a psychotropic medication.71 Moreover, some patients may be using herbal remedies instead of or along with prescription medications. Since these can have significant adverse effects and drugdrug interactions, its important for nurses to ask patients about all substances they might be taking.
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In a hospital setting, nurses are responsible for patient education and discharge information. Its helpful to patients, especially older patients, to go over this information with them well before discharge. Questions to ask the patient might include: Do you understand the purpose and dosing of each of your medications? Is there someone who can help you at home, such as a home health aide or a family member? Will you take your medications from the pill bottles or will you use a medication planner box? What time do you usually eat meals? What do you usually eat? Do you know which medications must be taken before eating? Are there any medications you were taking before your hospitalization that have now been discontinued?

this aspect of care typically involves nurses. Referrals to senior centers for activities and shared meals can help facilitate social interactions and support.81 Senior transportation programs, based on either public transportation or volunteer rideshare systems, can give older adults access to health care appointments, pharmacy visits, and social events. Nurses can provide contact information for useful agencies and programs, and when possible, take a few minutes to explain the available services to patients and family members. These simple interventions may lower the patients risk of depression and either prevent or lessen the severity of depressive symptoms. Health care reform and planning efforts are affecting how nurses care for patients. There is an increasing emphasis on health promotion,82, 83 and nurses, who are trained to be patient advocates and health educators, have a crucial role to play in this regard. And in the collaborative care model, care managers (often nurses) in the primary care office monitor patients symptoms, provide patient and family education, schedule activities, and communicate with all care providers.84 There is evidence that collaborative care is more effective than standard care for treating depression. A meta-analysis of 37 studies of patients with depression found that, compared with standard care, collaborative care in primary care settings increased medication adherence and improved short- and longterm depression outcomes more effectively.85 A recent study by Klinkman and colleagues evaluated a collaborative carebased intervention for adults with depression, a high proportion of whom were chronically depressed, and found it produced sustained improvement in clinical outcomes.86 Another intervention, Depression Care for Patients at Home (also called Depression CAREPATH), is a depression care management model developed for use by nurses, physical therapists, and other primary providers in the home.87 The protocol includes the five basic functions of care management: symptom assessment, case coordination, medication management, education, and patient self-care strategies. Preliminary data indicate that the intervention contributes to positive outcomes. Recently, the Patient Protection and Affordable Care Act established the Medicare Shared Savings Program for Accountable Care Organizations (ACOs), which was implemented earlier this year (for the latest updates, visit http://go.cms.gov/Muvmqw). Under this program, certain individual providers and various types of organizations can be recognized as ACOs; those that provide high-quality patient care while lowering health care costs will receive a share of the Medicare savings.88 Nurses now have valuable new opportunities within ACOs, both as clinicians and as
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NEW OPPORTUNITIES FOR NURSES

There is evidence that collaborative care is more effective than standard care fortreating depression.
Nurses can also assist patients in drawing up a daily schedule of meals and medication times. This offers another opportunity to discuss other aspects of medication management, such as whether the patient can afford the medication and has access to a pharmacy to have the prescription filled. Patients sometimes hesitate to tell clinicians that they cant afford their medications or that theyre taking less than the prescribed dose in order to make their supply last longer. When possible, its best to address such potential problems in advance. For example, there may be prescription assistance programs available or an older, less expensive medication that could be tried. In an office setting, nurses can provide patient education and medication review. Through electronic prescribing, most prescribers can tell if a medication is covered by a patients insurance. But judgments about what constitutes an affordable copay can vary widely. Asking patients Will you be able to get all of your medications? allows them to share problems with either finances or transportation. Like hospitalized patients, outpatients will benefit from a discussion about the daily drug regimen and the need to dispose of any discontinued medications. Many older people with depression are either socially isolated or at risk for such isolation. In the hospital, many social interventions are provided by the social services department, but in the office setting,
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leaders in quality assurance and process improvement initiatives,89 to improve the care of all patients, including older adults with depression. Its also worth noting that care coordination and preventive health including screening for depressionare among the measures used in establishing whether an ACO meets quality-of-care standards.90 For more than 76 additional continuing nursing education articles on geriatric topics, go to www. nursingcenter.com/ce.
Cynthia G. Cahoon is a full-time assistant professor of nursingat Keene State College and a part-time psychiatric NP at Monadnock Family Services, both in Keene, NH. Contact author: ccahoon@keene.edu. The author has disclosed no potential conflicts of interest, financial or otherwise.

REFERENCES
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