3

Clinical Research

The rapid growth of clinical research in geriatric medicine over the past decade permits a broad-based attack on myriad important and previously neglected research questions across several research areas. These include investigations of age-dependent changes in an array of physiologic systems, pathophysiology and management of a number of diseases relevant to aging populations, and characterization of the problems of frail, elderly people, including those in long-term care facilities.

Building on the impressive though unsystematic database that has been developed, a consensus is emerging regarding the most important lines of future research inquiry. That consensus, sharpened by the systematic discussions involved in preparing this National Research Agenda, focuses on two key areas that can serve as the basis for specific research questions and proposals: (1) research into the causes, prevention, management, and rehabilitation of disability in older persons, including a focus on geriatric syndromes; and (2) studies of age-dependent physiologic change and specific pathologic entities.

Recommendations for specific studies within these two major topic areas overlap significantly, reflecting both the multifactorial nature of disease and disability in old age and the absence of clear, common pathways of declining function in older people. Such overlap also is inherent in the area of clinical research since the field ranges from molecular biology and genetics to epidemiology, and



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Extending Life, Enhancing Life: A National Research Agenda on Aging 3 Clinical Research The rapid growth of clinical research in geriatric medicine over the past decade permits a broad-based attack on myriad important and previously neglected research questions across several research areas. These include investigations of age-dependent changes in an array of physiologic systems, pathophysiology and management of a number of diseases relevant to aging populations, and characterization of the problems of frail, elderly people, including those in long-term care facilities. Building on the impressive though unsystematic database that has been developed, a consensus is emerging regarding the most important lines of future research inquiry. That consensus, sharpened by the systematic discussions involved in preparing this National Research Agenda, focuses on two key areas that can serve as the basis for specific research questions and proposals: (1) research into the causes, prevention, management, and rehabilitation of disability in older persons, including a focus on geriatric syndromes; and (2) studies of age-dependent physiologic change and specific pathologic entities. Recommendations for specific studies within these two major topic areas overlap significantly, reflecting both the multifactorial nature of disease and disability in old age and the absence of clear, common pathways of declining function in older people. Such overlap also is inherent in the area of clinical research since the field ranges from molecular biology and genetics to epidemiology, and

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Extending Life, Enhancing Life: A National Research Agenda on Aging draws on information supplied by basic biomedical research, health services studies, and the behavioral and social sciences. Clinical research shares many techniques and subjects with other areas of investigation but has a special focus on the connections between organic illness and functional status and on specific interventions to treat or prevent organic diseases. Several recent Institute of Medicine (IOM) studies on research into the effectiveness and outcomes of health care have described the potential for interaction between clinical research and other areas of investigation in the study of older patients (IOM, 1989, 1990a). In addition to overlapping with other areas of research, the clinical research priorities described below share a common opportunity for investigation—study of the value of rehabilitative care in clinical outcomes, in cost benefits, and in cost effectiveness. RESEARCH PRIORITIES The first priority is research into the causes, prevention, management, and rehabilitation of functional disability in elderly persons. The overwhelming importance of functional capacity as a determinant of older persons' needs dictates a special focus on factors that limit the independence of elderly individuals. Increasingly, the clinical geriatric research community recognizes and agrees that it is well positioned to make significant short-term advances in the understanding of the physiologic and pathophysiologic mechanisms underlying the dependency and frailty that characterize the final stages of life. Although at any given time, a majority of older persons are free of significant disability, the rate of disability rises with age. The National Health Interview Survey (National Center for Health Statistics, 1985) reported that 23 percent of all elderly persons are unable to perform at least one of the activities of daily living (ADLs). These ADLs include bathing, dressing, grooming, going to the toilet, being able to move from bed to chair, being continent, and being able to feed oneself. About half of those 85 years of age and older need assistance to perform one or more ADLs or to carry out one or more instrumental activities of daily living (IADLs). These include shopping, using public transportation, cooking, using the telephone, housekeeping, and managing finances (Dawson et al., 1987). In order for an older person to be independent, he or she must be able to perform these activities. Clearly, with increasing inability to per-

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Extending Life, Enhancing Life: A National Research Agenda on Aging form ADLs and IADLs, one's dependency on others for care increases. As many as one to one-and-a-half million elderly individuals residing in the community or in institutions are unable to carry out five or more ADLs (Branch et al., 1984). However, recent studies indicate that such deficits are not static and may indeed respond to rehabilitation (Williams, 1988). Within the general area of functional disability research, two general areas stand out: studies of health promotion and disease prevention in older persons and studies of specific geriatric syndromes. Health Promotion and Disease Prevention in Old Age The mechanisms and diseases that lead to age-related increases in disability have not been elucidated. With few exceptions, research in health promotion and disease prevention has not focused on older cohorts. Although substantial data on the relationship of traditional cardiovascular risk factors to the subsequent incidence of cardiovascular disease in older men and women are emerging from the aging Framingham cohorts, few data are available to indicate whether intervention in these risk factors affects subsequent rates of cardiovascular disease, including stroke, heart attacks, and congestive heart failure. Some limited data exist in the area of diastolic hypertension, and a major multicenter study is under way to evaluate the contributions of isolated elevations in systolic blood pressure to these end points, particularly stroke. However, few studies adequately address remediable risk factors for other important geriatric disorders, including osteoporosis, dementia, disability, and total mortality. Too often, investigators have generalized findings from middleaged adults to older individuals without recognizing the major effects of the substantially altered physiologic substrates with advancing age. No a priori assumption can be made that risk factors for important diseases in middle age carry the same relative or the same attributable risk in old age. From a lifespan perspective, it is important to note that many prevention issues pertinent to older people should first be addressed to young adults (IOM, 1990a,b). While a substantial number of specific research areas have been identified, two are particularly salient: Research should be conducted on the interacting effects of age, lifestyle factors, and disease on the disability status of older persons. Studies should be undertaken to determine the effectiveness of various disease prevention strategies or practices in older persons.

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Extending Life, Enhancing Life: A National Research Agenda on Aging Studies of Geriatric Syndromes While functional disability may be the final common pathway of frailty for many older individuals, the specific clinical manifestations of disability vary among individuals. In many patients functional dependence is associated with the emergence of one or several specific geriatric clinical syndromes that may share some basic underlying pathophysiologic mechanisms. Geriatric syndromes represent a cluster of symptoms, conditions, and disabilities resulting in a variety of physiologic changes, pathologic conditions, comorbid conditions, and environmental challenges. These disorders are quite common in persons over age 75 and result in substantial disability, morbidity, and decreased quality of life. A number of these syndromes—including failure to thrive; impaired postural stability, strength, and mobility; mismanagement of medications; urinary incontinence; and delirium—have been neglected for some time but are particularly ripe for major research advances. Failure to Thrive (Inanition) This is a syndrome of weight loss, decreased appetite and poor nutrition, and inactivity, often accompanied by dehydration, depressive symptoms, impaired immune function, and low cholesterol. Occurring in both acute and chronic forms, failure to thrive leads to impaired functional status, morbidity from infection, pressure sores, and, ultimately, increased mortality. Failure to thrive also leads to increases in institutionalization and health care costs. One example of promising research into this syndrome is the conduct of cross-cohort and longitudinal studies to determine the prevalence and the underlying risk factors precipitating failure to thrive. Another important example is the study of interventions to prevent or treat such consequences of failure to thrive as pressure sores and depression. Impaired Postural Stability, Strength, and Mobility This is a syndrome that includes the common problems of falls, dizziness, syncope, fractures, muscle weakness, and impaired mobility. These problems tend to occur increasingly in persons over the age of 75 and result in significant functional disability and dependence. Each year in the United States there are over 200,000 hip fractures—the majority of which are precipitated by falls—in persons over the age of 65 (Cummings et al., 1985). One specific research recommendation in this area is to determine the pathophysiologic mecha-

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Extending Life, Enhancing Life: A National Research Agenda on Aging nisms and other factors underlying recurrent falls and mobility impairment, including gait disorder and muscle atrophy. Further study is needed to explore effects of pharmacologic agents and other therapy (graded exercise) on improving or impairing some of these functions. Mismanagement of Medications The management of multiple medical conditions in older patients often involves several medications. Polypharmacy, defined as the taking of three or more medications on a regular basis, is found in a third of persons over the age of 65 (Nolan and O'Malley, 1988). Recent studies indicate that polypharmacy is a significant cause of morbidity and hospitalization among elderly patients (Williamson and Chopin, 1980; Ives et al., 1987; Grymonpre et al., 1988). Many of the geriatric syndromes described in this report occur as side effects of prescription medications. Yet, at the same time, many older persons' easily treated conditions are not managed aggressively enough with the appropriate pharmacologic agents. This mismanagement of medications compromises independence and quality of life, and it increases the costs of health care. More studies of the fundamental pharmacodynamics of various medications in older individuals would forward clinical care in this area. Additionally, opportunity exists for excellent ground-breaking interdisciplinary investigation of medication use and effects that link basic clinical and behavioral science approaches. This might include gene delivery systems (cells carrying engineered genes), specific enzyme-blocking agents, and monoclonal antibodies. Urinary Incontinence Urinary incontinence, although it varies in intensity and in the degree to which its victims are disabled, is a highly prevalent, costly, morbid, and seriously neglected problem in elderly persons. The prevalence of urinary incontinence is approximately 30 percent in community-dwelling older persons (Diokno et al., 1986) and reaches 50 percent for those in nursing homes (Ouslander et al., 1982). Costs of incontinence are measured not only in terms of the financial burden of its management (e.g., linen changes; use of absorbent pads; and use of diapers, condoms, and catheters) and its clinical morbidity, but also in psychosocial terms. Our knowledge regarding the mechanisms underlying urinary incontinence and the appropriate approach to its control is rudimentary. There is a great need for

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Extending Life, Enhancing Life: A National Research Agenda on Aging clinical studies to determine the neuroanatomic and neurophysiologic basis of urinary incontinence and the efficacy and risk of treatment (e.g., drugs, surgery, training, and elimination of risk factors). Finally, there is an urgent need to develop new, effective, and safe treatments—preventive, ameliorative, or curative—for incontinence. Delirium Delirium, the development of acute confusional states, is a global disturbance of cognitive function accompanied by an alteration, and often fluctuation, in the level of attentiveness and, usually, consciousness. Delirium frequently is overlooked or misdiagnosed, and often mistaken for dementia. Approximately one-third of hospitalized elderly individuals develop an acute confusional state, markedly complicating their hospital course and dramatically increasing not only morbidity but also health care costs (Lipowski, 1989). Despite its high prevalence and tremendous morbidity and costs, little is known about the underlying mechanisms of or effective interventions for delirium. The second research priority involves studies of the interaction of age-dependent physiological changes and important diseases in old age. The scientific and medical community needs to evaluate the interaction of age-related physiologic changes with diseases that either occur predominantly in aged populations or present different symptoms, course, or sequelae when occurring in the aged. This area of research is largely interdisciplinary since a number of lifestyle and socioenvironmental factors have an important influence on the emergence of disease in aging populations. Research on the interaction of aging and disease processes provides a critical link to issues of functional capacity since each major disease category mentioned in this report imposes a large burden on the aging population; prevention of or more effective intervention into these disorders might well reduce the onset of disability. To effect the study of the interaction of aging in disease, research knowledge of biologic and physiologic processes from many levels must be integrated. Crucial to this effort is the appreciation that research gains in the areas of both normal and disease states act synergistically to increase our understanding of pathophysiologic mechanisms. This approach has been particularly well demonstrated

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Extending Life, Enhancing Life: A National Research Agenda on Aging in the use of molecular biological tools that delve into genetic regulatory processes that underlie the control of both normal and abnormal molecular and cellular processes. To gain an understanding of age-related pathophysiology, the medical and scientific community must exploit the most fundamental techniques of molecular and cell biology and apply them to the investigation of normal human aging. There is reason to be optimistic that a better-understood and better-mapped human genome, coupled with the application of now-standard techniques of reverse genetics, will allow the genetic contributions to many of these diseases to be defined specifically. This development, plus the extension to actual gene therapy of current techniques to introduce cells carrying engineered genes, may allow us to prevent, cure, or otherwise substantially modify many of these diseases. Cardiovascular Disease Cardiovascular disorders are a major target, for cardiac disease is the number one cause of death in persons over the age of 65 and cerebral vascular disease is the third most common cause of death in elderly persons (National Center for Health Statistics, 1989). Most of these disorders are due to atherosclerosis: excessive thickening and narrowing of coronary, cerebral, and peripheral arteries. Unfortunately, inadequate data address these problems because, to date, elderly persons have not been represented adequately in clinical studies of cardiovascular therapies. Thus, increased research on cardiovascular disorders among older persons is needed. Emphasis should be placed (1) on understanding the genetic as well as the environmental risk factors and the molecular basis of atherosclerosis, and (2) on developing standard and recombinant-based drug technologies as well as new approaches to prevent (in younger adults) and treat hypertension, lipid disorder, and the thrombotic complications of atherosclerosis. The role of nutrition, and the interaction of genetic and nutritional factors in the cause and prevention of these diseases, are important areas for future research. Dementia, Pseudodementia, and Psychiatric Disorders Recent studies have shown that dementia after age 75 reaches well over 40 percent; an overwhelming proportion of these patients have senile dementia of the Alzheimer's type (Hagnell et al., 1983; Sayetta, 1986). If dementia were cited on the death certificates of persons in whom it was a primary underlying disease, it would be the

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Extending Life, Enhancing Life: A National Research Agenda on Aging fourth or fifth leading cause of death in the United States (Weiler, 1987). Furthermore, in this country dementia now is the leading cause of institutionalization (Von Vostrand, 1979). Affective disorders are underreported in older persons even though they account for substantial disability in this age group (Finlayson and Martin, 1982). Although there are many outstanding research opportunities in this area, the greatest need is for studies linking basic and clinical approaches to the pathophysiology, cause, prevention, and treatment of Alzheimer 's disease and other dementias. Excellent opportunities are available for basic molecular and cell biologic studies to determine the mechanisms and causes of central nervous system cell death in the aged, particularly the role of growth factors in central nervous system changes associated with both normal aging and injury. These studies should include assessment of cellular and molecular markers and new approaches to imaging and neurotransmitter mapping of the nervous system. Such studies clearly overlap with the research areas emphasized in Chapter 2. In addition, clinical studies that focus on management strategies for demented older persons have major interrelations with social, behavioral, and health services research agendas. Musculoskeletal Disorders Musculoskeletal disorders rank second to circulatory system diseases as a cause of both disability and health care costs in the United States. These conditions rank second in frequency as a reason for visits to physicians and third in frequency of hospitalization. Osteoarthritis is the most prevalent joint condition after age 65 (National Center for Health Statistics, 1989), and ranks second (after cardiovascular disease) in producing severe disability in those over age 60. Osteoporosis is also extremely common; annually, over one million osteoporosis-related fractures occur in the United States (Resnick and Greenspan, 1989). Fractures of the vertebral bodies and the hip are the two most common types of fracture in elderly persons, and both cause significant morbidity. Of those suffering from hip fracture, 50 percent never walk again (Melton and Riggs, 1983). Resultant costs from these disorders total more than $65 billion annually. The application of restriction fragment-length polymorphism and other techniques of reverse genetics will help to provide the tools necessary to define the genetic basis of osteoarthritis and osteoporosis in many patients suffering from these common disorders. Such approaches should receive a high priority, particularly if current

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Extending Life, Enhancing Life: A National Research Agenda on Aging techniques of genetic engineering can be extended to gene replacement. Infectious Disease and Immunosenescence Infections, especially pneumonia and those of the urinary tract, are a major cause of disability and mortality in old persons. However, the exact extent of disability from infectious disorders in older people is largely unknown. Knowledge is incomplete about the prevention and treatment of infection in this population. Specific research opportunities include studies of the basic mechanisms of immune deficiency in older individuals, including changes at the cellular level involving T-cell subsets, natural killer cells, macrophages, and receptor-mediated responses. Vaccine development needs to take into account the special characteristics of the elderly population. Vaccines that can bypass the need for immune T cells and vaccines made with live attenuated organisms with antigen attached to a rigid backbone may be more effective in old people. These efforts should utilize new technologies such as DNA recombinant vaccines and genetically engineered attenuated viruses. The focus on immunosenescence is also directly related to the next research focus, cancer in older persons, since impaired immunity contributes to cancer development. Neoplasia Cancer and its related complications are the number two cause of death in persons over the age of 65 (National Center for Health Statistics, 1989); for elderly persons death due to cancer is the second leading cause of lost years of life. The basis for the age-associated frequency of and disability related to cancer is unknown. In addition, efforts at primary (e.g., prevent onset of disease), secondary (e.g., prevent onset of complications of disease), and tertiary (e.g., treat complications of disease) prevention of cancer have been limited almost entirely to the younger population. For example, little information exists on the efficacy of smoking cessation programs and the efficacy and toxicity of standard chemotherapeutic regimens for those 65 years or older. As with several of the other suggested areas of research identified in this report, there is a clear and substantial overlap between the clinical research related to neoplasia and the focus on aging and cell proliferation suggested in the basic biomedical component of this research agenda. Reverse genetics, recombinant DNA products, and delivery systems using gene trans-

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Extending Life, Enhancing Life: A National Research Agenda on Aging fer approaches should be particularly valuable in this area. Interactions between environmental (e.g., carcinogens and nutritional factors) and genetic factors in the cause and prevention of cancer warrant intensive study. Disorders of Metabolism and Homeostasis Strong epidemiologic evidence indicates that metabolic dysfunctions have significant impact on the pathogenesis of numerous disorders affecting the health of older individuals. Metabolic problems may precede the development of clinical manifestations of disease, accelerating the progression of atherosclerosis, hypertension, neuropathy, and musculoskeletal disease. Disorders of metabolism and homeostasis influence the onset and severity of most of the alterations described elsewhere in this report. The metabolic disorders considered in generating these recommendations include diabetes mellitus, altered muscle metabolism, altered bone mineral metabolism, and lipid disorders. Intensive studies should be undertaken to clarify the pathophysiology and genetic basis and to elucidate the long-term complications of these disorders in elderly individuals. Research on relationships among genetic, pathogenic, and nutritional factors will be of great value. ADDITIONAL RESEARCH OPPORTUNITIES Although the committee emphasizes the foregoing areas of research for priority consideration, other areas should not be neglected in the research agenda on aging. These additional opportunities include dental and oral problems in aging, especially the prevention and treatment of periodontal disease, cancer of the mouth, and orofacial pain; diagnosis and treatment of neurogenic dysphagia; investigation of hearing impairment, its prevention, and its treatment; study of conditions (particularly glaucoma, cataracts, and macular degeneration) contributing to loss of vision in the aged; and various skin conditions associated with aging (keratomas, skin cancer, and dry skin). While each of the foregoing research areas leads to detailed specific secondary research objectives, each area also represents the interface of several disciplines. Major opportunities in clinical geriatric research exist in interfaces between physician-scientists and colleagues from the social and behavioral sciences. Increasingly, productive interaction between basic and clinical scientists is resulting in research strategies and protocols that provide the opportunity for application of

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Extending Life, Enhancing Life: A National Research Agenda on Aging molecular biological and other basic science techniques to clinical problems and populations. RESOURCE RECOMMENDATIONS The ambitious, though appropriate and overdue, clinical research program recommended in this chapter can only be implemented effectively if two major resources become available. The first is funding to support the specific research projects that flow from the two major thematic areas in this chapter (described in greater detail in the Executive Summary and Recommendations for Funding). Additional funding is required to launch an effective research program in the major consensus areas identified as most deserving of support. There would be little delay in the development of excellent research proposals in these areas since the National Institute on Aging (NIA) and other federal agencies already have a substantial number of approved but unfunded research proposals with excellent priority scores. The additional research funds could be applied to such applications, thus raising the level of support from the current less than one in four (24 percent) to one in two. However, allocation of substantial funds to support research projects will not ensure the successful completion of the clinical research agenda. The second major necessary resource is professional talent. For example, a recent IOM report (IOM, 1987; Rowe et al., 1987) shows a critical need for the development of scientists with a commitment to and appropriate training for research in geriatrics. Both basic biomedical and more clinically oriented investigators are desperately needed in all disciplines related to clinical research in older persons. Two strategies are suggested to attract young health professionals and Ph.D. students into the fields of geriatrics and gerontology. First, increased funds are needed to establish the ongoing fellowship and postdoctoral programs that will be the life-blood of the next generation of clinical gerontologists. These funds would permit graduation of an additional 200 fellows and postdoctoral students per year, as well as provide support for 180 junior faculty and midlevel investigators who have recently moved into the fields of geriatrics and gerontology. A second strategy to develop a cadre of outstanding clinically oriented investigators in geriatrics and gerontology is the addition of at least 10 highly sophisticated Geriatric Research and Training Centers (Claude Pepper Centers) to the current three supported by the NIA. This strategy has been recommended in a separate report of the IOM that focuses on workforce needs in geriatrics. Subsequent

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Extending Life, Enhancing Life: A National Research Agenda on Aging to that report, enabling legislation has been drafted and adopted by Congress. These centers would be developed in the setting of currently well-established academic research and clinical programs on aging. A moderate amount of core support should be provided to these centers for continuity of key research personnel and ongoing efforts; however, such centers would be expected to compete for additional research funds on a continuing basis to ensure that their work remains current and is peer reviewed. The primary goal of these centers would be to produce substantial numbers of very well-trained, clinical-research-oriented investigators. To date, three centers have been funded. Ample expertise already exists at enough academic programs to warrant immediate funding of 10 additional centers, followed by funding of further centers over the next several years as the need is demonstrated. Finally, it is abundantly clear that the facilities and infrastructure available in the United States to support the research enterprise are seriously deficient. Accordingly, the committee recommends additional support for infrastructure and for construction of new research space and renovation of outdated space. CROSSCUTTING ISSUES Clinical research in geriatrics and gerontology requires an approach that engages many disciplines. Insights from molecular and cell biology provide a basic biomedical foundation for much clinical investigation, including newer therapies for Alzheimer's disease and the diagnosis of age-associated cancers such as carcinoma of the colon. Behavioral and social research and the insights offered by studies in health care delivery make possible clinical programs to study the responses of older people to illness, and to find better ways of intervening to reduce disability and morbidity among the aged. Of equal importance in clinical research are crosscutting issues that involve gender differences in response to illness or in the metabolic disposition of drugs as well as racial and ethnic variation in the way older individuals experience illness, both from a patient care perspective and from the vantage of exploring differences in physiological response to disease. An example of the influence of gender differences on outcome of disease is seen in the lower rates of morbidity and mortality in women who have hypertension than in men with hypertension. Racial differences also appear to influence prognosis in some diseases; higher death and complication rates occur in hypertensive black men than in white men. Another critical crosscutting issue is that of ethics in clinical

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Extending Life, Enhancing Life: A National Research Agenda on Aging research. Obtaining informed consent from cognitively impaired elders, using drugs with high risk to benefit ratios in geriatric populations, and resolving conflicts arising from confrontations between medical paternalism and the need for patient autonomy are all examples of the pervasiveness of this issue in clinical geriatric medicine and in geriatric and gerontological research. REFERENCES Branch, L. G., S. Katz, K. Kniedmann, and J. A. Papsidero. 1984. A prospective study of functional status among community elders. American Journal of Public Health 74: 266-268. Cummings, S. R., J. L. Kelsey, M. C. Nevitt, and K. J. O'Dowd. 1985. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiology Review 7: 178-208. Dawson, D., G. Hendershop, and J. Fulton. 1987. Aging in the Eighties: Functional Limitations of Individuals 65 and Over. Advance Data No. 133, National Center for Health Statistics. Washington, D.C.: U.S. Government Printing Office. Diokno, A. C., B. M. Brock, M. B. Brown, and A. R. Herzog. 1986. Prevalence of urinary incontinence and other urological symptoms in the non-institutionalized elderly. Journal of Urology 136: 1022-1025. Finlayson, R. E. and L. M. Martin. 1982. Recognition and management of depression in the elderly. Mayo Clinic Proceedings 57: 115-120. Grymonpre, R. E., P. A. Mitenko, D. S. Sitar, F. Y. Aoke, and P. R. Montgomery. 1988. Drug-associated hospital admissions in older medical patients. Journal of the American Geriatrics Society 36: 1094-1098. Hagnell, O., J. Lanke, B. Rorsman, R. Ohman, and L. Ojesjö. 1983. Current trends in the incidence of senile and multi-infarct dementia Archives of Psychiatry and Neurological Science 233: 423-428. Institute of Medicine. 1987. Academic geriatrics for the year 2000. Report of the Committee on Leadership for Academic Geriatric Medicine Journal of the American Geriatrics Society 35: 773-791. Institute of Medicine. 1989. Effectiveness Initiative: Setting Priorities for Clinical Conditions Washington, D.C.: National Academy Press. Institute of Medicine. 1990a. Effectiveness and Outcomes in Health Care. Washington, D.C.: National Academy Press. Institute of Medicine. 1990b. The Second 50 Years: Promoting Health and Preventing Disability. Washington, D.C.: National Academy Press. Ives, T. J., E. J. Bentz, and R. E. Gwyther. 1987. Drug-related admissions to a family medicine inpatient service. Archives of Internal Medicine 147: 1117-1120. Lipowski, Z. J. 1989. Delirium in the elderly patient. New England Journal of Medicine 320: 578-582. Melton, L. J., III and B. L. Riggs. 1983. The epidemiology of age-related fractures. In The Osteoporotic Syndrome, L. V. Avioli, ed. New York: Grune and Stratton. National Center for Health Statistics. 1985. National Health Interview Survey. Vital and Health Statistics, Series 10, No. 150. DHHS Pub. No. (PHS) 85-1578. Washington, D.C.: U.S. Government Printing Office. National Center for Health Statistics. 1989. Vital and Health Statistics Report,

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Extending Life, Enhancing Life: A National Research Agenda on Aging No. 173 and 37, No. 5, Supplement. Washington, D.C.: U.S. Government Printing Office. Nolan, L. and K. O'Malley. 1988. Prescribing for the elderly. Part 20. Prescribing patterns: Differences due to age. Journal of the American Geriatrics Society 36: 245-254. Ouslander, J. G., R. L. Kane, and I. B. Abrass. 1982. Urinary incontinence in elderly nursing home patients. Journal of the American Medical Association 248: 1194-1198. Resnick, N., and S. L. Greenspan. 1989. Senile osteoporosis reconsidered. Journal of the American Medical Association 261: 1025-1029. Rowe, J. W., E. Grossman, and E. Bond. 1987. Academic geriatrics for the year 2000: An Institute of Medicine report New England Journal of Medicine 316: 425-1428. Sayetta, R. B. 1986. Rates of senile dementia-Alzheimer's type in the Baltimore longitudinal study. Journal of Chronic Disease 39: 271-285. Von Vostrand, J. 1979. The National Nursing Home Survey: 1977 Summary for the United States, National Center for Health Statistics. Vital and Health Statistics, Series 13, No. 43. DHEW Pub. No. 43 (PHS) 79-1794. Washington, D.C.: U.S. Government Printing Office. Weiler, P. 1987. The public health impact of Alzheimer's disease. American Journal of Public Health 77: 1157-1158. Williams, T. F. 1988. Rehabilitation: Goals and Approaches in Older People. Pp. 136-143 in Geriatric Medicine, 2nd Ed., J. W. Rowe and R. W. Besdine, eds. Boston: Little, Brown. Williamson, J., and J. Chopin. 1980. Adverse reactions to prescribed drugs in the elderly: A multicenter investigation. Age and Ageing 9: 73-80.