Heather Allore

BACKGROUND: The questions patients are asked about their preferences with regard to life-sustaining treatment usually focus on specific interventions, but the outcomes of treatment and their likelihood affect patients' preferences. METHODS: We administered a questionnaire about treatment preferences to 226 persons who were 60 years of age or older and who had a limited life expectancy due to cancer, congestive heart failure, or chronic obstructive pulmonary disease. The study participants were asked whether they would want to receive a given treatment, first when the outcome was known with certainty and then with different likelihoods of an adverse outcome. The outcome without treatment was specified as death from the underlying disease. RESULTS: The burden of treatment (i.e., the length of the hospital stay, extent of testing, and invasiveness of interventions), the outcome, and the likelihood of the outcome all influenced treatment preferences. For a low-burden treatment with the restoration of current health, 98.7 percent of participants said they would choose to receive the treatment (rather than not receive it and die), but 11.2 percent of these participants would not choose the treatment if it had a high burden. If the outcome was survival but with severe functional impairment or cognitive impairment, 74.4 percent and 88.8 percent of these participants, respectively, would not choose treatment. The number of participants who said they would choose treatment declined as the likelihood of an adverse outcome increased, with fewer participants choosing treatment when the possible outcome was functional or cognitive impairment than when it was death. Preferences did not differ according to the primary diagnosis. CONCLUSIONS: Advance care planning should take into account patients' attitudes toward the burden of treatment, the possible outcomes, and their likelihood. The likelihood of adverse functional and cognitive outcomes of treatment requires explicit consideration.

BACKGROUND: Little is known about the natural course of frailty. We performed a prospective study to determine the transition rates between frailty states and to evaluate the effect of the preceding frailty state on subsequent frailty transitions. METHODS: We studied 754 community-living persons, aged 70 years or older, who were nondisabled in 4 essential activities of daily living. Frailty, assessed every 18 months for 54 months, was defined on the basis of weight loss, exhaustion, low physical activity, muscle weakness, and slow walking speed. Participants were classified as frail if they met 3 or more of these criteria, as prefrail if they met 1 or 2 of the criteria, and as nonfrail if they met none of the criteria. RESULTS: Of the 754 participants, 434 (57.6%) had at least 1 transition between any 2 of the 3 frailty states during 54 months. The rates were 36.8%, 21.5%, and 9.2% for 1, 2, and 3 transitions, respectively. During the 18-month intervals, transitions to states of greater frailty were more common (rates up to 43.3%) than transitions to states of lesser frailty (rates up to 23.0%), and the probability of transitioning from being frail to nonfrail was very low (rates, 0%-0.9%), even during an extended period. The likelihood of transitioning between frailty states was highly dependent on one's preceding frailty state. CONCLUSIONS: Frailty among older persons is a dynamic process, characterized by frequent transitions between frailty states over time. Our findings suggest ample opportunity for the prevention and remediation of frailty.

BACKGROUND: Despite the importance of functional status to older persons and their families, little is known about the course of disability at the end of life. METHODS: We evaluated data on 383 decedents from a longitudinal study involving 754 community-dwelling older persons. None of the subjects had disability in essential activities of daily living at the beginning of the study, and the level of disability was ascertained during monthly interviews for more than 10 years. Information on the conditions leading to death was obtained from death certificates and comprehensive assessments that were completed at 18-month intervals after the baseline assessment. RESULTS: In the last year of life, five distinct trajectories were identified, from no disability to the most severe disability: 65 subjects had no disability (17.0%), 76 had catastrophic disability (19.8%), 67 had accelerated disability (17.5%), 91 had progressive disability (23.8%), and 84 had persistently severe disability (21.9%). The most common condition leading to death was frailty (in 107 subjects [27.9%]), followed by organ failure (in 82 subjects [21.4%]), cancer (in 74 subjects [19.3%]), other causes (in 57 subjects [14.9%]), advanced dementia (in 53 subjects [13.8%]), and sudden death (in 10 subjects [2.6%]). When the distribution of the disability trajectories was evaluated according to the conditions leading to death, a predominant trajectory was observed only for subjects who died from advanced dementia (67.9% of these subjects had a trajectory of persistently severe disability) and sudden death (50.0% of these subjects had no disability). For the four other conditions leading to death, no more than 34% of the subjects had any of the disability trajectories. The distribution of disability trajectories was particularly heterogeneous among the subjects with organ failure (from 12.2 to 32.9% of the subjects followed a specific trajectory) and frailty (from 14.0 to 27.1% of the subjects followed a specific trajectory). CONCLUSIONS: In most of the decedents, the course of disability in the last year of life did not follow a predictable pattern based on the condition leading to death.

BACKGROUND: Functional decline in physically frail, elderly persons is associated with substantial morbidity. It is uncertain whether such functional decline can be prevented. METHODS: We randomly assigned 188 persons 75 years of age or older who were physically frail and living at home to undergo a six-month, home-based intervention program that included physical therapy and that focused primarily on improving underlying impairments in physical abilities, including balance, muscle strength, ability to transfer from one position to another, and mobility, or to undergo an educational program (as a control). The primary outcome was the change between base line and 3, 7, and 12 months in the score on a disability scale based on eight activities of daily living: walking, bathing, upper- and lower-body dressing, transferring from a chair, using the toilet, eating, and grooming. Scores on the scale ranged from 0 to 16, with higher scores indicating more severe disability. RESULTS: Participants in the intervention group had less functional decline over time, according to their disability scores, than participants in the control group. The disability scores in the intervention and control groups were 2.3 and 2.8, respectively, at base line; 2.0 and 3.6 at 7 months (P=0.008 for the comparison between the groups in the change from base line); and 2.7 and 4.2 at 12 months (P=0.02). The benefit of the intervention was observed among participants with moderate frailty but not those with severe frailty. The frequency of admission to a nursing home did not differ significantly between the intervention group and the control group (14 percent and 19 percent, respectively; P=0.37). CONCLUSIONS: A home-based program targeting underlying impairments in physical abilities can reduce the progression of functional decline among physically frail, elderly persons who live at home.

We evaluated TLR function in primary human dendritic cells (DCs) from 104 young (age 21-30 y) and older (> or =65 y) individuals. We used multicolor flow cytometry and intracellular cytokine staining of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) and found substantial decreases in older compared with young individuals in TNF-alpha, IL-6, and/or IL-12 (p40) production in mDCs and in TNF-alpha and IFN-alpha production in pDCs in response to TLR1/2, TLR2/6, TLR3, TLR5, and TLR8 engagement in mDCs and TLR7 and TLR9 in pDCs. These differences were highly significant after adjustment for heterogeneity between young and older groups (e.g., gender, race, body mass index, number of comorbid medical conditions) using mixed-effect statistical modeling. Studies of surface and intracellular expression of TLR proteins and of TLR gene expression in purified mDCs and pDCs revealed potential contributions for both transcriptional and posttranscriptional mechanisms in these age-associated effects. Moreover, intracellular cytokine production in the absence of TLR ligand stimulation was elevated in cells from older compared with young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in DCs; notably, defects in cytokine production were strongly associated with poor Ab response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response.