[Aging and frailty--status of rights and legal responsibility].
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Effective fecundability declines with age and parity. Furthermore, women differ in their effective fecundability: some women have persistently low or high monthly chances of live-birth conception. Estimates are presented concerning the magnitude of these effects in a natural-fertility population: 406 Hutterite women in North America who had 3,206 births, largely in the 1940s and 1950s. The estimates are based on models that incorporate the effects of persistent heterogeneity and that use the full information provided by multiple-spell duration data. In addition, hazards rather than probabilities are modeled, piecewise linear hazard functions are used, and age and parity effects are decomposed systematically. These methods permit the development of more elaborate models of changing fecundability and of heterogeneity in postpartum amenorrhea.
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Geriatric Medicine is concerned chiefly with the care of frail elderly people, especially when they become ill. Physicians face special challenges in dealing with such patients, who tend to have multiple interacting medical and social problems, impaired function, altered pharmacokinetics and pharmacodynamics, atypical disease presentations and to be affected by polypharmacy. The joy of geriatrics is in systematically meeting each of these challenges, but the techniques that geriatricians use to do so must not be kept secret. More must be done to encourage all physicians to use these techniques in caring for frail elderly people who are ill.
Allium cepa L. root meristems were given two short caffeine treatments spaced by 15 hours, the time which roughly corresponds to the duration of one cell cycle. In this way two subsequent cytokineses were prevented, and multinucleate cells with their in complement distributed into two, three or four nuclei were formed. Though all nuclei started to replicate synchronously in these cells, some of them (fast nuclei) completed their replication earlier than others (slow nuclei). The present report shows that two successive checkpoints operate before prometaphase in these cells. The first one prevents the entry of the fast nuclei into prophase until the slow ones have completed their replication. The second checkpoint ensures the synchronous entry into prometaphase after all nuclei have reached and finished prophase. By treating the multinucleate cells with an inhibitor of DNA synthesis at that time when fast but not slow nuclei had finished their replication, it was observed that both checkpoint mechanisms became leaky with time. Under these conditions the fast nuclei entered prophase in the presence of nuclei which were prevented from finishing the replication of their DNA. Subsequently, even prometaphase was triggered after a prolonged prophase. Finally, as expected from the presence of mitotic stages in these cells, nuclei with incompletely replicated DNA endured premature chromosome condensation. The prematurely condensed chromosomes either remained in a prometaphase-like stage until reconstitution nuclei formed or they followed the progression of the fast nuclei into metaphase and anaphase leading to the appearance of acentric chromosomal segments which after reconstitution gave rise to aneuploid nuclei containing unstable and broken DNA.
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OBJECTIVES: To measure relative fitness and frailty in older people without specific frailty instruments and to relate that measurement to long-term health outcomes. DESIGN: Retrospective cohort studies. SETTING: Two population-based studies of people aged approximately 70 at baseline and followed up to 10 years (in the Canadian Study of Health and Aging (CSHA)) or 26 years in the Gothenburg H-70 cohort study. PARTICIPANTS: Nine hundred sixty-two men and 1,178 women. MEASUREMENTS: Deficit accumulation (the exposure) was counted using self-reported (CSHA) or clinically designated (H-70) symptoms, signs, diseases, and disabilities. Relative fitness and frailty were measured in relation to the degree of deficit accumulation evaluated in four quartiles, representing those most fit to those most frail. The items that made up the frailty index were selected randomly without replacement in 1,000 iterations. The outcomes were risks of death or residential long-term care. RESULTS: Worse frailty, however measured, was associated with worse survival; the Kaplan-Meier curves of random iterations of the frailty definition showed virtually no interquartile overlap for mortality. For any given level of frailty, men died younger than women. Worse frailty was also associated with a higher risk of institutionalization. CONCLUSION: Frailty appears to be a robust concept that is readily operationalized, with the risk of adverse outcomes being largely established by age 70.
The associations in mortality of adult adoptees and their biological or adoptive parents have been studied in order to separate genetic and environmental influences. The 1003 Danish adoptees born 1924-26 have previously been analysed in a Cox regression model, using dichotomised versions of the parents' lifetimes as covariates. This model will be referred to as the conditional Cox model, as it analyses lifetimes of adoptees conditional on parental lifetimes. Shared frailty models may be more satisfactory by using the entire observed lifetime of the parents. In a simulation study, sample size, distribution of lifetimes, truncation- and censoring patterns were chosen to illustrate aspects of the adoption dataset, and were generated from the conditional Cox model or a shared frailty model with gamma distributed frailties. First, efficiency was compared in the conditional Cox model and a shared frailty model, based on the conditional approach. For data with type 1 censoring the models showed no differences, whereas in data with random or no censoring, the models had different power in favour of the one from which data were generated. Secondly, estimation in the shared frailty model by a conditional approach or a two-stage copula approach was compared. Both approaches worked well, with no sign of dependence upon the truncation pattern, but some sign of bias depending on the censoring. For frailty parameters close to zero, we found bias when the estimation procedure used did not allow negative estimates. Based on this evaluation, we prefer to use frailty models allowing for negative frailty parameter estimates. The conclusions from earlier analyses of the adoption study were confirmed, though without greater precision than using the conditional Cox model. Analyses of associations between parental lifetimes are also presented.
Molecular epidemiological studies confirm a substantial contribution of individual genes to variability in susceptibility to disease and death for humans. To evaluate the contribution of all genes to susceptibility and to estimate individual survival characteristics, survival data on related individuals (eg twins or other relatives) are needed. Correlated gamma-frailty models of bivariate survival are used in a joint analysis of survival data on more than 31,000 pairs of Danish, Swedish and Finnish male and female twins using the maximum likelihood method. Additive decomposition of frailty into genetic and environmental components is used to estimate heritability in frailty. The estimate of the standard deviation of frailty from the pooled data is about 1.5. The hypothesis that variance in frailty and correlations of frailty for twins are similar in the data from all three countries is accepted. The estimate of narrow-sense heritability in frailty is about 0.5. The age trajectories of individual hazards are evaluated for all three populations of twins and both sexes. The results of our analysis confirm the presence of genetic influences on individual frailty and longevity. They also suggest that the mechanism of these genetic influences may be similar for the three Scandinavian countries. Furthermore, results indicate that the increase in individual hazard with age is more rapid than predicted by traditional demographic life tables.
Frailty is a state of reduced physiologic reserve associated with increased susceptibility to disability. Reduced physiologic capacity in neurologic control, mechanical performance, and energy metabolism are the major components of frailty. Although disease is an important cause of frailty, there is sufficient epidemiologic and experimental evidence to conclude that frailty is also due to the additive effects of low-grade physiologic loss resulting from a sedentary lifestyle and more rapid loss due to acute insults (illness, injuries, major life events) that result in periods of limited activity and bedrest. The pathogenesis of frailty involves a complicated interaction of factors that block recovery from rapid physiologic loss. To some extent, frailty is preventable. Approaches to prevention include (1) the periodic monitoring of key physiologic indicators of frailty, (2) the prevention of physiologic loss and acute and subacute episodes of physiologic loss, (3) the prediction of episodes of physiologic loss and the reduction of frailty prior to the loss, and (4) the removal of obstacles to recovery once physiologic loss has occurred.
In analysing a clinical trial with the logrank test, the hazards between the two groups are usually assumed to be proportional. Nevertheless, this hypothesis is no longer valid with unobserved covariates. As a consequence, there is a loss of power of the logrank test for testing the null hypothesis H(0) of no treatment effect. We propose a test suited for taking into account unobserved covariates. The proposed approach is based on a proportional hazard frailty model whereby the omitted covariates are considered as an unobserved frailty variable. The procedure is as follows. In a first step, the weighted logrank test optimal for testing H(0) against a general proportional hazard frailty model is obtained and its specialization for a gamma frailty variable is derived. In a second step, the proposed test is obtained by combining the maximin efficiency robustness principle and the gamma frailty distribution properties. Simulation studies investigate the power properties of the test for different frailty distributions. A breast cancer clinical trial is analysed as an example. The proposed test might be recommended rather than the logrank for practical situations in which one expects heterogeneity related to omitted covariates.
BACKGROUND: Selecting elderly persons who need geriatric interventions and making accurate treatment decisions are recurring challenges in geriatrics. Chronological age, although often used, does not seem to be the best selection criterion. Instead, the concept of frailty, which indicates several concurrent losses in resources, can be used. METHODS: The predictive values of chronological age and frailty were investigated in a large community sample of persons aged 65 years and older, randomly drawn from the register of six municipalities in the northern regions of the Netherlands (45% of the original addressees). The participants' generative capacity to sustain well-being (i.e., self-management abilities) was used as the main outcome measure. RESULTS: When using chronological age instead of frailty, both too many and too few persons were selected. Furthermore, frailty related more strongly (with beta values ranging from -.25 to -.39) to a decline in the participants' self-management abilities than did chronological age (with beta values ranging from -.06 to -.14). Chronological age added very little to the explained variances of all outcomes once frailty was included. CONCLUSIONS: Using frailty as the criterion to select older persons at risk for interventions may be better than selecting persons based only on their chronological age.
BACKGROUND: The effect of change in weight in later years on risk of osteoporotic fractures in uncertain. Prior studies have assessed the relationship between weight change and risk of hip fracture only and have not examined whether the association between weight loss and increased risk of hip fracture is because of voluntary or involuntary weight loss. OBJECTIVES: To determine the association between weight change in later years and the risk of fractures in elderly women and to assess the effect of weight loss intention on this relationship. METHODS: The association between weight change and fracture risk was assessed in 6754 ambulatory, non-black women aged 65 years or older enrolled in the Study of Osteoporotic Fractures who had measurements of weight performed at both the baseline and fourth examinations (mean, 5.7 years between examinations). These 6754 women were followed up for all incident nonspine fractures and frailty fractures (defined as fractures of the proximal femur, pelvis, and proximal humerus) occurring after the fourth examination (average follow-up, 19.5 months). All incident fractures were confirmed by radiographic report. RESULTS: During an average of 19.5 months after the fourth examination, 264 women (4%) had at least 1 nonspine fracture, including 83 women who suffered frailty fractures. After adjustment for age, women who lost weight between the baseline and fourth examinations had an increased risk of subsequent nonspine fracture (relative risk [RR] per 10% decrease in weight, 1.32; 95% confidence interval [CI], 1.11-1.55). This observed increase in the risk of nonspine fracture was entirely caused by an increase in the risk of frailty fracture (age-adjusted RR per 10% decrease in weight, 1.86; 95% CI, 1.42-2.43). Weight change was not significantly related to other types of nonspine fractures (age-adjusted RR per 10% decrease in weight, 1.09; 95% CI, 0.90-1.33). Further adjustment for cigarette smoking, physical activity, estrogen use, medical conditions, health status, body weight, femoral neck bone mass, and rate of change in calcaneal bone mass did not substantially alter the association between weight change and frailty fracture (multivariate RR per 10% decrease in weight 1.68; 95% CI, 1.17-2.41). Weight change was an even stronger predictor of risk of frailty fracture in those women who were not trying to lose weight (multivariate RR per 10% decrease in weight, 1.81; 95% CI, 1.26-2.61). CONCLUSIONS: Involuntary weight loss in later years substantially increases the risk of frailty fracture including hip fracture in elderly women. Weight change is not related to risk of other nonspine fractures in older women.
Frailty in older adults is increasingly a recognized syndrome of decline, sometimes subtle, in function and health that may be amenable to available approaches to care. Frailty manifests the following core clinical features: loss of strength, weight loss, low levels of activity, poor endurance or fatigue, and slowed performance. The presence of 3 or more of these features is associated with adverse outcomes including falls, new or worsened function impairment, hospitalization, and death. In this article, we use the case of Mrs K to describe the challenges of recognizing frailty in clinical practice, common problems and symptoms that frail older adults experience, and approaches to these issues that clinicians may incorporate into their practices. We discuss the importance of advance care planning, provider-patient communication, and appropriate palliative care and hospice referral for frail older adults. Frailty is associated with symptomatic long-term disease, decline in function, and abbreviated survival. Therefore, when frailty is severe, delivery of palliative care focused on relief of discomfort and enhancement of quality of life is highly appropriate. The application of multidisciplinary, team-based palliative approaches and of up-to-date geriatrics knowledge is beneficial for treating these patients because of the complexity of their coexisting social, psychological, and medical needs.
An approach towards analyzing survivorship data is proposed for the study of changes in stress resistance with age in the population of Drosophila melanogaster. This is based on the model of heterogeneous mortality (frailty model). Results of the data analysis show that observed populations of flies are heterogeneous and the accelerated selection, debilitative effect and changes in individual frailties are the aftermath of stress. These results also reveal that debilitative effect and accelerated selection are much better pronounced in survivals of flies that are stressed at an older age. Mild stress, when applied at both ages, produced a reduction in frailty variance. Stress of greater magnitude produced higher frailty variance in the young-treated flies. Among the old-treated insects, stress of longer duration led to a reduction of both the mean and the variance of frailty distribution. Population of young-treated flies became more heterogeneous, population of old-treated flies became less heterogeneous, and both populations became more robust in average after stress.
This article extends the previous work of Fung et al. (2004) investigating the ability of the time-scale log-linear regression model, proposed by Dominici et al. (2003), to detect mortality displacement (sometimes known as harvesting) in time-series data relating air pollution to excess mortality. We conducted a simulation study based on two different compartment models of the death process: pure frailty model and mixed frailty model. We assume that nonaccidental death only affects frail population in a pure frailty model and affects both frail people and other individuals in the mixed frailty model. With a pure frailty model and a moderate-size pollution effect, we identified a characteristic mortality displacement pattern in the different time-scale coefficients of log relative risk. However, once a covariate like temperature was introduced into the model, such a mortality displacement pattern disappeared. Furthermore, a false mortality displacement effect was present in the incorrectly specified model, when temperature was not taken into account. We believe that time-scale regression has limited value for detecting mortality displacement in time-series data.
BACKGROUND: Several studies in older people have found a U-shaped or J-shaped association of blood pressure with mortality. The increased mortality associated with the lowest levels of blood pressure in older people have been explained by concurrent illnesses and frailty, but previous studies used blood pressure measured on a single occasion. Such a casual value is different from the long-term average of blood pressure. We investigated the relation between the average level of 5-day consecutive home blood pressure and mortality in older people while adjusting for potential confounding factors including morbidity and frailty at baseline. METHODS: In 1992, 1186 community residents of a rural Japanese town, Kahoku, aged 65 or older, measured their blood pressure in their homes 20 times (four times per day, 5 consecutive days). The mean value of the 20 measurements was used to examine the association between home BP and subsequent 4-year mortality. A proportional hazards model was fitted while adjusting for activities of daily living impairment, medical history, antihypertensive medication, smoking, use of alcohol, and depression. RESULTS: A total of 134 persons died during the four-year follow-up period. There was no significant evidence that frailty is more prevalent in the lowest or highest systolic BP group than in intermediate groups. A U-shaped association between the average level of home systolic blood pressure and mortality was found in men while adjusting for potential confounding factors, including morbidity and frailty. We also showed the U-shaped curve of the association of systolic BP with all cause and noncardiovascular mortality in the whole population and the linear association of systolic BP with cardiovascular mortality. CONCLUSIONS: We showed a U-shaped association between the average level of systolic blood pressure measured at home and mortality in older men while adjusting for potential confounding factors including morbidity and frailty. Not only high home systolic BP, but also low home systolic BP, is an independent risk factor for mortality in older men. The mechanisms underlying the association between BP and mortality differ by levels of systolic BP. Cardiovascular deaths tended to be higher in the highest SBP group, and only noncardiovascular deaths were increased in the lowest SBP group. The latter finding suggests that low SBP may be not only an independent risk of mortality but also an indicator of a subclinical noncardiovascular comorbid condition.