Dissertations / Theses on the topic 'Fraility'

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From the moment of birth, the human body plays host to a rich diversity of microbes. Body sites such as the skin, the gut and the mouth support communities of microorganisms (collectively known as the microbiome) that are both numerous and diverse. As our understanding of the microbiome advances, it is evident that these microbial populations participate in a multitude of symbiotic associations with us. The disruption of these associations can lead to a range of diseases beyond mere pathogenesis as microbial nutrition, signaling, and immune defense break down. It is known that changes in microbial composition occur as the human host ages and that diet and living conditions influence the microbiome of older individuals. However, the link between the microbiome and frailty is as yet mostly unexplored. Although the microbiome is likely to influence health factors that contribute to frailty, further work is needed to determine whether overall microbial signatures of frailty exist and, if so, what the diagnostic and therapeutic utility of these signatures might be.

Background: Frailty is a geriatric syndrome of impaired resistance to stressors which has been implicated in the pathogenesis and prognosis of cardiovascular disease. Our objective was to systematically explore the role of frailty in patients with cardiovascular disease, and determine the incremental prognostic value of frailty (as measured by gait speed) for predicting adverse events in elderly patients with cardiovascular disease undergoing cardiac surgery.
Methods: After performing a systematic review of the literature, a multi-center prospective cohort of elderly patients undergoing cardiac surgery was assembled. Patients were evaluated with a questionnaire and timed 5-meter gait speed test, with frailty defined as a time taken to walk 5 meters ≥6 seconds. The composite endpoint was postoperative mortality or major morbidity.
Results: Based on nine previous studies, the prevalence of frailty was found to be 2-4 fold greater in patients with cardiovascular disease. Two studies suggested that frailty was a risk factor for mortality, although none specifically addressed frailty as a risk factor for adverse events in response to a cardiac surgery. Our cohort consisted of 131 patients undergoing cardiac surgery with a mean age of 75.8±4.4 years and 34% females. Thirty patients experienced the composite endpoint and frailty (slow gait speed) was an independent predictor (odds ratio 3.05, 95% confidence interval 1.23, 7.54). Addition of frailty to traditional risk assessment models resulted in notable improvements in model performance.
Conclusion: The prevalence of frailty is increased in patients with cardiovascular disease. Frailty, as measured by 5-meter gait speed, is a simple and effective test to identify a subset of vulnerable elders who have an incrementally higher risk of adverse events after cardiac surgery. Further studies are needed to validate the optimal cut-off for slow gait speed.
Objectif: La fragilité est un syndrome gériatrique qui signifie une diminution de la résistance au stress physiologique impliquée dans la pathogénèse et le pronostique des maladies cardiovasculaires. Notre objectif était de revoir de façon systématique le rôle de la fragilité dans les maladies cardiovasculaires et de déterminer la valeur incrémentielle de la fragilité (telle que mesurée par la vitesse de marche) pour prédire la mortalité et la morbidité chez les sujets âgés atteints de maladie cardiovasculaire subissant une chirurgie cardiaque.
Méthodes: Après avoir revu la littérature systématiquement, une cohorte multicentrique prospective de sujets âgés subissant une chirurgie cardiaque a été assemblée. Les sujets ont été évalués à l'aide d'un questionnaire et du test de vitesse de marche sur 5 mètres avec la fragilité définie comme étant un temps ≥6 secondes pour marcher 5 mètres. L'issue primaire étant un composé de la mortalité postopératoire et des complications majeures.
Résultats: Neuf études précédentes ont démontré que la prévalence de la fragilité était 2-4 fois plus élevée chez les patients avec une maladie cardiovasculaire. Deux études ont démontré que la fragilité était un facteur de risque pour la mortalité, cependant, aucune étude n'avait précisément adressé la fragilité comme facteur de risque après une chirurgie cardiaque. Notre cohorte incluait 131 sujets subissant une chirurgie cardiaque dont l'âge moyen était de 75.8±4.4 ans et 34% étaient des femmes. Trente patients ont développé l'issue primaire et la fragilité (faible vitesse de marche) était un prédicteur indépendant (odds ratio 3.05, 95% confidence interval 1.23, 7.54). L'inclusion de la fragilité au modèle de prédiction traditionnel a eu comme résultat une nette amélioration des performances du modèle.
Conclusion: La prévalence de fragilité est plus élevée chez les sujets âgés atteints de maladie cardiovasculaire. La vitesse de marche est un test simple et efficace pour identifier une sous-population de patients vulnérables ayant un risque plus élevé de mortalité et morbidité après une chirurgie cardiaque. D'autres études sont nécessaires pour valider la valeur seuil optimale de vitesse de marche.

Introduction For some people, ageing is associated with the experience of increased co-morbidity, functional impairment, poor resilience and heightened vulnerability to external stressors, resulting in reduced lifespan as well as health-span. This frailty phenomenon poses challenges to health care systems in the form of increased patient complexity and resource utilisation. The acute care setting, characterised by time-pressure and high patient turn-over, is under strain and struggles to recognise and subsequently reliably intervene, to prevent, reverse or halt the decline of this vulnerable cohort. Methods This mixed-methods study probes existing evidence and ‘real-world’ processes with a systematic review of frailty assessments developed or validated in the acute care setting and a survey of contemporaneous clinical practice in London Acute Medical Units. Content validation and understanding of contextual factors for ideal frailty assessment in acute care is explored using Delphi consensus and Focus Group methodology respectively. The resultant model is developed on existing retrospective national Hospital Episode Statistics data, and prospectively tested on observational data in a local Acute Medical Unit setting. Results Existing frailty scores are preponderantly biophysical in nature, and have poor predictive power for adverse outcomes in the acute care setting. In clinical practice, single-dimension assessment tools predominate. Frailty syndromes and previous high resource utilisation in the form of a simple, clinically relevant tool useful to the multidisciplinary team gain consensus as optimal assessment for the setting. Retrospective testing of the frailty model displays moderate predictive powers for adverse events (inpatient mortality, emergency readmission and institutionalisation) and prospective testing provides concurrent (Frailty Index, Age, Co-Morbidity) and comparative predictive validity (Frailty Index, Co-Morbidity, admission National Early Warning Score) with existing risk stratification models in this setting. Conclusions A risk prediction model based on frailty syndromes and previous high resource utilisation is a valid, feasible and useful for the acute care setting.

This study explores women's narratives from within and outside of the frail/non-frail binary of public home care services. It focuses on the stories that are commonly told about older women's needs and bodies and the regulatory potential of these accounts. Considering power, language, diversity and change, this study focuses on the way that twelve diverse older women at various social locations (e.g., ability, age, culture, ethnicity, 'race', sexual orientation, and socio-economic status) understand, make meaning, and negotiate the concept of frailty in relation to their everyday lives. The sample includes six women considered 'frail' in relation to service (i.e., according to clinical judgement & home care eligibility guidelines), as well as women not considered 'frail' (i.e., non-service recipients).
The twelve older women's storied responses, illustrations and experiences challenge the various stories that are told about them. Their complex accounts both reflect and reject dominant notions, blur the boundary between the frail and non-frail classifications, expose frailty as contextual, temporal and relative, as well as illustrate the connections between medical and social needs. Their individual accounts highlight how they make meaning of their life events in relation to their diverse experiences and identities, as well as how these identities and interpretations are key to their negotiations of life and needs. The variations between the imposed stories about frailty and women's self-perceptions highlight the research, policy and practice relevance of a narrative approach focused on in-depth local accounts, raise questions about the current priorities within home care services, as well as the future of social work practice with older women considered frail.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.
Title from electronic title page (viewed Mar. 26, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Nursing." Discipline: Nursing; Department/School: Nursing.

This thesis focuses on two fundamental topics, specifically in medical statistics: the modelling of correlated survival datasets and the variable selection of the significant covariates and random effects. In particular, two types of survival data are considered: the classical survival datasets, where subjects are likely to experience only one type of event and the competing risks datasets, where subjects are likely to experience one of several types of event. In Chapter 2, among other topics, we highlight the importance of adding frailty terms on the proposed models in order to account for the association between the survival time and characteristics of subjects/groups. The main novelty of this thesis is to simultaneously select fixed effects and frailty terms through the proposed statistical models for each survival dataset. Chapter 3 covers the analysis of the classical survival dataset through the proposed Cox Proportional Hazard (PH) model. Utilizing a Cox PH frailty model, may increase the dimension of variable components and estimation of the unknown coefficients becomes very challenging. The method proposed for the analysis of classical survival datasets involves simultaneous variable selection on both fixed effects and frailty terms through penalty functions. The benefit of penalty functions is that they identify the non-significant parameters and set them to have a zero effect in the model. Hence, the idea is to 'doubly-penalize' the partial likelihood of the Cox PH frailty model; one penalty for each term. Estimation and selection implemented through Newton-Raphson algorithms, whereas closed iterative forms for the estimation and selection of fixed effects and prediction of frailty terms were obtained. For the selection of frailty terms, penalties imposed on their variances since frailties are random effects. Based on the same idea, we further extend the simultaneous variable selection in the competing risks datasets in Chapter 4, using extended cause-specific frailty models. Two different scenarios are considered for frailty terms; in the first case we consider that frailty terms vary among different types of events (similar to the fixed effects) whereas in the second case we consider shared frailties over all the types of events. Moreover, our 'individual penalization' approach allows for one covariate to be significant for some types of events, in contrast to the frequently used 'group-penalization' where a covariate is entirely removed when it is not significant over all the events. For both proposed methods, simulation studies were conduced and showed that the proposed procedure followed for each analysis works well in simultaneously selecting and estimating significant fixed effects and frailty terms. The proposed methods are also applied to real datasets analysis; Kidney catheter infections, Diabetes Type 2 and Breast Cancer datasets. Association of the survival times and unmeasured characteristics of the subjects was studied as well as a variable selection for fixed effects and frailties implemented successfully.

The risk of becoming frail increases with age. One million Canadians are frail, placing them at greater risk for disease and disability. Frailty is easily observed yet difficult to define. No gold-standard definition exists, but most clinicians support frailty as a medical syndrome characterized as a state of mild to severe vulnerability. Sex-differences complicate frailty; females experience this syndrome sooner yet paradoxically live longer than males. Exercise might be an effective therapy for frailty; however, which components are most effective is yet unknown. This study hypothesized: 1) More individuals in an exercise (EX) intervention would reverse frailty, versus a control (CON) group; and 2) Changes in frailty would be related to improvement in functional task performance and measures of strength. Female participants 65-81 years of age, classified as pre-frail as determined by a score of; 1-2 on the Cardiovascular Health Study-Frailty Phenotype (FP) tool or 4-6 on the Clinical Frailty Scale (CFS) or a normal gait speed (GS) between 1.0-1.5 m/sec. The EX group (n = 9) completed a 12-week exercise intervention (3 days/week, 60 min/session). Exercise included multi-component training (MCT), inclusive of aerobic, flexibility, resistance and balance training, with a focus on the latter two modalities. The CON group (n = 11) maintained their normal daily routine. According to the FP, CFS and GS, 25, 37.5 and 62.5% more EX group participants reversed frailty status than the CON group, respectively. There was a statistically significant improvement in GS (0.24 m/sec), grip strength (3.9 kg) and sit-to-stand (STS) time (5.0 sec) within the EX group from baseline to follow-up. STS was faster in the CON group at baseline but no significant between-group difference existed at follow-up. There was also a statistically significant improvement in knee extension isometric torque (7.4 Nm) and isotonic velocity (37.5 º/sec) within the EX group from baseline to follow-up. Elbow flexion isotonic velocity was faster (40.8 º/sec) in the EX group at follow-up but no significant between-group difference existed at baseline. A MCT intervention that utilizes progressive resistance and balance exercise may be safe and effective at reversing frailty in pre-frail females.
Graduate Studies, College of (Okanagan)
Graduate

Frailty can be broadly defined as the vulnerable health status that occurs in older adults. With the ageing population understanding frailty is becoming an increasingly important issue. While no consensus exists on the exact definition of frailty, two models have become prominent in geriatric research. These are the frailty phenotype, a model that measures frailty according to the syndromic aggregation of 5 physical criteria and the frailty index (FI), a broad index of age related health deficits. While recent years have seen a substantial increase in research into frailty, there remains a relative paucity of data from European studies and studies in men. Of the many mechanisms suggested to contribute to frailty there has been particular interest in the role of declining levels of anabolic hormones, partly because replacement of these hormones represents a potential strategy for managing this condition. The broad aim of this thesis was to explore the condition of frailty and its relationship to anabolic hormones, particularly testosterone (T) in ageing European Men. This project involved analysis of data from 2 studies: The European Male Ageing Study (EMAS), a longitudinal cohort study of 3369 men from 8 European centres and a trial of T treatment in 262 men with low testosterone and symptoms of frailty. A set of phenotypic frailty criteria were developed for use in the EMAS, using this model the prevalence of frailty was 2.6%. This increased with age from 0.1% in men aged 40-49 up to 6.7% in men aged 70-79. This model was compared against an FI, the correlation between the two models was moderate, r=0.41, and both models were related to incident falling at 2 year follow up; Ordinal OR (95% CI), 3.15 (1.75 to 5.66) for the frailty phenotype and 5.28 (3.35 to 8.32) for the FI in adjusted analyses. In the hormone analyses frailty was related to lower free T according to both models, Ordinal OR (95% CI); 1.19 (1.02 to 1.39) for the phenotype and β-coefficient (95% CI); 0.006 (0.003 to 0.009) for the FI (FI values range from 0-0.7). Free T was particularly related to the sarcopenia criteria OR (95% CI); 1.40 (1.09 to 1.80). Frailty was also related to LH, FSH and SHBG. Deficiency in multiple anabolic hormones was related to frailty, in adjusted analyses each additional deficiency was associated with an RRR (95% CI); 1.71 (1.38 to 2.13) increased risk of phenotypic frailty and a β-coefficient (95% CI); 0.016 (0.012 to 0.02) increase in FI score. The trial analyses focussed on a 6 month post treatment follow up phase. It was found that gains in lean mass and muscle strength were not maintained at 6 months post treatment. The adjusted difference between groups at 6 months post treatment for knee extensor strength was 4.0 (-3.9 to 11.9) Nm compared to 8.1 (-0.2 to 16.5) Nm at the end of treatment, similarly the difference in lean mass declined from 1.2 (0.8 to 1.7) kg at end of treatment to 0.3 (-0.1 to 0.8) kg at 6 months post treatment. In summary, the frailty phenotype was adapted and validated for use in the EMAS study. Analyses using this model and the trial follow up analyses are supportive of an influence of T on lean body mass in ageing men. The other hormone relationships seen suggest frailty may be broadly related to changes in the endocrine system in ageing men. The lack of sustained benefit from T treatment combined with the relationships with multiple endocrine markers suggests more complex management strategies may be required for this condition.

Background: Frailty, a state indicating vulnerability to poor health outcomes, is a common condition in later life. However, research and intervention progress is hindered by the current lack of a consensus frailty definition and poor understanding of relationships between frailty and depression. Objectives: The goal of this research is to understand the interrelationships between frailty and depression among older adults. Specifically, this project aims 1) to examine the construct overlap between depression and three definitions of frailty (biological syndrome, medical burdens, and functional domains), 2) to determine the degree to which this overlap varies by age, gender, race/ethnicity and other individual characteristics, 3) to evaluate how the association between frailty and depression influences prediction of adverse health outcomes. Methods: This project uses data from the 2004-2012 Health and Retirement Study (HRS), an ongoing, nationally-representative cohort study of adults over the age of 55. Frailty was indexed by three alternative conceptual models: 1) biological syndrome, 2) cumulative medical burdens, and 3) functional domains. Depressive symptoms were indexed by the 8-item Center for Epidemiologic Studies Depression (CESD) scale. Latent class analysis and confirmatory factor analysis were used to assess the construct overlap between depressive symptoms and frailty. Latent growth curve modeling were used to evaluate associations between frailty and depression, and to estimate their joint influence on two adverse health outcomes: nursing home admission and falls. Results: The measurement overlap of frailty and depression was high using a categorical latent variable approach. Approximately 73% of individuals with severe depressive symptoms, and 85% of individuals with primarily somatic depressive symptoms, were categorized as concurrently frail. When modeled as continuous latent factors, each of the three frailty latent factors was significantly correlated with depression: biological syndrome (ρ = .67, p <.01); functional domains (ρ = .70, p <.01); and medical burdens (ρ = .62, p <.01). Higher latent frailty trajectories were associated with higher likelihood of experiencing nursing home admission and serious falls. This association with adverse health outcomes was attenuated after adjustment for depression as a time-varying covariate. Conclusions: Findings suggest that frailty and frailty trajectories are potentially important indicators of vulnerability to adverse health outcomes. Future investigations of frailty syndrome, however it is operationalized, should account for its substantial association with depression in order to develop more accurate measurement and effective treatment.

The prevalence of screen-detected premalignancies is too large for it to be feasible that all can progress to carcinoma at the same average rate, unless that rate is very low indeed. There are likely to be frailties in the rates of progression. Failure to take heterogeneity into account will lead to biased estimates and could result in inappropriate screening policy. Approaches to investigation of heterogeneity in the propensity for screen-detected disease to progress comprise the main objectives of this project. We used Markov models with constant hazard rates in sequence throughout the process of disease natural history within subjects, with heterogeneity terms by means of (1) frailty models for continuous heterogeneity, (2) mover-stayer models for dichotomous heterogeneity (in both cases for progression between sequential homogeneous models), and (3) latent variables and states to estimate the parameters of progressive disease natural history in the presence of unobserved factors. Approaches had to be developed to address problems of tractability and estimation. For example, in the presence of frailty, solution of the Kolmogorov equations by routine matrix algebra is no longer possible. Heterogeneous models, both discrete and continuous, were found to be tractable, and estimation was possible for a variety of designs and data structures. Such models illuminated various issues in real screening applications. Quantifying heterogeneity of potential progress of disease is of potential importance to the screening process. There are trade-offs between model complexity, identifiability and data availability, but there are clear examples, such as that of cervical screening, where a heterogeneous model improves model fit and gives more realistic estimates than a homogenous.

Frailty has emerged as an increasingly important concept in the understanding and care of the elderly. Despite this, no consensus has been established in the frailty literature regarding a theoretical framework, operational definition, or measurement strategies. The International Classification of Function, Disability and Health (ICF) provides an attractive framework to exemplify and consolidate the diverse literature on frailty. The ICF is a classification system developed by the World Health Organization (WHO) to provide a common language and universal conceptual framework to describe health and health-related states. The overall objective of this proof-of-concept study is to determine the extent to which the identification and measurement of frailty is compatible with the ICF framework. A total of 156 words were identified by health professionals from two articles that were shown to be influential in the frailty literature. These words were subsequently linked to the ICF following a standardized mapping protocol. The 202 codes that were identified comprised a comprehensive set of functional status indicators (FSIs), or characteristics that describe the clinical entity of frailty, in a uniform and standardized manner. A total of 21 of these FSIs were identified from items on both the Francophone and Anglophone versions of the Système de Mesure d'Autonomie Functionelle (SMAF), a measure specific to quantifying function in the elderly.
La fragilité a émergé comme un concept de plus en plus important dans la compréhension et les soins des personnes âgées. En dépit de ceci, aucun consensus n'a été établi dans la littérature concernant un cadre théorique, une définition opérationnelle, ou des stratégies de mesure. La classification internationale de la fonction, de l'incapacité et de la santé, (CIF), fournit un cadre attrayant pour illustrer et consolider la littérature diverse sur la fragilité. La CIF est un système de classification développé par l'organisation mondiale de la santé (OMS) pour fournir un langage commun et un cadre conceptuel universel pour décrire la santé et les conditions de santé. L'objectif global de cette étude de preuve-de-concept est de déterminer jusqu'à quel point d'identification et de mesure de la fragilité sont compatibles avec le cadre de la CIF. Un total de 156 mots a été identifié par des professionnels de la santé à partir de deux articles qui se sont avérés influents dans la littérature. Par la suite, ces mots ont été liés à la CIF selon un protocole standardisé de recoupement. Les 202 codes qui ont été identifiés comportent un ensemble complet d'indicateurs d'états fonctionnels (IEFs), ou des caractéristiques qui décrivent l'entité clinique de la fragilité, d'une façon uniforme et standardisée. Un total de 21 de ces IEFs a été identifié à partir des questions des versions françaises et anglaises du Système de Mesure d'Autonomie Fonctionnelle (SMAF), une mesure spécifique pour quantifier la fonction chez les personnes âgées.

This research focuses on two theories: (i) competing risks and (ii) random eect (frailty) models. The theory of competing risks provides a structure for inference in problems where cases are subject to several types of failure. Random eects in competing risk models consist of two underlying distributions: the conditional distribution of the response variables, given the random eect, depending on the explanatory variables each with a failure type specic random eect; and the distribution of the random eect. In this situation, the distribution of interest is the unconditional distribution of the response variable, which may or may not have a tractable form. The parametric competing risk model, in which it is assumed that the failure times are coming from a known distribution, is widely used such as Weibull, Gamma and other distributions. The Gamma distribution has been widely used as a frailty distribution, perhaps due to its simplicity since it has a closed form expression of the unconditional hazard function. However, it is unrealistic to believe that a few parametric models are suitable for all types of failure time. This research focuses on a distribution free of the multivariate frailty models. Another approach used to overcome this problem is using nite mixture of parametric frailty especially those who have a closed form of unconditional survival function. In addition, the advantages and disadvantages of a parametric competing risk models with multivariate parametric and/or non-parametric frailty (correlated random eects) are investigated. In this research, four main models are proposed: rst, an application of a new computation and analysis of a multivariate frailty with competing risk model using Cholesky decomposition of the Lognormal frailty. Second, a correlated Inverse Gaussian frailty in the presence of competing risks model. Third, a non-parametric multivariate frailty with parametric competing risk model is proposed. Finally, a simulation study of nite mixture of Inverse Gaussian frailty showed the ability of this model to t dierent frailty distribution. One main issue in multivariate analysis is the time it needs to t the model. The proposed non-parametric model showed a signicant time decrease in estimating the model parameters (about 80% less time compared the Log-Normal frailty with nested loops). A real data of recurrence of breast cancer is used as the applications of these models.

In recent years, the transplant community has explored and adopted tools for quantifying clinical insight into illness severity and frailty. This dissertation work explores the interplay between objective and subjective assessments of physical health status and the implications for liver transplant candidate and recipient outcomes. The first aim characterizes national epidemiologic trends and the impact of Centers for Medicare and Medicaid quality improvement policies on likelihood of waitlist removal based on the patient being too frail to benefit from liver transplant (“too sick to transplant”). This aim includes more than a decade (2002–2012) of comprehensive national transplant waitlist data (Scientific Registry of Transplant Recipients (SRTR)). The second aim will assess and define objective parameters of liver transplant patient frailty by measuring decline in lean core muscle mass (“sarcopenia”) using abdominal CT scans collected retrospectively at a single U.S. transplant center between 2006 and 2015. The relationship between these objective sarcopenia measures and subjective functional status assessed using the Karnofsky Functional Performance (KPS) scale are described and quantified. The third aim quantifies the extent to which poor functional status (KPS) pre-transplant is associated with worse post-transplant survival and includes national data on liver transplantations conducted between 2005 and 2014 (SRTR). The results of this dissertation will help providers in the assessment of frailty and subsequent risk of adverse outcomes and has implications for strategic clinical management in anticipation of surgery. This research will also to serve to inform national policy on the design of transplant center performance measures.

In recent years, the transplant community has explored and adopted tools for quantifying clinical insight into illness severity and frailty. This dissertation work explores the interplay between objective and subjective assessments of physical health status and the implications for liver transplant candidate and recipient outcomes. The first aim characterizes national epidemiologic trends and the impact of Centers for Medicare and Medicaid quality improvement policies on likelihood of waitlist removal based on the patient being too frail to benefit from liver transplant (“too sick to transplant”). This aim includes more than a decade (2002–2012) of comprehensive national transplant waitlist data (Scientific Registry of Transplant Recipients (SRTR)). The second aim will assess and define objective parameters of liver transplant patient frailty by measuring decline in lean core muscle mass (“sarcopenia”) using abdominal CT scans collected retrospectively at a single U.S. transplant center between 2006 and 2015. The relationship between these objective sarcopenia measures and subjective functional status assessed using the Karnofsky Functional Performance (KPS) scale are described and quantified. The third aim quantifies the extent to which poor functional status (KPS) pre-transplant is associated with worse post-transplant survival and includes national data on liver transplantations conducted between 2005 and 2014 (SRTR). The results of this dissertation will help providers in the assessment of frailty and subsequent risk of adverse outcomes and has implications for strategic clinical management in anticipation of surgery. This research will also to serve to inform national policy on the design of transplant center performance measures.

When analyzing data in a survival setting, whether of people or objects, one of the assumptions made is that the population is homogeneous. This is not true in reality and certain adjustments can be made in the model to account for heterogeneity. Frailty is one method of dealing with some of this heterogeneity. It is not possible to measure frailty directly and hence it can be very difficult to determine which frailty model is appropriate for the data in interest. This thesis investigates three model selection methods in their effectiveness at determining which frailty distribution best describes a given set of data. The model selection methods used are the Bayes factor, neural networks, and classification trees. Results favored classification trees. Very poor results were observed with neural networks.

Frailty, the increased vulnerability of an individual to stressors, and sarcopenia, the loss of muscle mass with age, share many of the same clinical outcomes, associations and suggested pathophysiology. The pathophysiology of both conditions is incompletely characterised but it is postulated the immune system is central to development and propagation. 40 healthy young, 40 healthy older, and 37 frail older adults were recruited to three groups. A further 73 healthy young adults were recruited for ultrasound assessment of muscle. Ultrasound was reviewed as a diagnostic technique in the identification of sarcopenia using a simple scanning protocol to produce the bilateral anterior thigh thickness (BATT). The BATT was measured in a reference population, 113 in total, and proposed criteria for the identification of low muscle mass in older adults was based on this reference population. Neutrophils exhibit a frailty related decline in migratory accuracy towards chemoattractants; this was both independent of age and associated with physical and cognitive parameters of frailty. Incubation of neutrophils from frail older adults with PI3kinase inhibitors class 1A \(\delta\) and class lB y restored migratory accuracy and this presents a novel therapeutic target for management of frailty.

Background: Advances in HIV management have resulted in life expectancy gains and consequent ageing in people living with HIV (PLWH). Frailty represents a state of vulnerability to stressor events and is associated with adverse outcomes. Frailty has been demonstrated in PLWH at earlier ages and in higher prevalence than HIV-negative cohorts. A comprehensive evaluation of frailty and frailty correlates is lacking in a UK based HIV cohort. Aims: To establish frailty prevalence for a cohort of older adults with HIV in Sussex, and describe associations between frailty and sarcopenia and potential biological, psychosocial and cognitive predictors. Methods: 253 participants aged ≥50 (median 59.6) were recruited between October 2014-October 2015. Frailty was defined by modified Fried frailty phenotype including five criteria: exhaustion, low activity, weight loss, weak grip and slow walking speed. Presence of ≥3 denoted frailty, 1-2 pre-frailty and 0 robust. Associations with frailty were evaluated from demographic, clinical, psychosocial, neurocognitive and functional parameters. A subgroup of 108 underwent DXA scanning to assess for the presence of sarcopenia. Results: 48/253 met frailty criteria, giving a prevalence of 19% (95% CI 14.6- 24.3). A further 111/253 (43.9%) were prefrail and 94/253 (37.1%) robust. Frailty was associated with increasing age, number of comorbidities and worsening mood symptoms, but not HIV factors. Additional correlates with frailty included financial insecurity, smoking, number of non-antiretroviral medications, chronic pain, low physical activity, and elevated IL-6. In the DXA subgroup, low muscle mass was common at 50% with 20% meeting criteria for sarcopenia, which was associated with increased odds of frailty. Negative psychosocial resources and poorer cognitive performance were associated with frailty, with positive psychological traits potentially buffering against higher frailty states. Conclusion: Frailty is common and occurs prematurely in older adults with HIV. Frailty was associated with predictors across biological, psychological and social parameters, suggesting a need to shift emphasis away from a purely biomedical approach to frailty in PLWH.

Concepts of mental health and normality cannot be understood apart from cultural norms and values. The most significant of cultural constructions that shape our view of madness is gender. Madness has been perceived for centuries metaphorically and symbolically as a feminine illness and continues to be gendered into the twenty-first century. Works of art and literature and psychiatric medicine influence each other as well as our understanding and perception of mental illness. Throughout history, images of mental illness in women send the message that women are weak, dangerous, and require containment. What are the cultural links between femininity and insanity, and how are they represented? Through the lenses of disciplines such as theatre criticism, feminist theory, and psychiatry, this thesis examines the history of madness as a gendered concept and its depictions in art and literature. Additionally, it will explore the representation of female madness in contemporary dramatic literature as compared to the medical model used during the era in which it was written as well as the social and cultural conditions and expectations of the period. The three plays under consideration are: Long Day’s Journey Into Night, written in 1941 by Eugene O’Neill; Fefu and Her Friends, written in 1977 by Maria Irene Fornés; and Next to Normal, produced on Broadway in its current form in 2009 and written and scored by Brian Yorkey and Tom Kitts. None of these plays tell a tidy story with a straightforward ending. In none do treatment facilities offer refuge or health professionals offer answers. Struggling characters resort to drug abuse, fall prey to internalization, or leave treatment all together, having been subjected to enough victimization. The relationship between patient and physician is depicted to be, at best, ambivalent. The themes in these plays illuminate women’s mental illness as an extensive problem with many contributing factors, and the origins of which are quite complex.

Background: This thesis explores the concept of frailty, as a latent vulnerability in older people, with the aim of refining its measurement by generating a new measure of frailty - the British Frailty Index (FI). This index was developed and validated in a cohort of community-dwelling older women, the British Women's Heart and Health Study (BWHHS), in 23 towns in Britain. Findings were replicated in another large Medical Research Council (MRC) Assessment of Older People study Methods: A systematic literature review examined the evolution of the concept and definitions of frailty. A meta-analysis on the prognostic value of current frailty measures confirmed extensive heterogeneity in the prediction of all-cause mortality despite consideration of age, sex, type of measure and duration of follow up. A 'General Specific' model of frailty was derived from factor analysis in the BWHHS population and replicated in the MRC cohort. Construct, external criterion and predictive validity of the British FI were assessed and its performance compared to another widely used index - the Canadian Frailty Index - with single indicators of frailty. Results: Frailty was explained by seven factors; physical ability, cardiovascular and respiratory disease and symptoms, visual impairments, other comorbidities, psychological problems and physiological measures. Associations with frailty included increased age, female sex, smoking, living alone, not living in own home, poor social contact and low socioeconomic position. Frailty was an independent predictor of all-cause mortality in both cohorts and predicted hospitalization and institutionalization in the MRC study, performing better than the Canadian Index. Conclusion: This thesis provides better understanding of the multi-dimensional domains of frailty in older people. The British FI demonstrates validity in relation to adverse outcomes, provides a more reliable measurement tool and its application offers further opportunities for the prevention, detection and treatment of frailty at a clinical level.

Heart failure is a progressive condition that affects over 5.7 million Americans and costs associated with heart failure account for 2-3 % of the national health care budget. The high rates of morbidity and mortality along with increased costs from readmissions associated with advanced heart failure have led to the exploration of advanced treatments such as left ventricular assist devices (LVADs). LVADS have demonstrated morbidity and mortality benefit but cost remains extensive with costs per quality-adjusted years > $400,000. With this in mind, it is important to identify those who are most likely to benefit from an LVAD to avoid unfavorable outcomes and cost. Although general guidelines and criteria for patient eligibility have been established, choosing patients for LVAD implantation remains challenging. A new focus on patient selection involves the presence of frailty. While frailty has been studied in the elderly population and in patients undergoing cardiac surgery, frailty in patients undergoing left ventricular assist device (LVAD) remains controversial. The purpose of this dissertation was to examine measures of frailty in patients undergoing LVAD implantation. The specific aims of this dissertation were to: (1) identify a feasible frailty measure in adults with end-stage heart failure who underwent LVAD implantation by testing the hypothesis that frailty would predict 30 day rehospitalization rates using Fried’s criteria, Short Physical Performance Battery test, handgrip strength, serum albumin and six minute walk test (2) Determine whether frailty measures improve 3 months post LVAD implantation (3) compare sensitivity of these three measures to change in frailty. Surgical approaches, including heart transplantation and LVAD implantation, for patients with end-stage heart failure was discussed in this dissertation. Data from two subsets of participants who underwent LVADS at the University of Kentucky between 2014 and 2017 were included in the analysis for this dissertation. In the first study, we found that none of the measures are good predictors of frailty in patients with advanced heart failure who undergo LVAD implantation. Handgrip was the only marker of frailty that predicted 30 day readmission but the relationship was a negative association. In the second study, six-minute walk and low serum albumin levels reflect short-term improvement in frailty. These simple measures may be used to determine those patients who are responsive to LVAD implantation. The findings of these studies filled some gaps in our understanding of markers of frailty in patients undergoing LVADs. We gained a better understanding of which markers of frailty are likely to improve in most people after LVAD implantation and thus frailty should not preclude candidate selection for an LVAD. Subsequently, more research is needed to investigate these markers and outcomes.

A síndrome da fragilidade, definida como a redução da reserva energética e da resistência aos estressores, associada à indicação tardia de alguns procedimentos cirúrgicos, resulta em maior ocorrência de situações de risco para os pacientes cardiopatas, com maior predisposição para o desenvolvimento de complicações pós-operatórias, que estão relacionadas a um aumento nos casos de readmissão hospitalar e tempo prolongado de internação. Com o objetivo de melhorar o manejo pós-operatório e aperfeiçoar nossa avaliação da gravidade, prevenção e estratificação de risco, a fisioterapia pré-operatória utiliza testes funcionais que traduzem a real condição física e pulmonar do paciente, permitindo a identificação de fatores potencialmente de risco. Como forma de avaliar a prevalência de fragilidade na população candidata a cirurgia cardíaca, a associação dos testes funcionais com fragilidade e a morbidade e mortalidade peri e pósoperatória, avaliamos os candidatos à cirurgia cardíaca de acordo com os cinco critérios de propostos por Fried: perda de peso não intencional, sinais de depressão, redução da força de preensão palmar, baixo nível de atividade física e redução da velocidade da marcha, além da capacidade pulmonar (manovacuometria, ventilometria e peak flow), da tolerância ao esforço (TC6) e função cognitiva (MEEM). Após a cirurgia foram coletadas informações com relação ao procedimento cirúrgico e recuperação pós-operatória e então os indivíduos foram divididos em dois grupos: frágeis e não frágeis e subdivididos de acordo com a faixa etária em idosos e não idosos. Foram avaliados 100 indivíduos, sendo 59 valvopatas e 41 coronariopatas; 13% foram considerados não-frágeis, 70% pré-frágeis e 17% frágeis; a pressão inspiratória máxima foi significativamente menor nos indivíduos frágeis (52±21 contra 75±33 nos não-frágeis; p=0,044), assim como a força de preensão palmar (31±11 contra 22±8; p=0,007); 11 pacientes evoluíram com óbito após o procedimento, sendo 7,2% dos não frágeis contra 29,4% dos indivíduos frágeis (p=0,019). A partir dos resultados encontrados podemos concluir que a prevalência de fragilidade nos pacientes candidatos a cirurgia cardíaca foi alta, mesmo entre os indivíduos não considerados idosos e que além disso, os indivíduos frágeis apresentaram menor força de preensão palmar, menor capacidade vital e menores pressões inspiratórias e expiratórias que as observadas em pacientes não-frágeis, bem como maior mortalidade hospitalar.
Frailty syndrome, defined as the reduction of energy reserve and resistance to stressors, associated with late indication of some surgical procedures, results in a higher occurrence of risk situations for the patients with heart disease, with a greater predisposition to the development of postoperative complications, which are related to an increase in cases of hospital readmission and high length of stay. In order to improve postoperative management and our assessment of severity, prevention and risk stratification, preoperative physiotherapy uses functional tests that translate the patient\'s actual physical and pulmonary condition, allowing the identification of potentially risk factors. As a way of evaluating the prevalence of frailty in population for cardiac surgery, the association of functional tests with frailty, and peri and postoperative morbidity and mortality, we evaluated the candidates for cardiac surgery according to five criteria proposed by Fried: loss of weight, depression, low handgrip strength, low level of physical activity and reduction of walking speed, as well as lung capacity (manovacuometry, ventilometry and peak flow), effort tolerance (6MWT) and cognitive function (MMSE). After surgery, information was collected regarding the surgical procedure and postoperative recovery and then, subjects were divided into two groups: fragile and nonfragile and subdivided according to the age group in the elderly and not elderly. We evaluated 100 individuals, being 59 valvopaths and 41 coronary disease; 13% were considered nonfragile, 70% pre-fragile and 17% fragile; the maximum inspiratory pressure was significantly lower in the fragile individuals (52 ± 21 vs 75 ± 33 in non-fragile, p = 0.044), as well as the handgrip strength (31 ± 11 vs. 22 ± 8, p = 0.007); 11 patients died after the procedure (7.2% non-fragile versus 29.4% fragile individuals; p = 0.019). From the results found, we can conclude that the prevalence of frailty in cardiac surgery patients was high, even among individuals not considered elderly, and, in addition, fragile individuals had lower handgrip strength, lower vital capacity and lower inspiratory pressures and expiratory rates than those observed in non-fragile patients, as well as higher in-hospital mortality.

L’Esclerosi Lateral Amiotròfica (ELA) és una malaltia neurodegenerativa de la motoneurona. Totes les neurones del sistema motor es veuen afectades pel flux degeneratiu en aquesta malaltia des de l’escorça motora primària fins a la junta neuromuscular. Al 1993, la descoberta de mutacions en el gen SOD1 va obrir nous horitzons experimentals amb la creació dels primers rosegadors transgènics per aquesta malaltia. Des d’aquell moment i fins a l’actualitat la mutació més estudiada en l’ELA ha estat la SOD1-G93A a tot el món. Els models transgènics per aquesta mutació de la SOD1 han revelat mecanismes essencials de la neurodegeneració en aquesta malaltia incloent l’excitotoxicitat, la disfunció proteica i la degeneració axosinàptica entre altres. En aquest treball hem explorat els canvis moleculars que tenen lloc als terminals-C, uns terminals molt especialitzats en les α-moto neurones, dels rosegadors transgènics SOD1-G93A. A més, també hem focalitzat la nostra atenció a la relació patològica que s’estableix en l’ELA familiar (ELAF) entre la mutació SOD1-G93A i les mitocòndries de les motoneurones. En relació als terminals C en moto neurones durant la ELAF, hem trobat canvis associats a l’aparició dels símptomes com ara expressió incrementada del factor neurotròfic Neuregulina-1 localitzat també per primer cop a la cisterna subsinàptica dels terminals C aposats a les α-moto neurones. La Neuregulina-1 en aquestes estructures de reticle endoplasmàtic va ser observada a dins de vesícules extracel·lulars (VEs), suggerint que l’anàlisi de la Neuregulina-1 en VEs durant ELA és especialment prometedor com a biomarcador potencial en aquesta malaltia. Així nosaltres hem desenvolupat també un nou mètode per tal d’aïllar VEs, donat que aquest és un pas essencial previ a l’estudi de les proteïnes associades amb aquestes estructures. El nostre mètode aplicat a la purificació de VEs en teixits complexos fou capaç de facilitar la identificació de la Neuregulina-1 en VEs provinents de teixits clínics i fluids biològics. En relació a les implicacions de la mitocòndria en la ELA, hem trobat que la mutació SOD1-G93A estabilitza la proteïna PINK1 a la mitocòndria seguidament activant el factor nuclear NFκB en neurones. La interacció seqüencial entre la SOD1 mutant i NFκB crea una clara disfunció en la capacitat proteolítica del proteosoma, el qual promou coagregació de la SOD1 mutant i el PINK1 en aquestes cèl·lules. Aquests resultats afegeixen un substancial coneixement mecanístic sobre els rols de la mitocòndria en els events neurodegeneratius clàssics de l’ELA, com ara en l’agregació de proteïnes disfuncionals en moto neurones. Seguint el nostre estudi de l’afectació mitocondrial en la ELA, hem creat i caracteritzat un nou model de Drosophila que expressa la mutació humana SOD1-G93A exclusivament en fibres musculars toràciques sota el promotor 24B. Aquest model de Drosophila transgènica recapitula amb èxit el fenotip mitocondrial prèviament observat de l’ELA presentant importants avantatges sobretot en l’elecció de nous compostos terapèutics. En definitiva, els resultats generats en aquesta tesi proporcionen evidència experimental, extensa comprensió molecular i insinuen nous horitzons terapèutics sobre els mecanismes moleculars i els events neurodegeneratius associats a la disfunció sinàptica i mitocondrial en l’ELAF.
La Esclerosis Lateral Amiotrófica (ELA) es una enfermedad neurodegenerativa de la motoneurona. Todas las motoneuronas se ven afectadas desde la corteza motora primaria hasta la unión neuromuscular. En 1993 la descubierta de mutaciones en el gen SOD1 abrió nuevos límites experimentales con la creación de los primeros roedores transgénicos para esta enfermedad. Desde ese momento y hasta la actualidad, la mutación más estudiada en la ELA ha sido la mutación SOD1-G93A. Los modelos transgénicos de esta mutación han revelado mecanismos esenciales de la neurodegeneración en la ELA, incluyendo la excitotoxicidad, la disfunción proteica y la degeneración axosináptica entre otras. En este trabajo hemos explorado los cambios moleculares que tienen lugar en los terminales C, unos terminales altamente especializados de las α-motoneuronas, en un modelo murino de ELA con la mutación SOD1-G93A. Además, también hemos focalizado nuestra atención sobre la relación patológica que se establece en la ELA familiar (ELAF) entre la mutación SOD1-G93A y las mitocondrias. En relación a los terminales C durante la ELAF, hemos encontrado cambios asociados con la aparición de síntomas, como por ejemplo el incremento de la expresión del factor neurotrófico Neuregulina-1, localizado por primera vez en la cisterna subsináptica de los terminales C. La Neuregulina-1 en esas estructuras de retículo endoplasmático fue observada dentro de vesículas extracelulares (VEs), sugiriendo que el análisis de la Neuregulina-1 dentro de VEs en la ELA resulta especialmente prometedor como biomarcador potencial para esta enfermedad. Así, nosotros hemos desarrollado también un nuevo método para purificar VEs, dado que este es un paso esencial previo al estudio de las proteínas asociadas con estas estructuras. Nuestro método aplicado a la purificación de VEs de tejidos complejos fue capaz de facilitar la identificación de la Neuregulina en VEs provenientes de tejidos clínicos y fluidos biológicos. En relación a las implicaciones de la mitocondria en la ELA, hemos encontrado que la mutación SOD1-G93A estabiliza la proteína PINK1 en las mitocondrias activando el factor nuclear NFκB en neuronas. La interacción secuencial entre la SOD1 mutante y el NFκB crea una clara disfunción sobre la capacidad proteolítica del proteosoma, la cual a su vez promueve co-agregación de la SOD1 mutante y PINK1 en estas células. Estos resultados suman un sustancial conocimiento mecanístico sobre los roles de la mitocondria en eventos degenerativos clásicos de la ELA, como es la agregación de proteínas disfuncionales en motoneuronas. Siguiendo nuestro estudio de la afectación mitocondrial en la ELA, hemos creado y caracterizado un nuevo modelo de Drosophila que expresa la mutación humana SOD1-G93A en fibras musculares torácicas bajo el promotor 24B. Este modelo de Drosophila transgénica recapitula con éxito en fenotipo mitocondrial característico de la ELA presentando importantes ventajas para la elección de nuevos compuestos terapéuticos. En definitiva, los resultados generados en esta tesis proporcionan evidencia experimental, extensa comprensión molecular y insinúan nuevos horizontes terapéuticos acerca de los mecanismos moleculares y eventos neurodegenerativos asociados con la disfunción sináptica y la disfunción mitocondrial en la ELAF.
Amyotrophic Lateral Sclerosis (ALS) is an orphan age-associated neurodegenerative disease. All motoneurones in ALS are affected by degenerative flow from the primary motor cortex to the neuromuscular junction. In 1993, mutations of the gene SOD1 opened new research avenues allowing for the generation of familial ALS experimental models in rodents. Since then, the FALS mutation SOD1-G93A has been extensively studied worldwide in ALS to date. Transgenic models for this SOD1 mutation have revealed essential mechanisms of neurodegeneration including excitotoxicity, proteinopathy and axosynaptic degeneration among others. In this dissertation, we explored the molecular changes that occur in C-terminals, a very specialised synapse type from α-motoneurones of SOD1-G93A rodents. Also, we focused on the pathological relationship between the FALS mutant SOD1-G93A and mitochondria in motoneurones. With regard to C-terminals in FALS motoneurones, we found changes that were symptomatically associated with the up-regulated expression of the neurotrophic factor Neuregulin-1 located for the first time in the subsurface system of C-boutons juxtaposed to α-motoneurones. Furthermore, Neuregulin-1 in these endoplasmic reticulum structures was observed inside extracellular vesicles, suggesting that analysis of Neuregulin-1 from extracellular vesicles in ALS holds promise as a potential reliable biomarker for that neurodegenerative disease. We therefore have developed a new method for isolation of extracellular vesicles, as this remains as an essential step for the study of molecules associated with these structures. Our method applied to purify extracellular vesicles from complex biological tissues was able to facilitate the identification of Neuregulin-1 in extracellular vessicles from clinical tissues and biological fluids. Regarding implications of mitochondria in ALS, we have found that the FALS mutant hSOD1-G93A stabilises PINK1 in mitochondria and subsequently activates NFκB in neuronal cells. Sequential interaction between hSOD1 and NFκB impairs the proteosome proteolitic function promoting co-aggregation of SOD1 and PINK1 in these cells. These results add substantial mechanistic insight on the roles of mitochondria in classical ALS-associated neurodegenerative events, including aggregation of dysfuntional proteins in motoneurones. Following our study of mitochondria affectation in ALS, we have created and characterised a novel Drosophila model that expresses human SOD1-G93A in thoracic muscles under the genetic muscular promoter 24B. Flies expressing human SOD1-G93A in thoracic muscles successfully recapitulate FALS mitochondrial phenotype with several advantages in front of the current available rodent models for this FALS mutation. Taken together, the results generated in this thesis provide experimental evidence, further molecular comprehension and promise novel therapeutic approaches to the molecular mechanisms and neurodegenerative events associated with synaptic frailty and mitochondrial disfunction in FALS.

The post-2007 global financial crisis, characterised by huge firm losses, especially in the USA and Europe, initiated a new strand of literature, where default models are adjusted for unobserved risk factors, including measurement errors, missing firm specific and macroeconomic variables. These new models assume that default correlations are not only driven by observable firm-specific and macroeconomic factors, but also by unobserved risk factors. This thesis present three empirical essays. The first essay estimates and predicts the within-sector failure rate and dependence of firms on the London Stock Exchange. The study offers an additive lognormal frailty model that accounts for both unobserved factors and regime changes. The analysis reveals that during distressed market periods the sector-based failure rates and dependencies tend to be high. The second essay proposes a novel approach based on a bias-corrected estimator to investigate the impact of informative firm censoring and unobserved factors on hazard rates of US firms. The approach uses inverse probability of censoring weighted scheme that explicitly accounts for firm specific factors, economic cycles, industry-level dependence and market activities induced by unobservable factors. The analysis shows that during distressed market periods the effect of informative censoring averagely increases the hazards rates, and varies across industries. The third essay employs a mixed effects Cox model to estimate the failure dependence caused by firms’ exposure to country-based and group-level unobserved factors within the Eurozone. The empirical results show that a higher failure dependence among firms in groups of countries with similar economic and financial conditions than countries with different conditions. Overall, the thesis contributes to the empirical literature on firm default in the broad area of corporate finance by offering a different approach of capturing default dependence and its variations during unfavourable market conditions and adjusting for the effects of non-default firm exit on active firms.

Community case management services provide targeted care to patients with long term health conditions (LTCs) and complex needs, at high risk of adverse events such as emergency hospital admissions. However, there is no standardised evidence informed programme for providing such care, including for patient monitoring. The complexity of older patients, those most likely to have multiple LTCs, and who often present with frailty and atypical symptoms, enhance the difficulty of on-going monitoring and targeting of care. There is an established relationship between ageing and LTCs, frailty and muscle strength, and function and service use, suggesting that muscle strength may be a useful aid to monitoring. Whilst muscle strength is a known indicator for future health, it is not known whether monitoring it is feasible or useful as a short term indicator in older people, especially those at high risk of adverse events. Patients are initially identified for case management by predictive modelling and/or clinical judgement, but little is known about the patients who go on to receive such care. The feasibility and usefulness of routine measures of muscle strength to help clinicians provide timely interventions were investigated alongside case management patients’ health, functional and physical status. An initial pilot study in healthy older adults (n=21) investigated four portable measures of strength, grip strength, sniff nasal inspiratory pressure (SNIP), peak inspiratory flow (PIF) and peak expiratory flow (PEF), and confirmed, via the collection of repeated measures at two time points one week apart, the reliability and acceptability of all but SNIP. A follow on feasibility study explored the acceptability and stability of the three successfully piloted measures in case management patients (n=8) and clinicians (n=5) via researcher administered questionnaire, with the reliability and stability of the measures assessed using a variety of statistical tests including intra-class correlation coefficients and Bland-Altman plots, on data collected over a maximum 7 week period. Concurrently measures of physical and functional ability and health were conducted. A third study analysed routine primary and secondary care case management patient data (n=101), allowing the development of a health and demographic profile of patients, including an assessment of frailty. The pilot and feasibility studies confirmed the reliability and acceptability of three portable measures of strength, PIF, PEF and grip strength. The high level of muscle strength stability observed in patients over the short-medium term, despite adverse events, suggested that whilst monitoring muscle strength may be feasible it would not be useful over this time period. Analysis of routine primary and secondary care data, identified case management patients as predominately female, with age skewed towards the older old and experiencing high levels of deprivation. Multiple LTCs were commonly recorded, and a wide variety of conditions noted. Health service use varied greatly, with few patients recording frequent usage. A frailty index suggested that frailty was common, and highlighted the potential for the development of a useful frailty index using routine data to improve the targeting of case management services towards those who are most at risk.

Background: Frailty has an impact on outcomes in the acute care and in the community setting but there is minimal research that examines frailty in the geriatric rehabilitation setting. Purpose: The purpose of this thesis was to answer the question “What is the association between frailty status and rehabilitation outcomes among older adults?” Methods: A systematic review using the Cochrane Handbook’s guidelines and adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was completed. Four databases were searched as well as grey literature. Screening, extraction, and quality assessments were completed by two reviewers. Data synthesis was completed through vote counting. Results: Twelve studies met the inclusion criteria from which data were extracted. There is a negative association between frailty and discharge functional status, functional change, discharge to home, and a positive association between frailty and length of stay. Conclusion: Further research is needed on this topic to replicate these findings through meta-analyses. Frailty needs to be addressed in the geriatric rehabilitation setting to improve the functional status of frail patients and reduce extended stays in rehabilitation and decrease discharges to a new place of residence.

Frailty in older adults is characterised as a vulnerable state, which predicts a range of health outcomes (e.g., injurious falls, institutionalisation, and mortality). The physiological and practical outcomes of frailty are recognised, but the psychosocial processes are largely unexplored so they were the focus the thesis. The overall aim of the thesis was to advance the understanding of frailty in older adults and its relationship with ageing perceptions. Three studies were conducted to achieve this aim. The first piece of work was a systematic review that investigated the association between older adults’ perceptions of ageing, broadly defined, and their health and functioning. The review showed that negative ageing perceptions were associated with poor health and functioning across a variety of health domains relevant to understanding frailty including: self-rated health; comorbidities; disability; memory; quality of life; mortality. However, conclusions from the review were limited by the quality and cross-sectional nature of the studies. Consequently, the second piece of work analysed data from a large longitudinal sample to test the relationship between older adults’ ageing perceptions and frailty explicitly. Older adults with more negative perceptions of ageing were more likely to be frail after adjusting for age, sex, depression symptoms, and socioeconomic status. However, ageing perceptions were found to be a weak predictor of frailty six years later. To investigate the mechanisms of the relationship between ageing perceptions and frailty, a qualitative exploration of older adults’ understanding of frailty and their beliefs concerning its progression and consequences was conducted as the third piece of work. Twenty-nine participants participated in semi-structured interviews, which were analysed using a Grounded Theory approach. An understanding of frailty as a negative identity and the strategies by which self-identification “as frail” occurs and is resisted were developed. Participants believed that the consequences of self-identifying as frail were poor health and functioning, disengagement from physical and social activities, depressive thoughts, negative affect, stigmatisation, and discrimination. Most participants actively resisted the identity, and they used a variety of resistance strategies. Collectively, the findings from this project indicate that older adults’ ageing perceptions are related to the development and progression of frailty. Ageing perceptions are associated with older adults’ health and how they view themselves – whether they identify as frail and the different strategies they may use to resist identification. Whilst additional research is needed, the results of this research suggest an influential psychosocial aspect to frailty. Accordingly, a new model of frailty and its relationship with older adults’ ageing perceptions is offered. The model has implications for the way frailty is identified, supported and treated.

Background: Numerous multidimensional assessment tools have been developed to measure frailty; however, the clinical feasibility of these tools is limited. We previously developed and validated an upper-extremity function (UEF) assessment method that incorporates wearable motion sensors. The purpose of the current study was to: 1) cross-sectionally validate the UEF method in a larger sample in comparison with the Fried index; 2) develop a UEF frailty index to predict frailty categories including non-frail, pre-frail, and frail based on UEF parameters and demographic information, using the Fried index as the gold standard; and 3) develop a UEF continuous score (points scores for each UEF parameter and a total frailty score) based on UEF parameters and demographic information, using the Fried index as the gold standard. Methods: We performed a cross-sectional validation and index development study within the Banner Medical Center, Tucson, and Banner Sun Health Research Institute, Sun City, Arizona. Community-dwelling and outpatient older adults (>= 60 years; n = 352; 132 non-frail, 175 pre-frail, and 45 frail based on Fried criteria) were recruited. For the UEF test, each participant performed a 20-s elbow flexion, within which they repetitively and rapidly flexed and extended their dominant elbow. Using elbow motion outcomes two UEF indexes were developed (categorical and score). The Fried index was measured as the gold standard. Results: For the categorical index, speed of elbow flexion, elbow range of motion, elbow moment, number of flexion, speed variability and reduction within 20 s, as well as body mass index (BMI) were included as the pre-frailty/frailty predictor parameters. Results from 10-fold cross-validation showed receiver operator characteristic area under the curve of 0.77 +/- 0.07 and 0.80 +/- 0.12 for predicting Fried pre-frailty and frailty, respectively. UEF score (0.1 to 1.0) was developed using similar UEF parameters. Conclusions: We present an objective, sensor-based frailty assessment tool based on physical frailty features including slowness, weakness, exhaustion (muscle fatigue), and flexibility of upper-extremity movements. Within the current study, the method was validated cross-sectionally using the Fried index as the gold standard and the UEF categorical index and UEF frailty score were developed for research purposes and potentially for future clinical use.

La recherche sur le traitement des cancers a évolué durant les dernières années principalement dans une direction: la médecine personnalisée. Idéalement, le choix du traitement doit être basé sur les caractéristiques dupatient et de sa tumeur. Cet objectif nécessite des développements biostatistiques, pour pouvoir évaluer lesmodèles pronostiques, et in fine proposer le meilleur. Dans une première partie, nous considérons le problèmede l’évaluation d’un score pronostique dans le cadre de données multicentriques. Nous étendons deux mesuresde concordance aux données groupées analysées par un modèle à fragilité partagée. Les deux niveaux inter etintra-groupe sont étudiés, et l’impact du nombre et de la taille des groupes sur les performances des mesuresest analysé. Dans une deuxième partie, nous proposons d’améliorer la prédiction du risque de décès en tenantcompte des rechutes précédemment observées. Pour cela nous développons une prédiction issue d’un modèleconjoint pour un événement récurrent et un événement terminal. Les prédictions individuelles proposées sontdynamiques, dans le sens où le temps et la fenêtre de prédiction peuvent varier, afin de pouvoir mettre à jourla prédiction lors de la survenue de nouveaux événements. Les prédictions sont développées sur une série hospitalièrefrançaise, et une validation externe est faite sur des données de population générale issues de registres decancer anglais et néerlandais. Leurs performances sont comparées à celles d’une prédiction issue d’une approchelandmark. Dans une troisième partie, nous explorons l’utilisation de la prédiction proposée pour diminuer ladurée des essais cliniques. Les temps de décès non observés des derniers patients inclus sont imputés en utilisantl’information des patients ayant un suivi plus long. Nous comparons trois méthodes d’imputation : un tempsde survie moyen, un temps échantillonné dans une distribution paramétrique et un temps échantillonné dansune distribution non-paramétrique des temps de survie. Les méthodes sont comparées en termes d’estimationdes paramètres (coefficient et écart-type), de risque de première espèce et de puissance
Research on cancer treatment has been evolving for last years in one main direction: personalised medicine. Thetreatment choice must be done according to the patients’ and tumours’ characteristics. This goal requires somebiostatistical developments, in order to assess prognostic models and eventually propose the best one. In a firstpart, we consider the problem of assessing a prognostic score when multicentre data are used. We extended twoconcordance measures to clustered data in the context of shared frailty model. Both the between-cluster andthe within-cluster levels are studied, and the impact of the cluster number and size on the performance of themeasures is investigated. In a second part, we propose to improve the prediction of the risk of death accountingfor the previous observed relapses. For that, we develop predictions from a joint model for a recurrent event anda terminal event. The proposed individual prediction is dynamic, both the time and the horizon of predictioncan evolve, so that the prediction can be updated at each new event time. The prediction is developed ona French hospital series, and externally validated on population-based data from English and Dutch cancerregistries. Its performances are compared to those of a landmarking approach. In a third part, we explore theuse of the proposed prediction to reduce the clinical trial duration. The non-observed death times of the lastincluded patients are imputed using the information of the patients with longer follow-up. We compared threemethods to impute the data: a survival mean time, a time sampled from the parametric distribution and atime sampled from a non-parametric distribution of the survival times. The comparison is made in terms ofparameters estimation (coefficient and standard-error), type-I error and power

The elderly form a physiological heterogeneous group. This thesis is concerned with the activity of plasma aspirin esterase and several other plasma esterases in the fit, community-dwelling and frail hospitalized elderly. I, Several studies have produced evidence to suggest that drug metabolism is altered in the frail elderly and some of this work has centred around the plasma esterases. Kinetic analysis of plasma from young people, and fit and frail elderly people showed that the reduced plasma aspirin esterase in the latter group was most likely due to a reduced amount of cholinesterase enzyme (a reduced maximal activity) rather than that of a compromised affinity of the enzyme (increased Km). Purification of whole plasma achieved the removal of 97% of the albumin component of plasma aspirin esterase. Subsequent kinetic analysis confirmed that there was no change in the Km value of plasma aspirin esterase in the three groups as a result of isolating the cholinesterase enzyme. Following this, it was postulated that the reduced activity of several plasma esterases in the frail elderly may be due to their often poor nutritional status. A group of frail elderly people were randomised and half received a supplemented hospital diet. Plasma aspirin esterase, cholinesterase, paraoxonase, phenylacetate esterase, red blood cell intracellular esterase and red blood cell acetylcholinesterase in addition to anthropometric measurements were measured at 0,4 and 8 weeks of the study period. The control group did not gain weight whereas the group who received a supplemented diet gained an average 1.3Kg (non-significant). The post study weight and TSF measurements between the fed and control groups differed signifcantly at p<0.05. There were no significant changes in any of the esterases at 8 weeks however plasma cholinesterase did show a significant increase in activity at 4 week (p < 0.05) and plasma paraoxonase showed a trend towards an improved activity.

Trabalho de Projeto do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
Background: Frailty defines a state of vulnerability facing a stressor event. Frail admitted patients represent a high-risk group for adverse health outcomes that benefit from a Comprehensive Geriatric Assessment (CGA). Screening instruments are crucial for identifying such patients; however, their potential has never been explored in Portuguese hospitals. The objective of this study is to evaluate the population of Internal Medicine inpatients at risk of frailty.Methods: Prospective study based on FRAIL scale (FS), PRISMA-7 (P7) (cut-off of 5) and medical records, conducted in a tertiary university hospital in Coimbra, Portugal, involving patients aged 65 and older admitted to Internal Medicine Service. We compared the demographic and clinical characteristics of patients with readmission and mortality within 30 and 90 days after discharge, as well as, the relationship between these outcomes and hospital admission length of stay and inhospital mortality with the state of frailty (defined by FS and P7).Results: Frailty was assessed in 100 patients. Of these, 69% and 47% were considered frail, through FS and P7, respectively. Independently of the scale, frailty was associated with greater hospital lengths of stay and the only inhospital death was of a frail patient. The patients who died within 90 days of discharge had statistically significant higher P7 score (4.9±1.6 versus 3.4±1.7, p= 0.0144) which translated into a risk of death during this period 5.5 times superior (RR 5.53, CI 95% 1.28 - 23.86, p= 0.0118) compared with the one of the not-frail patients defined by the same scale. No other risk relations, namely with FS, were concluded.Conclusions: FS and P7 are simple tools that can be used early in clinical admission to select patients to undergo CGA and improve health outcomes. Our study identified a significant percentage of patients that may have frailty. Frailty was associated with longer lengths of stay and presumably higher costs. FS and P7 application in the Portuguese population should be regarded with reservations as both demonstrated little association with readmission and mortality (except for 90 days' mortality with P7). Additional investigation is still required to further clarify this concept.
Introdução: Fragilidade define o estado de vulnerabilidade aumentado face a fatores extrínsecos de stress. Doentes frágeis internados representam um grupo de elevado risco de efeitos adversos que beneficiam de uma Avaliação Geriátrica Global (AGG). Ferramentas de rastreio de fragilidade são cruciais na identificação destes doentes; no entanto, o seu potencial nunca foi devidamente explorado em meio hospitalar português. O objetivo deste estudo é estudar a síndrome de fragilidade no doente agudo idoso internado no serviço de Medicina Interna.Métodos: Este estudo prospetivo, baseado na escala FRAIL (FS), PRISMA-7 (P7) (cut-off de 5) e em registos médicos, ocorreu num hospital universitário terciário em Coimbra, Portugal, e envolveu doentes com idade igual ou superior a 65 anos internados no Serviço de Medicina Interna. Comparámos as características clinicas e demográficas dos pacientes com a readmissão e mortalidade nos 30 e 90 dias após alta, assim como a relação destes outcomes, da duração do internamento e da mortalidade intra-hospitalar com o estado de fragilidade do doente (definido pela FS e P7).Resultados: Fragilidade foi pesquisada em 100 pacientes. Destes, 69% e 47% foram considerados frágeis, usando a FS e P7, respetivamente. Independentemente da escala utilizada, fragilidade associou-se com internamentos mais longos e a única morte intra-hospitalar registada foi de um doente considerado frágil. Os doentes que morreram nos 90 dias após alta tinham scores de P7 estatisticamente superiores (4.9±1.6 versus 3.4±1.7, p= 0.0144) o que se traduziu num risco de morte durante esse período 5.5 vezes superior (RR 5.53, CI 95% 1.28 - 23.86, p= 0.0118) quando comparado com o de doentes considerados não frágeis pela mesma escala. Não foram obtidas outras relações de risco, nomeadamente com FS.Conclusão: FS e P7 constituem instrumentos de rastreio simples de seleção de doentes à admissão para serem sujeitos a AGG com impacto clínico positivo. O nosso estudo identificou uma percentagem significativa de pacientes no serviço de Medicina Interna que poderão ser frágeis. A presença de fragilidade associou-se a internamentos mais longos e presumivelmente com maiores custos. A aplicação destas escalas na população portuguesa deve ser considerada com reserva, ambas demonstraram estar pouco associadas com readmissão e mortalidade (exceto a mortalidade a 90 dias e P7). Investigação adicional continua a ser necessária visando o esclarecimento mais aprofundado deste conceito.

碩士
國立體育大學
運動保健學系碩士班
100
BACKGROUND: Frailty is associated with reduced age-related functional reserve and dysregulation of multiple systems, leading to vulnerability status or adverse health condition. It is therefore important to know how frailty affects heath of old people in the globally aging world. Frailty phenotype of Cardiovascular Health Study (CHS) by Fried and Clinical Frailty Scale of Canadian Study of Health and Aging (CFS) by Rockwood were used to investigate the prevalence of frailty in Taiwan using a large sample size. Results from the aforesaid instruments both indicated mobility was an important aspect for frailty evaluation. However, the relationship between other functional performances and frailty has yet to be clarified. PURPOSE: The aim of this study was to compare the percentages in levels of frailty, and its different effect on functional performances among levels of frailty using CHS and CFS in the community-dwelling elderly. METHODS: Subjects were over the age of 65 resided near Linkou, New Taipei City and Gueishan, Taoyuan areas. They were implemented CFS, CHS, and functional performance tests, including BMI, one-leg standing with eyes-open and eyes-closed, functional forward reach (FFR), back scratch, chair sit-and-reach, grip strength, 30-s chair stand (CS), 2-minute step test (ST), 6-minute walk, 8-ft up-and-go (TUG), and 5-meter walk with usual (UW) and fast pace (FW). One-way analysis of covariance (ANCOVA) was used for analysis. Significant level was set at p<.05. RESULTS：122 subjects (58 men; 64 women, meanage = 75.92) were recruited in the study. Percentages of non-frailty (NF), pre-frailty (PF) and frailty levels were 65.6%, 30.3%, 4.1% in CHS and 48.3%, 49.1%, 2.5% in CFS respectively. Significant differences were both found in CHS and CFS across levels of frailty in FFR (p=.000 vs. p=.038), CS (p=.043 vs. p=.012), ST (p=.003 vs. p=.000), TUG (p=.001 vs. p=.000), and UW (p=.001 vs. p=.006) and FW (p=.034 vs. p=.002) with abovementioned performances in NF superior to those in PF. CONCLUSION: The common results from both CHS and CFS showed statistically significant differences in balance, low extremity strength, cardiovascular fitness, and mobility between NF and PF groups. It is crucial to incorporate components of these functional performances as a basis in physical frailty prevention and intervention for the older population dwelled in the community.

碩士
中原大學
生物醫學工程研究所
100
The occurring of physical frailty often causes the loss of body function and generates adverse disease. The process of frailty is subtle and slow, so without a long term record, to have the diagnosis by a single meeting is quite difficult. Traditionally, the diagnosis of doctors depends on their own experience, but it is too subjective and difficult to compare during varied periods. Although there are existing instruments can precisely assist in the diagnosis, these devices are still too expensive and complicated, and the measurement and data interpretation are also difficult. Therefore, an expert is needed during operation. Due to above reasons, these devices and methods are difficult to be used commonly. This research is going to present an analysis system of physical frailty, including the front-end hardware measurement devices and back-end data analysis and storage interface. By this system, the doctors can avoid high cost of equipment and have a simpler measurement process; on the other hand, it can help doctors to establish a data set of long-term changes in physical activity that can notice the occurring of limb degradation easily. The analysis system using a three-axis acceleration sensor as a front-end physical activity signal capture device, and hardware devices can have different measurement modes by different setting from the interface. With different mode, this system can measure varied parameters of gait and data of physical activity. On the back-end part, the programs are separated into two sets, the hospital end and the home end. The software for hospital can record the gait parameters, and data can be sent to the computer and displayed in real-time by Bluetooth devices in a wireless way. The software for home use is to collect the long-term data of activity. User wears the device on the waist and it can record the activity status daily. Before bedtime, the user can remove the device, and charge by USB port of computer and receive data form device. At last, the two sets of programs can upload data to the server and have unified management and storage. The doctor can use the interface of data analysis to recall the data of patients, so the differences of patients’ physical activities in varied time can be recheck, as an important factor of diagnosis. In this study, a lightweight and portable device has been successfully developed, and all the measurement of different physical activities can be evaluated by using the same set of hardware. It can avoid the inconvenient and complicated use of equipment and significantly decrease the cost. By the integrating of data from hospital end and the home end, the doctor can understand the long-term data of gait parameters of patients. By quantification of physical activity data, this system can help doctors have an objective and easy diagnosis of the frailty in the clinical.

Nutritional frailty refers to the downward spiral of increasing frailty that may occur in old age as a result of rapid, unintentional loss of body weight and sarcopenia. In the studies described in this thesis, the prevalence of under-nutrition was high and these undernourished older people were more likely to be hospitalized, spend longer in hospital, be admitted to facilities with increased level of care, fall and report weight loss. Also, medical and emotional well-being, good oral and dental health and access to nutritious food were all shown to be associated with better nutritional health. Screening for under-nutrition is important. The ‘DETERMINE Your Nutritional Health Checklist’ was found to be a simple awareness tool that could be easily used to increase knowledge in carers and older people. The rapid screen, in which an older person is classified as under-nourished if they have: 1) body mass index < 22 kg/m2 and/or 2) unintentional weight loss > 7.5% in the previous 3 months, was found to be simple and highly specific and suitable for use in facilities with financial, time and staffing constraints. The Mini Nutritional Assessment tool with its better sensitivity and specificity may be better in resource rich settings as results from this tool can guide management. In one of the studies, fasting plasma ghrelin levels in under-nourished older people were comparable to that in nourished older people, not higher as in previous studies (in other states of negative energy balance) and this may indicate a failure in energy homeostasis. Relatively reduced ghrelin levels in under-nourished older people may contribute to the development and/or progression of the anorexia of ageing and this requires further evaluation. Many frail older people are at risk of post-prandial hypotension and its many adverse health effects. Dietary carbohydrate manipulation by substituting sucrose with fructose may be beneficial in reducing the post-prandial blood pressure fall in older people. In conclusion, nutritional frailty is prevalent and has many adverse health consequences. Early detection and systematic intervention may help reduce morbidity.
Thesis (Ph.D.) -- University of Adelaide, Dept. of Medicine, 2005