How frail is frail? A systematic scoping review and synthesis of high impact studies.

AIMS: While the frailty index (FI) is a continuous variable, an FI score of 0.25 has construct and predictive validity to categorise community-dwelling older adults as frail or non-frail. Our study aimed to explore which FI categories (FI scores and labels) were being used in high impact studies of adults across different care settings and why these categories were being chosen by study authors. METHODS: For this systematic scoping review, Medline, Cochrane and EMBASE databases were searched for studies that measured and categorised an FI. Of 1314 articles screened, 303 met the eligibility criteria (community: N = 205; residential aged care: N = 24; acute care: N = 74). For each setting, the 10 studies with the highest field-weighted citation impact (FWCI) were identified and data, including FI scores and labels and justification provided, were extracted and analysed. RESULTS: FI scores used to distinguish frail and non-frail participants varied from 0.12 to 0.45 with 0.21 and 0.25 used most frequently. Additional categories such as mildly, moderately and severely frail were defined inconsistently. The rationale for selecting particular FI scores and labels were reported in most studies, but were not always relevant. CONCLUSIONS: High impact studies vary in the way they categorise the FI and while there is some evidence in the community-dweller literature, FI categories have not been well validated in acute and residential aged care. For the time being, in those settings, the FI should be reported as a continuous variable wherever possible. It is important to continue working towards defining frailty categories as variability in FI categorisation impacts the ability to synthesise results and to translate findings into clinical practice.

Validation of a frailty index in older cancer patients with solid tumours.

BACKGROUND: Frailty is an indicator of physiological reserve in older people. In non-cancer settings, frailty indices are reliable predictors of adverse health outcomes. The aims of this study were to 1) derive and validate a frailty index (FI) from comprehensive geriatric assessment (CGA) data obtained in the solid tumour chemotherapy setting, and 2) to explore whether the FI-CGA could predict chemotherapy decisions and survival in older cancer patients with solid tumours. METHODS: Prospective cohort study of a consecutive series sample of 175 cancer patients aged 65 and older with solid tumours. A frailty index was calculated using an accumulated deficits model, coding items from the comprehensive geriatric assessment tool administered prior to chemotherapy decision-making. The domains of physical and cognitive functioning, nutrition, mood, basic and instrumental activities of daily living, and comorbidities were incorporated as deficits into the model. RESULTS: The FI-CGA had a right-skewed distribution, with median (interquartile range) of 0.27 (0.21-0.39). The 99% limit to deficit accumulation was below the theoretical maximum of 1.0, at 0.75. The FI-CGA was significantly related (p < 0.001) to vulnerability as assessed by the Vulnerable Elders Survey-13 and to medical oncologists' assessments of fitness or vulnerability to treatment. Baseline frailty as determined by the FI-CGA was also associated with treatment decisions (Treatment Terminated, Treatment Completed, No Planned Treatment) (p < 0.001), with the No Planned Treatment group significantly frailer than the other two groups. CONCLUSION: The FI-CGA is a potentially useful adjunct to cancer clinical decision-making that could predict chemotherapy outcomes in older patients with solid tumours.

Frailty and post-operative outcomes in older surgical patients: a systematic review.

BACKGROUND: As the population ages, increasing numbers of older adults are undergoing surgery. Frailty is prevalent in older adults and may be a better predictor of post-operative morbidity and mortality than chronological age. The aim of this review was to examine the impact of frailty on adverse outcomes in the 'older old' and 'oldest old' surgical patients. METHODS: A systematic review was undertaken. Electronic databases from 2010 to 2015 were searched to identify articles which evaluated the relationship between frailty and post-operative outcomes in surgical populations with a mean age of 75 and older. Articles were excluded if they were in non-English languages or if frailty was measured using a single marker only. Demographic data, type of surgery performed, frailty measure and impact of frailty on adverse outcomes were extracted from the selected studies. Quality of the studies and risk of bias was assessed by the Epidemiological Appraisal Instrument. RESULTS: Twenty-three studies were selected for the review and they were assessed as medium to high quality. The mean age ranged from 75 to 87 years, and included patients undergoing cardiac, oncological, general, vascular and hip fracture surgeries. There were 21 different instruments used to measure frailty. Regardless of how frailty was measured, the strongest evidence in terms of numbers of studies, consistency of results and study quality was for associations between frailty and increased mortality at 30 days, 90 days and one year follow-up, post-operative complications and length of stay. A small number of studies reported on discharge to institutional care, functional decline and lower quality of life after surgery, and also found a significant association with frailty. CONCLUSION: There was strong evidence that frailty in older-old and oldest-old surgical patients predicts post-operative mortality, complications, and prolonged length of stay. Frailty assessment may be a valuable tool in peri-operative assessment. It is possible that different frailty tools are best suited for different acuity and type of surgical patients. The association between frailty and return to pre-morbid function, discharge destination, and quality of life after surgery warrants further research.

Prescribing for older people discharged from the acute sector to residential aged-care facilities.

For frail older people, admission to hospital is an opportunity to review the indications for specific medications. This research investigates prescribing for 206 older people discharged into residential aged care facilities from 11 acute care hospitals in Australia. Patients had multiple comorbidities (mean 6), high levels of dependency, and were prescribed a mean of 7.2 regular medications at admission to hospital and 8.1 medications on discharge, with hyper-polypharmacy (≥10 drugs) increasing from 24.3% to 32.5%. Many drugs were preventive medications whose time until benefit was likely to exceed the expected lifespan. In summary, frail patients continue to be exposed to extensive polypharmacy and medications with uncertain risk-benefit ratio.

Patient frailty: the elephant in the operating room.

For most surgeons and many anaesthetists, patient frailty is currently the 'elephant in the (operating) room': it is easy to spot, but is often ignored. In this paper, we discuss different approaches to the measurement of frailty and review the evidence regarding the effect of frailty on peri-operative outcomes. We explore the limitations of 'eyeballing' patients to quantify frailty, and consider why the frail older patient, challenged by seemingly minor insults in the postoperative period, may suffer falls or delirium. Frailty represents a state of increased vulnerability to stressors, and older inpatients are exposed to multiple stressors in the peri-operative setting. Quantifying frailty is likely to increase the precision of peri-operative risk assessment. The Frailty Index derived from Comprehensive Geriatric Assessment is a simple and robust way to quantify frailty, but is yet to be systematically investigated in the pre-operative setting. Furthermore, the optimal care for frail patients and the reversibility of frailty with prehabilitation are fertile areas for future research.

Frailty in younger adults in hospital.

BACKGROUND: Even though frailty has been extensively measured in the acute care setting, relatively little is known about the frailty of younger adult inpatients. AIM: This study aimed to measure frailty in a sample of hospitalized adults aged 18 years and over and to examine how frailty in younger adult inpatients differs from middle-aged and older adult inpatients. DESIGN: Secondary analyses of prospectively collected cohort data. METHODS: Research nurses assessed 910 patients at admission to four Australian hospitals using the interRAI Acute Care instrument. Comparison of frailty index (FI) scores and domains was conducted across three age groups: younger (18-49 years), middle-aged (50-69 years) and older adults (≥70 years). Multivariable logistic regression examined risk of prolonged length of stay and unfavourable discharge destination. RESULTS: Younger adults (n = 214; 23.5%) had a mean (SD) FI of 0.19 (0.10). Approximately 27% (n = 57) of younger adults were frail (FI > 0.25). Mood and behaviour, health symptoms and syndromes, nutrition and pain were the most frequently affected domains in younger adults and 50% had ≥3 comorbidities. Frailty increased the risk of long length of stay (odds ratio (OR) = 1.77, P < 0.001) but not the risk of an unfavourable discharge (OR = 1.40, P = 0.20) in younger adults. CONCLUSIONS: This study showed that frailty is prevalent in younger patients admitted to acute care and is associated with adverse outcomes. This study was a critical first step towards establishing an understanding of frailty in younger hospitalized adults.

Study protocol for The GOAL Trial: comprehensive geriatric assessment for frail older people with chronic kidney disease to increase attainment of patient-identified goals-a cluster randomised controlled trial.

BACKGROUND: An increasing number of older people are living with chronic kidney disease (CKD). Many have complex healthcare needs and are at risk of deteriorating health and functional status, which can adversely affect their quality of life. Comprehensive geriatric assessment (CGA) is an effective intervention to improve survival and independence of older people, but its clinical utility and cost-effectiveness in frail older people living with CKD is unknown. METHODS: The GOAL Trial is a pragmatic, multi-centre, open-label, superiority, cluster randomised controlled trial developed by consumers, clinicians, and researchers. It has a two-arm design, CGA compared with standard care, with 1:1 allocation of a total of 16 clusters. Within each cluster, study participants ≥ 65 years of age (or ≥ 55 years if Aboriginal or Torres Strait Islander (First Nations Australians)) with CKD stage 3-5/5D who are frail, measured by a Frailty Index (FI) of > 0.25, are recruited. Participants in intervention clusters receive a CGA by a geriatrician to identify medical, social, and functional needs, optimise medication prescribing, and arrange multidisciplinary referral if required. Those in standard care clusters receive usual care. The primary outcome is attainment of self-identified goals assessed by standardised Goal Attainment Scaling (GAS) at 3 months. Secondary outcomes include GAS at 6 and 12 months, quality of life (EQ-5D-5L), frailty (Frailty Index - Short Form), transfer to residential aged care facilities, cost-effectiveness, and safety (cause-specific hospitalisations, mortality). A process evaluation will be conducted in parallel with the trial including whether the intervention was delivered as intended, any issue or local barriers to intervention delivery, and perceptions of the intervention by participants. The trial has 90% power to detect a clinically meaningful mean difference in GAS of 10 units. DISCUSSION: This trial addresses patient-prioritised outcomes. It will be conducted, disseminated and implemented by clinicians and researchers in partnership with consumers. If CGA is found to have clinical and cost-effectiveness for frail older people with CKD, the intervention framework could be embedded into routine clinical practice. The implementation of the trial's findings will be supported by presentations at conferences and forums with clinicians and consumers at specifically convened workshops, to enable rapid adoption into practice and policy for both nephrology and geriatric disciplines. It has potential to materially advance patient-centred care and improve clinical and patient-reported outcomes (including quality of life) for frail older people living with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04538157. Registered on 3 September 2020.

Income and the midlife peak in common mental disorder prevalence.

BACKGROUND: The prevalence of psychological distress and common mental disorders has been shown to peak in midlife but analyses have ignored the association of poor material circumstances with prevalence. This study aimed to test the hypothesis that the midlife prevalence peak occurs only in lower-income households. METHOD: Pooled data were used from the annual Health Survey for England, a nationally representative cross-sectional study, on community-dwelling individuals aged ≥ 16 years from years 1997 to 2006 (n=100 457). 12-item General Health Questionnaire scores, reported mental illness diagnoses and receipt of relevant medication were assessed in relation to household income and age. Analyses were separated by gender and adjusted for age, ethnicity, smoking, social class, education and co-morbidities. RESULTS: Prevalence of psychological distress, diagnoses and treatments rose with age until early middle age and declined subsequently. In analyses conducted separately by income categories, this pattern was marked in low-income groups but absent in high-income groups. Income-related inequalities in the prevalence of psychological distress were greatest in midlife; for example, in men aged 45-54 years the odds ratio of receiving psychiatric medication in the lowest income group compared with the highest was 7.50 [95% confidence interval (CI) 4.24-13.27] and in women aged 45-54 years the odds ratio of reporting mental illness was 10.25 (95% CI 6.16-17.05). CONCLUSIONS: An increased prevalence of psychological distress, common mental disorder diagnoses and treatment in midlife is not a universal phenomenon but is found only in those in low-income households. This implies the phenomenon is not inevitable but is potentially manageable or preventable.

Design of a fragment library that maximally represents available chemical space.

Cheminformatics protocols have been developed and assessed that identify a small set of fragments which can represent the compounds in a chemical library for use in fragment-based ligand discovery. Six different methods have been implemented and tested on Input Libraries of compounds from three suppliers. The resulting Fragment Sets have been characterised on the basis of computed physico-chemical properties and their similarity to the Input Libraries. A method that iteratively identifies fragments with the maximum number of similar compounds in the Input Library (Nearest Neighbours) produces the most diverse library. This approach could increase the success of experimental ligand discovery projects, by providing fragments that can be progressed rapidly to larger compounds through access to available similar compounds (known as SAR by Catalog).

Comparison of the prognostic importance of diagnosed diabetes, co-morbidity and frailty in older people.

AIMS: To compare the relative prognostic importance in older people of diagnosed diabetes, the number and severity of co-morbidities and frailty. METHODS: Two thousand three hundred and five people aged > or = 70 years comprised the clinical examination cohort of the Canadian Study of Health and Aging. Frailty was defined as a score of > or = 5 on a 7-point Clinical Frailty Scale. The cohort was followed for 5 years. RESULTS: Diabetes was more likely to be associated with medium-term mortality (adjusted hazard ratio (HR) 1.42; 95% confidence interval (CI) 1.20-1.69) than co-morbidity (HR 1.03; 95% CI 1.01-1.05). Frailty most strongly predicted death (HR 2.72; 95% CI 2.34-3.16). Frail older adults were 2.62 times (95% CI 1.36-5.06) more likely to have a complication of diabetes, independent of age, sex and number of years living with diabetes. People with diabetes were younger than those without (81.3 vs. 83.3 years) but a similar proportion were frail (42.2 vs.43.4%). The median life expectancy for frail older adults with diabetes was 23 months (95% CI 18-28 months). CONCLUSIONS: In this cohort, the risk of mortality in older people was defined more precisely by a clinical measure of frailty than by diabetes or burden of co-morbidity. Those with diagnosed diabetes were younger than those without but had the same frailty status; diabetes can therefore be considered to increase 'biological age' by 2 years in those aged over 70 years. The limited life expectancy of frail older people with diabetes highlights the importance of recognizing frailty and supports the individualization of care in older people with diabetes.

Frailty: A cost incurred by reproduction?

Evolutionary theories of senescence, such as the 'disposable soma' theory, propose that natural selection trades late survival for early fecundity. 'Frailty', a multidimensional measure of health status, may help to better define the long-term consequences of reproduction. We examined the relationship between parity and later life frailty (as measured by the Frailty Index) in a sample of 3,534 adults aged 65 years and older who participated in the English Longitudinal Study of Ageing. We found that the most parous adults were the most frail and that the parity-frailty relationship was similar for both sexes. Whilst this study provided some evidence for a 'parity-frailty trade-off', there was little support for our hypothesis that the physiological costs of childbearing influence later life frailty. Rather, behavioural and social factors associated with rearing many children may have contributed to the development of frailty in both sexes.

Effect of smoking on the accumulation of deficits, frailty and survival in older adults: a secondary analysis from the Canadian Study of Health and Aging.

OBJECTIVES: Smoking has adverse effects on a variety of organ systems but little is known about the relationship between smoking and frailty. We aimed to investigate differences in health status between smoking and non smoking older adults. DESIGN AND SETTING: The Canadian Study of Health and Aging, a nationally representative cohort study. PARTICIPANTS: Nine thousand and eight community-dwelling men and women age 65 years and over at baseline. MEASUREMENTS: Smoking status was determined using a Self-Assessed Risk Factor Questionnaire. Comparisons were made between never smokers, light smokers and heavy smokers with heavy smokers defined as those who smoked >or= 1 pack per day for 20 years or more. A frailty index (FI) generated from 40 self-reported health deficits was also modified to exclude 5 variables that could be directly attributed to smoking (e.g. cough). Decedent information was collected over 10 years. RESULTS: Average FI values increased exponentially with age. For both men and women, heavy smokers were the most frail, light smokers had intermediate frailty status and never smokers were fittest. Modification of the FI did not impact these differences. Heavy smokers had significantly worse mortality than non smokers and higher rates of death in smokers persisted in the oldest old. 120 month survival curves, grouped for age, sex and smoking status showed that male smokers > 75 years had the highest mortality rates. CONCLUSIONS: Smoking causes poorer health status at older ages which can be captured by the frailty index. Higher rates of death in smokers persist in the oldest old, with no emergence of "survivors" with fitness or longevity advantages.

Do sex differences in chronic disease underpin the sex-frailty paradox?

The 'male-female health-survival paradox' is a well-described clinical phenomenon. More recently, it has been conceptualized as a 'sex-frailty paradox': females may be considered to be more frail (because they have poorer health status) but also less frail (because they are less vulnerable to death) than males of the same age. Here, we review potential biological, behavioral and social mechanisms underpinning sex differences in morbidity, mortality and frailty before considering the question at the center of the sex paradox - why is it that females are able to tolerate poor health better than males? We explore, in detail, a frequently cited explanation for the sex paradox that centers on sex differences in chronic disease and conclude by presenting a new approach to this old hypothesis.

Do health assets have a protective effect for hospitalized frail older adults?

BACKGROUND: Although increasing frailty is predictive of increased mortality and length of stay for hospitalized older adults, this approach ignores health assets that individuals can utilize to recover following hospital admission. AIM: To examine whether health assets mitigate the effect of frailty on outcomes for older adults admitted to hospital. DESIGN: Patients of 1418 aged ≥ 70 years admitted to 11 hospitals in Australia were evaluated at admission using the interRAI assessment system for Acute Care, which surveys a large number of domains, including cognition, communication, mood and behaviour, activities of daily living, continence, nutrition, skin condition, falls and medical diagnosis. METHODS: The data set was interrogated for potential health assets and a multiple logistic regression adjusted for frailty index, age and gender as covariates was performed for the outcomes mortality, length of stay, re-admission and new need for residential care. RESULTS: Inpatient mortality was 3% and 4.5% of patients died within 28 days of discharge. Median length of stay was 7 days (IQR 4-11). In multivariate analysis that includes frailty, being able to walk further [OR 0.08 (0.01-0.63)], ability to leave the house [OR 0.35 (0.17-0.74)] and living alone [OR 0.28 (0.10-0.79)] were protective against mortality. The presence of a support person was associated with a decreased length of stay [OR 0.14 (0.08-0.25)]. CONCLUSION: The inclusion of health assets in predictive models can improve prognostication and highlights potential interventions to improve outcomes for hospitalized older adults.

The Utility of the Frailty Index in Clinical Decision Making.

Using clinical vignettes, this study aimed to determine if a measure of patient frailty would impact management decisions made by geriatricians regarding commonly encountered clinical situations. Electronic surveys consisting of three vignettes derived from cases commonly seen in an acute inpatient ward were distributed to geriatricians. Vignettes included patients being considered for intensive care treatment, rehabilitation, or coronary artery bypass surgery. A frailty index was generated through Comprehensive electronic Geriatric Assessment. For each vignette, respondents were asked to make a recommendation for management, based on either a brief or detailed amount of clinical information and to reconsider their decision after the addition of the frailty index. The study suggests that quantification of frailty might aid the clinical judgment now employed daily to proceed with usual care, or to modify it based on the vulnerability of the person to whom it is aimed.

Sex differences in frailty: A systematic review and meta-analysis.

BACKGROUND: It is a well-described clinical phenomenon that females live longer than males, yet tend to experience greater levels of co-morbidity and disability. Females can therefore be considered both more frail (because they have poorer health status) and less frail (because they have a lower risk of mortality). This systematic review aimed to determine whether this ageing paradox is demonstrated when the Frailty Index (FI) is used to measure frailty. METHODS: Medline, EMBASE and CINAHL databases were searched for observational studies that measured FI and mortality in community-dwellers over 65years of age. In five-year age groups, meta-analysis determined the sex differences in mean FI (MD=mean FIfemale-mean FImale) and mortality rate. RESULTS: Of 6482 articles screened, seven articles were included. Meta-analysis of data from five studies (37,426 participants) found that MD values were positive (p<0.001; MD range=0.02-0.06) in all age groups, indicating that females had higher FI scores than males at all ages. This finding was consistent across individual studies. Heterogeneity was high (I2=72.7%), reflecting methodological differences. Meta-analysis of mortality data (13,127 participants) showed that male mortality rates exceeded female mortality rates up until the 90 to 94-years age group. Individual studies reported higher mortality for males at each level of FI, and higher risk of death for males when controlling for age and FI. CONCLUSIONS: The pattern of sex differences in the FI and mortality of older adults was consistent across populations and confirmed a 'male-female health-survival paradox'.

Perioperative assessment of older surgical patients using a frailty index-feasibility and association with adverse post-operative outcomes.

This study aimed to examine the feasibility of using a frailty index (FI) based on comprehensive geriatric assessment (CGA), to assess the level of frailty in older surgical patients preoperatively and to evaluate the association of FI-CGA with poorer postoperative outcomes. Two hundred and forty-six patients aged ≥70 years undergoing intermediate- to high-risk surgery in a tertiary hospital were recruited. Frailty was assessed using a 57-item FI-CGA form, with fit, intermediate frail, and frail patients defined as FI ≤0.25, >0.25 to 0.4, and >0.4, respectively. Adverse outcomes were ascertained at 30 days and 12 months post-surgery. Logistic regression models assessed the relationship between FI and adverse outcomes, adjusting for age, gender and acuity of surgery. The mean age of the participants was 79 years (standard deviation [SD] 6.5%), 52% were female, 91% were admitted from the community, 43% underwent acute surgery, and 19% were assessed as frail. The FI-CGA form was reported as being easy to apply, with a low patient refusal rate (2.2%). The majority of items were easy to rate, although inter-rater reliability was not tested. In relation to outcomes, greater frailty was associated with increased 12-month mortality (6.4%, 15.6%, and 23% for fit, intermediate frail, and frail patients respectively, P=0.01) and 12-month hospital readmissions (33.9%, 48.9%, and 60% respectively, P=0.004). There were no statistically significant differences between fit, intermediate frail, and frail groups in perioperative adverse events (17.4%, 23.3%, and 19.1% respectively, P=0.577) or 30-day postoperative complications (35.8%, 47.8%, and 46.8% respectively, P=0.183). Our findings suggest that it is feasible to use the FI-CGA to assess frailty preoperatively, and that using the FI-CGA may identify patients at high risk of adverse long-term outcomes.

Structural insights into the mode of action of a pure antiestrogen.

BACKGROUND: Estrogens exert their effects on target tissues by binding to a nuclear transcription factor termed the estrogen receptor (ER). Previous structural studies have demonstrated that each class of ER ligand (agonist, partial agonist, and SERM antagonist) induces distinctive orientations in the receptor's carboxy-terminal transactivation helix. The conformation of this portion of the receptor determines whether ER can recruit and interact with the components of the transcriptional machinery, thereby facilitating target gene expression. RESULTS: We have determined the structure of rat ERbeta ligand binding domain (LBD) in complex with the pure antiestrogen ICI 164,384 at 2.3 A resolution. The binding of this compound to the receptor completely abolishes the association between the transactivation helix (H12) and the rest of the LBD. The structure reveals that the terminal portion of ICI's bulky side chain substituent protrudes from the hormone binding pocket, binds along the coactivator recruitment site, and physically prevents H12 from adopting either its characteristic agonist or AF2 antagonist orientation. CONCLUSIONS: The binding mode adopted by the pure antiestrogen is similar to that seen for other ER antagonists. However, the size and resultant positioning of the ligand's side chain substituent produces a receptor conformation that is distinct from that adopted in the presence of other classes of ER ligands. The novel observation that binding of ICI results in the complete destabilization of H12 provides some indications as to a possible mechanism for pure receptor antagonism.