Promoting Activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED): randomised controlled trial.

OBJECTIVE: To determine the effectiveness of an exercise and functional activity therapy intervention in adults with early dementia or mild cognitive impairment compared with usual care. DESIGN: Randomised controlled trial. SETTING: Participants' homes and communities at five sites in the United Kingdom. PARTICIPANTS: 365 adults with early dementia or mild cognitive impairment who were living at home, and family members or carers. INTERVENTION: The intervention, Promoting activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED), was a specially designed, dementia specific, rehabilitation programme focusing on strength, balance, physical activity, and performance of activities of daily living, which was tailored and progressive and addressed risk and the psychological needs of people with dementia. Up to 50 therapy sessions were provided over 12 months. The control group received usual care plus a falls risk assessment. Procedures were adapted during the covid-19 pandemic. MAIN OUTCOME MEASURES: The primary outcome was score on the carer (informant) reported disability assessment for dementia scale 12 months after randomisation. Secondary outcomes were self-reported activities of daily living, physical activity, quality of life, balance, functional mobility, fear of falling, frailty, cognition, mood, carer strain, service use at 12 months, and falls between months 4 and 15. RESULTS: 365 patient participants were randomised, 183 to intervention and 182 to control. The median age of participants was 80 years (range 65-95), median Montreal cognitive assessment score was 20 out of 30 (range 13-26), and 58% (n=210) were men. Intervention participants received a median of 31 therapy sessions (interquartile range 22-40) and reported completing a mean 121 minutes of PrAISED exercise each week. Primary outcome data were available for 149 intervention and 141 control participants. Scores on the disability assessment for dementia scale did not differ between groups: adjusted mean difference -1.3, 95% confidence interval -5.2 to 2.6; Cohen's d effect size -0.06, 95% confidence interval -0.26 to 0.15; P=0.51). Upper 95% confidence intervals excluded small to moderate effects on any of the range of outcome measures. Between months 4 and 15 the intervention group experienced 79 falls and the control group 200 falls (adjusted incidence rate ratio 0.78, 95% confidence interval 0.5 to 1.3; P=0.3). CONCLUSION: The intensive PrAISED programme of exercise and functional activity training did not improve activities of daily living, physical activity, or quality of life; reduce falls; or improve any other secondary health status outcomes, despite good uptake. Future research should consider alternative approaches to maintaining ability and wellbeing in people with dementia. TRIAL REGISTRATION: ISRCTN Registry ISRCTN15320670.

Genetic Testing in Natural History Studies: A Review of the Regulatory and Legal Landscape.

BACKGROUND: Natural history (NH) studies, using observational methods, are common in rare and orphan diseases (80% of which have a genetic component). There is profound interest in identifying genetic mutations driving these diseases in these studies to support the formulation of targeted precision medicines. The global regulatory classification of NH studies with novel molecular biomarker collection has not been clearly delineated, presenting researchers with the challenge of determining how these studies are classified and regulated across multiple geographies. OBJECTIVE: The aim of this investigation was to conduct a review of regulations related to NH studies and genetic testing to elucidate regulatory pathways to inform clinical researchers in the field. METHODS: Regulatory provisions for NH studies and genetic testing were obtained from Pharmaceutical Product Development (PPD)'s propriety regulatory intelligence database and by surveying the company's country-specific regulatory experts. A literature search was conducted in the Google Scholar search engine and PubMed for supplementary information. RESULTS: Nineteen countries were evaluated; 37% classified NH studies with biomarker collection as noninterventional and 26% required regulatory approval (increasing to 47% when molecular biomarker testing was introduced). No regulatory provisions for genetic testing could be identified in 32% of countries, and 58% did not have binding requirements for genetic counseling. CONCLUSION: Lack of harmonization of regulations governing NH studies with molecular biomarker collection contributes to the operational complexity of conducting multinational studies in orphan and rare diseases. A set of harmonized international guidelines for these studies would improve efficiency, and this may be on the horizon with the recent adaption of International Conference on Harmonisation (ICH) guideline E18.

A development study and randomised feasibility trial of a tailored intervention to improve activity and reduce falls in older adults with mild cognitive impairment and mild dementia.

BACKGROUND: People with dementia progressively lose abilities and are prone to falling. Exercise- and activity-based interventions hold the prospect of increasing abilities, reducing falls, and slowing decline in cognition. Current falls prevention approaches are poorly suited to people with dementia, however, and are of uncertain effectiveness. We used multiple sources, and a co-production approach, to develop a new intervention, which we will evaluate in a feasibility randomised controlled trial (RCT), with embedded adherence, process and economic analyses. METHODS: We will recruit people with mild cognitive impairment or mild dementia from memory assessment clinics, and a family member or carer. We will randomise participants between a therapy programme with high intensity supervision over 12 months, a therapy programme with moderate intensity supervision over 3 months, and brief falls assessment and advice as a control intervention. The therapy programmes will be delivered at home by mental health specialist therapists and therapy assistants. We will measure activities of daily living, falls and a battery of intermediate and distal health status outcomes, including activity, balance, cognition, mood and quality of life. The main aim is to test recruitment and retention, intervention delivery, data collection and other trial processes in advance of a planned definitive RCT. We will also study motivation and adherence, and conduct a process evaluation to help understand why results occurred using mixed methods, including a qualitative interview study and scales measuring psychological, motivation and communication variables. We will undertake an economic study, including modelling of future impact and cost to end-of-life, and a social return on investment analysis. DISCUSSION: In this study, we aim to better understand the practicalities of both intervention and research delivery, and to generate substantial new knowledge on motivation, adherence and the approach to economic analysis. This will enable us to refine a novel intervention to promote activity and safety after a diagnosis of dementia, which will be evaluated in a definitive randomised controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02874300; ISRCTN 10550694.

Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review.

BACKGROUND: Cognitive impairment is a risk factor for falls. Older adults with cognitive impairment (such as dementia) have an increased risk of falling compared with age-matched individuals without a cognitive impairment. To reduce falls in this population, interventions could theoretically target and train both physical and cognitive abilities. Combining and addressing cognitive components in falls rehabilitation is a novel and emerging area of healthcare. OBJECTIVES: The objective of this review was to identify the effectiveness of combined cognitive and physical interventions on the risk of falls in cognitively impaired older adults. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Older persons who were 65 years or older and identified as having a cognitive impairment either through diagnosis or assessment of global cognition. TYPES OF INTERVENTION(S): Multifactorial or multiple interventions where physical and cognitive elements were combined was compared against standard care or a single element intervention. TYPES OF STUDIES: Randomized controlled trials (RCTs), controlled clinical trials and experimental studies in which randomization was used. OUTCOMES: Outcomes related to falls, including falls rate, specific falls risk measures (i.e. Physiological Profile Assessment) or related clinical outcome measures (i.e. Timed Up and Go test, Tinetti and gait speed). SEARCH STRATEGY: A three-step search strategy was utilized in this review, including search of electronic databases: CENTRAL, JBISRIR, MEDLINE, EMBASE, AMED, CINAHL and PsychINFO. Initial keywords used were dementia, cognitive impairment, memory loss, exercise, rehabilitation and accidental falls. Grey literature (Google Scholar) and trials registers (Current Controlled Trials) searches were also completed. METHODOLOGICAL QUALITY: The methodological quality of included studies was assessed using Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) software. DATA EXTRACTION: Data was extracted from articles included in the review using the standardized data extraction tool from JBI-MAStARI. DATA SYNTHESIS: A quantitative meta-analysis was performed where possible. Otherwise, data synthesis was in the form of narrative review. Sub-group analysis according to level of cognitive impairment was completed where possible. RESULTS: Eight RCTs were included in this review; they evaluated the effectiveness of multicomponent exercise programs, including physical and cognitive activities, music-based group exercise and mind-body tai chi on falls related outcomes. Most of the studies were of good quality with an average quality score of 7.5. Four studies reported effectiveness based on the number of falls, half of which reported a significant difference between the groups, but pooling of results into meta-analysis was not possible because of differences in reporting of the outcome. Falls related outcomes that were combined in meta-analysis included balance (Berg balance scale), functional mobility (Timed Up and Go) and gait speed (m/s). There was a statistically significant improvement in balance and gait speed following the intervention; however, the studies were too heterogeneous to be included in the analysis from the functional mobility results. CONCLUSION: Overall, multicomponent interventions incorporating both physical and cognitive components demonstrated positive effects on balance, functional mobility and gait speed when compared with a control and had significantly better effect on balance and gait speed within mild cognitive impairment populations.

Predicting fracture risk in osteoporosis: the use of fracture prediction tools in an osteoporosis clinic population.

BACKGROUND: In the UK, the National Institute for Health and Care Excellence recommends either fracture risk assessment tool (FRAX) or QFracture to estimate the 10 year fracture risk of individuals. However, it is not known how these tools compare in determining risk and subsequent treatment using set intervention thresholds or guidelines. METHODS: The 10 year major osteoporotic (MO) and hip (HI) fracture risks were calculated for 100 women attending osteoporosis clinic in 2010 using FRAX and QFracture, and subsequent agreement to treatment between the tools was looked at using National Osteoporosis Foundation and National Bone Health Alliance thresholds (FRAX-20/3 and QFracture 20/3). We also looked at using these thresholds for QFracture and comparing them with the National Osteoporosis Guideline Group (NOGG) guidelines for FRAX (FRAX-NOGG). RESULTS: The 10 year risk for MO fracture for FRAX was 17.0% (IQR 10.8-24.0) and that of QFracture was 15.8% (IQR 9.5-27.7) (p=0.732). The 10 year risk for HI fracture for FRAX was 5.0% (IQR 2.1-8.9) and that of QFracture was 8.1% (IQR 2.5-21.6) (p<0.001). The agreement between FRAX-20/3 and QFracture-20/3 was greater than the agreement between FRAX-20/3 and FRAX-NOGG or QFracture-20/3 and FRAX-NOGG. CONCLUSIONS: The calculated 10 year risk for MO fracture between FRAX and QFracture was similar, whereas that of HI fracture was significantly different. The agreement to treatment between QFracture-20/3 and FRAX-NOGG was only 45%. Treatment decisions can differ depending on the fracture calculation tool used when coupled with certain intervention thresholds or guidelines.

Care in specialist medical and mental health unit compared with standard care for older people with cognitive impairment admitted to general hospital: randomised controlled trial (NIHR TEAM trial).

OBJECTIVE: To develop and evaluate a best practice model of general hospital acute medical care for older people with cognitive impairment. DESIGN: Randomised controlled trial, adapted to take account of constraints imposed by a busy acute medical admission system. SETTING: Large acute general hospital in the United Kingdom. PARTICIPANTS: 600 patients aged over 65 admitted for acute medical care, identified as "confused" on admission. INTERVENTIONS: Participants were randomised to a specialist medical and mental health unit, designed to deliver best practice care for people with delirium or dementia, or to standard care (acute geriatric or general medical wards). Features of the specialist unit included joint staffing by medical and mental health professionals; enhanced staff training in delirium, dementia, and person centred dementia care; provision of organised purposeful activity; environmental modification to meet the needs of those with cognitive impairment; delirium prevention; and a proactive and inclusive approach to family carers. PRIMARY OUTCOME: number of days spent at home over the 90 days after randomisation. SECONDARY OUTCOMES: structured non-participant observations to ascertain patients' experiences; satisfaction of family carers with hospital care. When possible, outcome assessment was blind to allocation. RESULTS: There was no significant difference in days spent at home between the specialist unit and standard care groups (median 51 v 45 days, 95% confidence interval for difference -12 to 24; P=0.3). Median index hospital stay was 11 versus 11 days, mortality 22% versus 25% (-9% to 4%), readmission 32% versus 35% (-10% to 5%), and new admission to care home 20% versus 28% (-16% to 0) for the specialist unit and standard care groups, respectively. Patients returning home spent a median of 70.5 versus 71.0 days at home (-6.0 to 6.5). Patients on the specialist unit spent significantly more time with positive mood or engagement (79% v 68%, 2% to 20%; P=0.03) and experienced more staff interactions that met emotional and psychological needs (median 4 v 1 per observation; P<0.001). More family carers were satisfied with care (overall 91% v 83%, 2% to 15%; P=0.004), and severe dissatisfaction was reduced (5% v 10%, -10% to 0%; P=0.05). CONCLUSIONS: Specialist care for people with delirium and dementia improved the experience of patients and satisfaction of carers, but there were no convincing benefits in health status or service use. Patients' experience and carers' satisfaction might be more appropriate measures of success for frail older people approaching the end of life. TRIAL REGISTRATION: Clinical Trials NCT01136148.

The relationship between executive function and falls and gait abnormalities in older adults: a systematic review.

BACKGROUND/OBJECTIVES: Older adults with dementia have at least a twofold increased risk of falls. Multi-factorial interventions have failed to demonstrate a reduction in falls in this group. Improved understanding of specific cognitive factors and their relationship to gait, balance and falls is required. METHODS: Systematic searches of Medline, Embase, PsycInfo, and CINAHL databases from inception to April 2011 were conducted to identify prospective studies in older adults examining executive function and its relationship with falls, balance and gait abnormalities. Two independent reviewers extracted data on study populations, executive function measures and study outcomes. RESULTS: Of 8,985 abstracts identified, 14 studies met inclusion criteria. Eleven studies examined executive function and falls. The remaining studies examined executive function and gait speed decline. Nine studies examining executive function and falls found a relationship between poor executive function and increased fall risk. All 3 studies examining executive function and gait found an association between poor executive function and declines in gait speed. Impaired executive function was associated with more serious falling patterns. CONCLUSIONS: Executive function was associated with falls and gait speed slowing in older adults. Future research should consider executive dysfunction as a training target for fall prevention, or as a factor mediating the failure of conventional fall prevention interventions.

The ageing of HIV: implications for geriatric medicine.

The prevalence of human immunodeficiency virus (HIV) in the over 50 age group is increasing as a consequence of younger adults ageing with HIV, in addition to new diagnoses in later life. We conducted searches in MEDLINE for English language studies published between January 1984 and January 2010 using search terms 'HIV', 'AIDS', 'HIV testing' and 'HIV complications' and selected articles relevant to adults aged 50 years and over. The prevalence, natural history and complications of HIV infection and treatment in older adults are reviewed. In 2007 the Centers for Disease Control and Prevention in the United States reported that 16.8% of new diagnoses of HIV that year were in individuals aged over 50 years. Older adults are vulnerable to late or missed diagnosis, and poorer treatment outcomes, due to the misconception that they are not at risk. A heightened awareness of HIV as a possible diagnosis in older adults is becoming increasingly important. As the HIV population ages, the emergence of disease and treatment complications such as cardiovascular disease, osteoporosis and dementia are evident. Management of older adults with HIV and multiple co-morbidities presents challenges to infectious diseases physicians and geriatricians alike. Inclusion of older adults in future HIV clinical trials will help design healthcare models to provide for this growing population.

Pharmacological options in the management of orthostatic hypotension in older adults.

Orthostatic hypotension (OH) is a common disorder in older adults with potentially serious clinical consequences. Understanding the key underlying pathophysiological processes that predispose individuals to OH is essential when making treatment decisions for this group of patients. In this article, we discuss the key antihypotensive agents used in the management of OH in older adults. Commonly, midodrine is used as a first-line agent, given its supportive data in randomized, controlled trials. Fludrocortisone has been evaluated in open-label trials and has long-established usage in clinical practice. Other agents are available and in clinical use, either alone or in combination, but larger randomized trial evaluations are yet to be published. It is important to bear in mind that a patient may be taking medications that predispose to or exacerbate the symptoms of OH. Withdrawal of such medications, where possible, should be considered before commencing other pharmacological agents that attenuate the symptoms of OH.