Large Sample Size Fallacy in Trials About Antipsychotics for Neuropsychiatric Symptoms in Dementia

Background: A typical antipsychotics for neuropsychiatric symptoms in dementia have been tested in much larger trials than the older conventional drugs. The advantage of larger sample sizes is that negative findings become less likely and the effect estimates more precise. However, as sample sizes increase, the trials also get more expensive and time consuming while exposing more patients to drugs with unknown safety profiles. Moreover, a large sample size might yield a statistically significant effect that is not necessarily clinically relevant. Objective: To assess (1) the variation in sample size and sample size calculations of antipsychotic trials in dementia, (2) the size of reported treatment effects and related statistical significance, and (3) general study characteristics that might be related to sample size. Study Design and Setting: We performed a meta-epidemiological study of randomized trials that tested antipsychotics for neuropsychiatric symptoms in dementia. The trials compared conventional or atypical antipsychotics with placebo or another antipsychotic. Two reviewers independently extracted sample size, sample size calculations, reported treatment effects with p-values, and general study characteristics (drug type, trial duration, type of funding). We calculated a reference sample size of 83 and 433 per study group for the placebo-controlled and head-to-head trials respectively. Results: We identified 33 placebo-controlled trials, and 18 head-to-head trials. Only 14 (42%) and 2 (11%), respectively, reported a sample size calculation. The average sample size per arm was 34 (range 6-179) in placebo-controlled trials testing conventional drugs, 107 (8-237) in such trials testing atypical drugs, and 104 (95-115) in such trials testing both drug types; it was 31 (10-88) in head-to-head trials. Thirteen out of 18 trials with sample sizes larger than required (72%) reported a statistically significant treatment effect, of which two (15%) were clinically relevant. None of the head-to-head trials reported a statistically significant treatment effect, even though some suggested non-inferiority. In placebo-controlled trials of atypical drugs, longer trial duration (>6 weeks) and commercial funding were associated with higher sample size. Conclusion: Sample size calculations were poorly reported in antipsychotic trials for dementia. Placebo-controlled trials of atypical antipsychotics showed large sample size fallacy while head-to-head trials were massively underpowered

Systematic review on barriers and facilitators of complex interventions for residents with dementia in long-term care

Objectives:Psychotropic drugs are frequently and sometimes inappropriately used for the treatment of neuropsychiatric symptoms of people with dementia, despite their limited efficacy and side effects. Interventions to address neuropsychiatric symptoms and psychotropic drug use are multifactorial and often multidisciplinary. Suboptimal implementation of these complex interventions often limits their effectiveness. This systematic review provides an overview of barriers and facilitators influencing the implementation of complex interventions targeting neuropsychiatric symptoms and psychotropic drug use in long-term care.Design:To identify relevant studies, the following electronic databases were searched between 28 May and 4 June: PubMed, Web of Science, PsycINFO, Cochrane, and CINAHL. Two reviewers systematically reviewed the literature, and the quality of the included studies was assessed using the Critical Appraisal Skills Programme qualitative checklist. The frequency of barriers and facilitators was addressed, followed by deductive thematic analysis describing their positive of negative influence. The Consolidated Framework for Implementation Research guided data synthesis.Results:Fifteen studies were included, using mostly a combination of intervention types and care programs, as well as different implementation strategies. Key factors to successful implementation included strong leadership and support of champions. Also, communication and coordination between disciplines, management support, sufficient resources, and culture (e.g. openness to change) influenced implementation positively. Barriers related mostly to unstable organizations, such as renovations to facility, changes toward self-directed teams, high staff turnover, and perceived work and time pressures.Conclusions:Implementation is complex and needs to be tailored to the specific needs and characteristics of the organization in question. Champions should be carefully chosen, and the application of learned actions and knowledge into practice is expected to further improve implementation

Effects of caregiver dementia training incaregiver-patientdyads:A randomized controlled study

Objectives Caregivers for people with dementia (PWD) have reported needing emotional and social support, improved coping strategies, and better information about the illness and available support services. In this study, we aimed to determine the effectiveness of an Australian multicomponent community-based training program that we adapted and implemented in a non-medical Dutch health care setting. Methods and design A randomized controlled trial was performed: 142 dyads of cohabiting caregivers and PwD were randomized to control (care as usual) or intervention (training program) groups and outcomes were compared. Programs lasted 1 week, comprised 14 sessions, and were delivered by specialist staff. We included 16 groups of two to six caregivers. The primary outcome was care-related quality of life (CarerQol-7D) at 3 months. The main secondary outcomes for caregivers were self-rated burden, health and mood symptoms, and for PwD were neuropsychiatric symptoms, quality of life, and agitation. Results No significant difference was observed for the primary outcome. However, caregivers experienced fewer role limitations due to physical function (adjusted mean difference, 13.04; 95% confidence interval [95%CI], 3.15-22.93), emotional function (13.52; 95%CI, 3.76-23.28), and pain reduction (9.43; 95%CI, 1.00-17.86). Positive outcomes identified by qualitative analysis included better acceptance and coping and improved knowledge of dementia and available community services and facilities. Conclusion Quantitative analysis showed that the multicomponent course did not affect care-related quality of life but did have a positive effect on experienced role limitations and pain. Qualitative analysis showed that the course met the needs of participating dyads

The Impact of Music on Stress Biomarkers:Protocol of a Substudy of the Cluster-Randomized Controlled Trial Music Interventions for Dementia and Depression in ELderly Care (MIDDEL)

Recently, a large cluster-randomized controlled trial was designed-Music Interventions for Dementia and Depression in ELderly care (MIDDEL)-to assess the effectiveness of music interventions on depression in care home residents with dementia (ClinicalTrials.gov NCT03496675). To understand the pathophysiological mechanisms, we observed the effect of repeated music interventions on stress in this population since chronic stress was associated with depression and an increased risk for dementia. An exploratory study was designed to assess: (1) changes in hair cortisol concentrations as an indicator of longer-term stress; (2) whether baseline stress is a predictor of therapy outcome; (3) pre- and post-treatment effects on salivary α-amylase and cortisol response as an indicator of immediate stress in 180-200 care home residents with dementia and depressive symptoms who partake in the MIDDEL trial. Insights into mediatory effects of stress to explain the effect of music interventions will be gained. Hair cortisol concentrations were assessed at baseline and at 3, 6, and 12 months along with the Perceived Stress Scale. Salivary α-amylase and cortisol concentrations were assessed at 1, 3, and 6 months. Saliva was collected just before a session and 15 and 60 min after a session, along with a stress Visual Analogue Scale.</p

Sounds in nursing homes and their effect on health in dementia:A systematic review

OBJECTIVES: Nursing home residents with dementia are sensitive to detrimental auditory environments. This paper presents the first literature review of empirical research investigating (1) the (perceived) intensity and sources of sounds in nursing homes, and (2) the influence of sounds on health of residents with dementia and staff. DESIGN: A systematic review was conducted in PubMed, Web of Science and Scopus. Study quality was assessed with the Mixed Methods Appraisal Tool. We used a narrative approach to present the results. RESULTS: We included 35 studies. Nine studies investigated sound intensity and reported high noise intensity with an average of 55-68 dB(A) (during daytime). In four studies about sound sources, human voices and electronic devices were the most dominant sources. Five cross-sectional studies focused on music interventions and reported positives effects on agitated behaviors. Four randomized controlled trials tested noise reduction as part of an intervention. In two studies, high-intensity sounds were associated with decreased nighttime sleep and increased agitation. The third study found an association between music and less agitation compared to other stimuli. The fourth study did not find an effect of noise on agitation. Two studies reported that a noisy environment had negative effects on staff. CONCLUSIONS: The need for appropriate auditory environments that are responsive to residents' cognitive abilities and functioning is not yet recognized widely. Future research needs to place greater emphasis on intervention-based and longitudinal study design

Individual differences in the temporal relationship between sleep and agitation:a single-subject study in nursing home residents with dementia experiencing sleep disturbance and agitation

OBJECTIVES: Previous studies on the interrelationship between sleep and agitation relied on group-aggregates and so results may not be applicable to individuals. This proof-of-concept study presents the single-subject study design with time series analysis as a method to evaluate the association between sleep and agitation in individual nursing home residents using actigraphy. METHOD: To record activity, three women and two men (aged 78-89 years) wore the MotionWatch 8© (MW8) for 9 consecutive weeks. Total sleep time and agitation were derived from the MW8 data. We performed time series analysis for each individual separately. To gain insight into the experiences with the actigraphy measurements, care staff filled out an investigator-developed questionnaire on their and participants' MW8 experiences. RESULTS: A statistically significant temporal association between sleep and agitation was present in three out of five participants. More agitation was followed by more sleep for participant 1, and by less sleep for participant 4. As for participants 3 and 4, more sleep was followed by more agitation. Two-thirds of the care staff members (16/24) were positive about the use of the MW8. Acceptability of the MW8 was mixed: two residents refused to wear the MW8 thus did not participate, one participant initially experienced the MW8 as somewhat unpleasant, while four participants seemed to experience no substantial problems. CONCLUSION: A single-subject approach with time series analysis can be a valuable tool to gain insight into the temporal relationship between sleep and agitation in individual nursing home residents with dementia experiencing sleep disturbance and agitation

Distancing Measures and Challenges Discussed by COVID-19 Outbreak Teams of Dutch Nursing Homes:The COVID-19 MINUTES Study

The most severe COVID-19 infections and highest mortality rates are seen among long-term care residents. To reduce the risk of infection, physical distancing is important. This study investigates what physical distancing measures were discussed by COVID-19 outbreak teams of Dutch long-term care organizations and what challenges they encountered. The COVID-19 MINUTES study is a qualitative multi-center study (n = 41) that collected minutes of COVID-19 outbreak teams from March 2020 to October 2021. Textual units about distancing measures were selected and analyzed using manifest content analysis for the first wave: early March-early May 2020; the intermediate period of 2020: mid-May-mid-September 2020; and the second wave: late September 2020-mid-June 2021. During all periods, COVID-19 outbreak teams often discussed distancing visitors from residents. Moreover, during the first wave they often discussed isolation measures, during the intermediate period they often discussed distancing staff and volunteers from residents, and during both the intermediate period and the second wave they often discussed distancing among residents. During all periods, less often admission measures were discussed. Challenges persisted and included unrest among and conflicts between visitors and staff, visitors violating measures, resident non-adherence to measures, and staffing issues. The discussed distancing measures and corresponding challenges may guide local long-term care and (inter)national policymakers during the further course of the COVID-19 pandemic, outbreaks of other infectious diseases, and long-term care innovations

Caregiver dementia training in caregiver-patient dyads: process evaluation of a randomized controlled study

Objectives We performed a randomized controlled study to evaluate the effects of caregiver training on the well-being of both people with dementia and their caregivers. Before the effect analysis, we conducted a process evaluation to estimate internal and external validity. This was anticipated to augment our understanding of the outcomes. Methods We focused on three questions. (a) Was the intervention performed as planned (internal validity)? (b) Can qualitative data be used to inform how the intervention evoked change? (c) Can the study outcomes be extrapolated to all caregivers living with people who have dementia (external validity)? Results Responses from participants assigned to the intervention group suggested that the intervention was feasible, could be performed as planned, and that modelling and discussions between participants were important. However, participant recruitment to the entire study was ultimately laborious because participants had issues with the study design (risk of being assigned to the control group) and referrers lacked familiarity with the training (new type of intervention). Participants were also younger and better educated compared with the general population. Some dropouts in the follow-up period occurred due to the number of questionnaires, and this was more pronounced in the control group. Conclusions Although we achieved high internal validity, we lack certainty about the external validity. We not only experienced general difficulty in recruiting participants but also tended to recruit a biased sample that was relatively young and well educated. These factors combine to limit our ability to extrapolate the results to the general population.Public Health and primary careGeriatrics in primary car

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe