Gallstones, Body Mass Index, C-Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data.

BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH AND RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10-5 ) and Europeans (P = 9 × 10-5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10-6 ). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.

Lifelines NEXT: a prospective birth cohort adding the next generation to the three-generation Lifelines cohort study.

Epidemiological research has shown there to be a strong relationship between preconceptional, prenatal, birth and early-life factors and lifelong health. The Lifelines NEXT is a birth cohort designed to study the effects of intrinsic and extrinsic determinants on health and disease in a four-generation design. It is embedded within the Lifelines cohort study, a prospective three-generation population-based cohort study recording the health and health-related aspects of 167,729 individuals living in Northern Netherlands. In Lifelines NEXT we aim to include 1500 pregnant Lifelines participants and intensively follow them, their partners and their children until at least 1 year after birth. Longer-term follow-up of physical and psychological health will then be embedded following Lifelines procedures. During the Lifelines NEXT study period biomaterials-including maternal and neonatal (cord) blood, placental tissue, feces, breast milk, nasal swabs and urine-will be collected from the mother and child at 10 time points. We will also collect data on medical, social, lifestyle and environmental factors via questionnaires at 14 different time points and continuous data via connected devices. The extensive collection of different (bio)materials from mother and child during pregnancy and afterwards will provide the means to relate environmental factors including maternal and neonatal microbiome composition) to (epi)genetics, health and developmental outcomes. The nesting of the study within Lifelines enables us to include preconceptional transgenerational data and can be used to identify other extended families within the cohort.

A 9-Week Aerobic and Strength Training Program Improves Cognitive and Motor Function in Patients with Dementia: A Randomized, Controlled Trial.

OBJECTIVE: To compare training and follow-up effects of combined aerobic and strength training versus aerobic-only training on cognitive and motor function in institutionalized patients with dementia and to explore whether improved motor function mediates improved cognitive function. METHODS: Using a 9-week, parallel, three-group, single-blind, randomized, controlled trial with a follow-up assessment at week 18, we assessed 109 patients with dementia (age 85.5 ± 5.1 years) in a psycho-geriatric nursing home. Each 9-week intervention consisted of 36, 30-minute sessions. A combined group (N = 37) received and completed two strength and two walking sessions per week, an aerobic group (N = 36) completed four walking sessions, and a social group (N = 36) completed four social visits per week. Cognitive and motor functions were assessed at baseline, after the 9-week intervention, and after a consecutive 9 weeks of usual care. RESULTS: Baseline corrected post-test scores in the combined versus the social group were higher for global cognition, visual memory, verbal memory, executive function, walking endurance, leg muscle strength, and balance. Aerobic versus social group scores were higher for executive function. Follow-up effects reversed toward baseline values. Motor improvement did not significantly mediate cognitive improvement. CONCLUSION: Compared with a nonexercise control group, a combination of aerobic and strength training is more effective than aerobic-only training in slowing cognitive and motor decline in patients with dementia. No mediating effects between improvements in cognitive function via improved motor function were found. Future research into the underlying mechanistic associations is needed.

Ranking Barriers, Motivators, and Facilitators to Promote Physical Activity Participation of Persons With Dementia: An Explorative Study.

BACKGROUND AND PURPOSE: Community-dwelling persons with dementia are inactive most of the day. The purpose of this study was to rank the barriers, motivators, and facilitators that hamper or promote physical activity (PA) participation for persons with dementia. This could provide knowledge that can be used to design effective interventions to promote PA participation for persons with dementia. METHODS: Twenty community-dwelling persons with dementia, mean (SD) age = 79 (5.4) years, 25% female, mean (SD) Mini-Mental Status Examination score = 23 (3.5); their informal caregivers, N = 20, mean (SD) age = 70 (11.5) years, 85% female; and an expert group of physiotherapists, N = 15, mean (SD) age = 41 (12.4) years, 73% female, were asked to rank preselected barriers, motivators, and facilitators of PA participation for persons with dementia. These statements were categorized at the intrapersonal, interpersonal, and community levels. RESULTS AND DISCUSSION: Persons with dementia and their informal caregivers selected only motivators and facilitators as being important for PA participation, with the motivator "beneficial health effects" considered the most important. The experts had a different perspective on PA participation; half of their ranked top 10 most important factors were barriers to PA participation for persons with dementia. This could be explained by the more critical role of a therapist, focusing on symptom control and treatment of disability; in this case, the elimination of barriers to maintain PA participation in their patients. Furthermore, all groups prioritized statements at the intrapersonal level. CONCLUSIONS: The results of this study suggest a difference in perspective between the more optimistic view of persons with dementia and their informal caregivers and the more critical view of physiotherapy experts regarding the most important factors that influence PA participation. In addition, there was a strong focus on the individual characteristics that influence PA behavior that warrant personalized interventions to promote PA in persons with dementia.

Implementing Individually Tailored Prescription of Physical Activity in Routine Clinical Care: Protocol of the Physicians Implement Exercise = Medicine (PIE=M) Development and Implementation Project.

BACKGROUND: The prescription of physical activity (PA) in clinical care has been advocated worldwide. This "exercise is medicine" (E=M) concept can be used to prevent, manage, and cure various lifestyle-related chronic diseases. Due to several challenges, E=M is not yet routinely implemented in clinical care. OBJECTIVE: This paper describes the rationale and design of the Physicians Implement Exercise = Medicine (PIE=M) study, which aims to facilitate the implementation of E=M in hospital care. METHODS: PIE=M consists of 3 interrelated work packages. First, levels and determinants of PA in different patient and healthy populations will be investigated using existing cohort data. The current implementation status, facilitators, and barriers of E=M will also be investigated using a mixed-methods approach among clinicians of participating departments from 2 diverse university medical centers (both located in a city, but one serving an urban population and one serving a more rural population). Implementation strategies will be connected to these barriers and facilitators using a systematic implementation mapping approach. Second, a generic E=M tool will be developed that will provide tailored PA prescription and referral. Requirements for this tool will be investigated among clinicians and department managers. The tool will be developed using an iterative design process in which all stakeholders reflect on the design of the E=M tool. Third, we will pilot-implement the set of implementation strategies, including the E=M tool, to test its feasibility in routine care of clinicians in these 2 university medical centers. An extensive learning process evaluation will be performed among clinicians, department managers, lifestyle coaches, and patients using a mixed-methods design based on the RE-AIM framework. RESULTS: This project was approved and funded by the Dutch grant provider ZonMW in April 2018. The project started in September 2018 and continues until December 2020 (depending on the course of the COVID-19 crisis). All data from the first work package have been collected and analyzed and are expected to be published in 2021. Results of the second work package are described. The manuscript is expected to be published in 2021. The third work package is currently being conducted in clinical practice in 4 departments of 2 university medical hospitals among clinicians, lifestyle coaches, hospital managers, and patients. Results are expected to be published in 2021. CONCLUSIONS: The PIE=M project addresses the potential of providing patients with PA advice to prevent and manage chronic disease, improve recovery, and enable healthy ageing by developing E=M implementation strategies, including an E=M tool, in routine clinical care. The PIE=M project will result in a blueprint of implementation strategies, including an E=M screening and referral tool, which aims to improve E=M referral by clinicians to improve patients' health, while minimizing the burden on clinicians.

ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans.

BACKGROUND: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence. METHODS: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication. RESULTS: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low. CONCLUSION: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.

Exergaming as a Physical Exercise Strategy Reduces Frailty in People With Dementia: A Randomized Controlled Trial.

OBJECTIVES: People with dementia are known to be physically frailer, more sedentary, and participate less in regular physical exercise compared to their healthy peers. Physical activity interventions have the potential to reduce the level of frailty in community-dwelling older adults. Exergaming combines physical exercise with cognitive stimulation in a virtual environment. It is an innovative and fun way of exercising, which may aid people with dementia to be more physically active. The primary aim of this study was to investigate the efficacy of a 12-week exergame training and equally long aerobic training, both compared to an active control group, on frailty in people with dementia. DESIGN: A 3-armed randomized controlled trial compared exergame training, aerobic training, and an active control intervention. PARTICIPANTS: 115 people with dementia [mean (standard deviation [SD]) age = 79.2 (6.9) years; mean (SD) Mini-Mental State Examination score = 22.9 (3.4)]. METHODS: Participants were randomized and individually trained 3 times a week during 12 weeks. The Evaluative Frailty Index for Physical activity (EFIP) was used to assess the level of frailty at baseline and after the 12-week intervention period. Between-group differences were analyzed with analysis of covariance. RESULTS: The exergame group showed a trend toward higher adherence compared to the aerobic group (87.3% vs 81.1%, P = .05). A significant reduction on the EFIP was found in the exergame group (EG) compared to the active control group (CG) [mean difference (95% confidence interval) between EG and CG: -0.034 [-0.062, -0.007], P = .012], with a small-to-moderate effect size (partial η2 = 0.055). CONCLUSIONS AND IMPLICATIONS: This is the first study to show that a 12-week exergame intervention reduces the level of frailty in people with dementia. This is an important and promising result, because frailty is a powerful predictor for adverse health outcomes, and its reduction may have positive effects on health status. Moreover, exergaming resulted in high adherence rates of physical exercise, which makes it an effective strategy to engage people with dementia in physical activity.

Recommendations for assessing motor performance in individuals with dementia: suggestions of an expert panel - a qualitative approach.

BACKGROUND: Recommendations for assessing motor performance in individuals with dementia (IWD) are rare, and most existing assessment tools previously applied in IWD were initially developed for healthy older adults. However, IWD and their healthy counterparts differ in motor and cognitive capabilities, which needs to be considered when designing studies for this population. This article aims to give recommendations for motor assessments for IWD and to promote standardisation based on a structured discussion of identified assessment tools used in previous trials. METHODS: Appropriateness and standardisation of previously applied motor assessments for IWD were intensively discussed using a qualitative approach during an expert panel. Furthermore, the use of external cues and walking aids, as well as psychometric properties were considered. Starting with a comprehensive overview of current research practice, the discussion was gradually specified and resulted in the elaboration of specific recommendations. RESULTS: The superior discussion emphasised the need for tailoring motor assessments to specific characteristics of IWD and attaching importance to standardised assessment procedures. Specific recommendations include the use of sequential approaches, which incorporate a gradual increase of complexity from simple to more difficult tasks, a selection of motor assessments showing sufficient relative reliability and appropriateness for IWD, as well as allowing external cues and walking aids when restricted to repeated instructions and commonly used devices, respectively. CONCLUSIONS: These are the first recommendations for assessing motor performance in IWD based on a comprehensive qualitative approach. Due to limited evidence, it was not possible to address all existing questions. It is therefore important to evaluate these recommendations in studies with IWD. Besides tailoring and evaluating available assessments, future research should focus on developing specific tools for IWD. Moreover, further progress in standardisation is necessary to enhance comparability between different trials. This article provides initial approaches for overcoming existing limitations in trials with IWD by giving recommendations and identifying future research questions, and therefore contributes to enhancing evidence regarding efficacy and effectiveness of physical activity interventions.

The quest for synergy between physical exercise and cognitive stimulation via exergaming in people with dementia: a randomized controlled trial.

BACKGROUND: Exercise is often proposed as a non-pharmacological intervention to delay cognitive decline in people with dementia, but evidence remains inconclusive. Previous studies suggest that combining physical exercise with cognitive stimulation may be more successful in this respect. Exergaming is a promising intervention in which physical exercise is combined with cognitively challenging tasks in a single session. The aim of this study was to investigate the effect of exergame training and aerobic training on cognitive functioning in older adults with dementia. METHODS: A three-armed randomized controlled trial (RCT) compared exergame training, aerobic training and an active control intervention consisting of relaxation and flexibility exercises. Individuals with dementia were randomized and individually trained three times a week during 12 weeks. Cognitive functioning was measured at baseline, after the 12-week intervention period and at 24-week follow-up by neuropsychological assessment. The domains of executive function, episodic memory, working memory and psychomotor speed were evaluated. Test scores were converted into standardized z-scores that were averaged per domain. Between-group differences were analysed with analysis of covariance. RESULTS: Data from 115 people with dementia (mean (SD) age = 79.2 (6.9) years; mean (SD) MMSE score = 22.9 (3.4)) were analysed. There was a significant improvement in psychomotor speed in the aerobic and exergame groups compared to the active control group (mean difference domain score (95% CI) aerobic versus control 0.370 (0.103-0.637), p = 0.007; exergame versus control 0.326 (0.081-0.571), p = 0.009). The effect size was moderate (partial η2 = 0.102). No significant differences between the intervention and control groups were found for executive functioning, episodic memory and working memory. CONCLUSIONS: To our knowledge, this is the first RCT evaluating the effects of exergame training and aerobic training on cognitive functioning in people with dementia. We found that both exergame training and aerobic training improve psychomotor speed, compared to an active control group. This finding may be clinically relevant as psychomotor speed is an important predictor for functional decline. No effects were found on executive function, episodic memory and working memory. TRIAL REGISTRATION: Netherlands Trial Register, NTR5581 . Registered on 7 October 2015.

Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis.

Combined cognitive and physical exercise interventions have potential to elicit cognitive benefits in older adults with mild cognitive impairment (MCI) or dementia. This meta-analysis aims to quantify the overall effect of these interventions on global cognitive functioning in older adults with MCI or dementia. Ten randomized controlled trials that applied a combined cognitive-physical intervention with cognitive function as an outcome measure were included. For each study effect sizes were computed (i.e., post-intervention standardized mean difference (SMD) scores) and pooled, using a random-effects meta-analysis. The primary analysis showed a small-to-medium positive effect of combined cognitive-physical interventions on global cognitive function in older adults with MCI or dementia (SMD[95% confidence interval]=0.32[0.17;0.47], p<0.00). A combined intervention was equally beneficial in patients with dementia (SMD=0.36[0.12;0.60], p<0.00) and MCI (SMD=0.39[0.15;0.63], p<0.05). In addition, the analysis showed a moderate-to-large positive effect after combined cognitive-physical interventions for activities of daily living (ADL) (SMD=0.65[0.09;1.21], p<0.01)and a small-to-medium positive effect for mood (SMD=0.27[0.04;0.50], p<0.01). These functional benefits emphasize the clinical relevance of combined cognitive and physical training strategies.

Comparison of Effect of Two Exercise Programs on Activities of Daily Living in Individuals with Dementia: A 9-Week Randomized, Controlled Trial.

OBJECTIVES: To compare the effects of two exercise programs on proxy- and performance-based measures of activities of daily living (ADLs) and to explore potential motor and cognitive mediators underlying ADL improvements in individuals with dementia. DESIGN: A parallel, three-group, single-blind, randomized, controlled trial. SETTING: Psychogeriatric wards. PARTICIPANTS: Individuals with dementia (mean age 85.6 ± 5.1). INTERVENTIONS: Each 9-week intervention consisted of thirty-six 30-minute sessions. A combined group (n = 35) participated in two strength and two walking sessions, an aerobic group (n = 35) participated in four walking sessions, and a social control group (n = 35) participated in four nonexercise social visits per week. The social group was used as a reference for the mediation analysis, which was performed in the combined and aerobic groups. MEASUREMENTS: ADLs were assessed using the Katz index (proxy-reported ADL performance), Erlangen-ADL test (E-ADL) (instrumental ADL performance), and 7-item Physical Performance Test (PPT-7) (physical ADL performance). RESULTS: There was a group effect for Katz index (P = .02), E-ADL (P < .001), and PPT-7 (P = .003). Differences from baseline to after the intervention were similar in the combined and aerobic groups. Exercise-induced changes in global cognition mediated changes in Katz index (95% confidence interval (CI) = 0.05-0.41), leg muscle strength mediated changes in E-ADL (95% CI = 0.03-0.43), and leg muscle strength (95% CI = 0.01-0.36) and walking endurance (95% CI = 0.01-0.43) mediated changes in PPT-7 only in the combined group. CONCLUSION: Physical exercise can improve ADL levels in individuals with dementia, but improvements are small and seem independent of exercise type. Additional analyses suggest that combined aerobic and strength exercise may be more effective than aerobic-only exercise to effectively target ADL dysfunction in individuals with dementia. Future research is warranted to justify these exercise-specific findings.

The Groningen Meander Walking Test: a dynamic walking test for older adults with dementia.

BACKGROUND: Current dynamic walking tests, used in studies with older adults with dementia, rely strongly on healthy cognitive and physical function. Therefore, the Groningen Meander Walking Test (GMWT) was developed specifically for people with dementia. The aim of the GMWT is to measure dynamic walking ability by walking over a meandering curved line, with an emphasis on walking speed and stepping accuracy, while changing direction. OBJECTIVE: The purpose of this study was to investigate the feasibility, test-retest reliability, and minimal detectable change (MDC) of the GMWT. DESIGN: A repeated-measures design was used. METHODS: Forty-two people with dementia participated in the study. Adherence rate, adverse events, repetition of instructions during test performance, test duration, and number of oversteps were assessed. RESULTS: The adherence rate was excellent, with no adverse events. No repetitive instructions were given during test performance, and test duration was short (mean=17.16 seconds) with few oversteps (mean=1.94 oversteps). Test-retest reliability for participants without a walking device was excellent for the GMWT time score (intraclass correlation coefficient [ICC]=.942), with an MDC of 2.96 seconds. Test-retest reliability for participants with a 4-wheeled walker (4WW) was moderate (ICC=.837), with an MDC of 10.35 seconds. For the overstep score, a marginal ICC of .630 was found, with an MDC of 4.38 oversteps. LIMITATIONS: No fall data were available, and there was a volunteer bias. CONCLUSIONS: The GMWT is a feasible test for people with dementia. With the GMWT time score, a reliable and sensitive field test to measure walking abilities in older adults with dementia is available. The GMWT overstep score can be used to give information about the execution according to protocol and should be emphasized during the instructions. Future studies need to investigate the validity of the GMWT.

Feasibility of a combined aerobic and strength training program and its effects on cognitive and physical function in institutionalized dementia patients. A pilot study.

OBJECTIVES: We examined the feasibility of a combined aerobic and strength training program in institutionalized dementia patients and studied the effects on cognitive and physical function. METHODS: Thirty-three patients with dementia, recruited from one nursing home, participated in this non-randomized pilot study (25 women; age = 85.2±4.9 years; Mini Mental State Examination = 16.8±4.0). In phase 1 of the study, seventeen patients in the Exercise group (EG) received a combined aerobic and strength training program for six weeks, five times per week, 30 minutes per session, in an individually supervised format and successfully concluded the pre and posttests. In phase 2 of the study, sixteen patients in the Social group (SG) received social visits at the same frequency, duration, and format and successfully concluded the pre and posttests. RESULTS: Indices of feasibility showed that the recruitment and adherence rate, respectively were 46.2% and 86.3%. All EG patients completed the exercise program according to protocol without adverse events. After the six-week program, no significant differences on cognitive function tests were found between the EG and SG. There was a moderate effect size in favor for the EG for the Visual Memory Span Forward; a visual attention test. There were significant differences between groups in favor for the EG with moderate to large effects for the physical tests Walking Speed (p = .003), Six-Minute Walk Test (p = .031), and isometric quadriceps strength (p = .012). CONCLUSIONS: The present pilot study showed that it is feasible to conduct a combined aerobic and strength training program in institutionalized patients with dementia. The selective cognitive visual attention improvements and more robust changes in motor function in favor of EG vs. SG could serve as a basis for large randomized clinical trials. TRIAL REGISTRATION: trialregister.nl 1230.

Recommended measures for the assessment of cognitive and physical performance in older patients with dementia: a systematic review.

UNLABELLED: AIM/GOAL: To recommend a set of neuropsychological and physical exercise tests for researchers to assess cognition and physical fitness in clinical trials with older patients with dementia; to create consensus, decrease heterogeneity, and improve research quality. METHODS: A literature search (2005-2011) yielded 89 randomized controlled trials. To provide information on test recommendations the frequency of test use, effect size of the test outcome, study quality, and psychometric properties of tests were analyzed. RESULTS: Fifty-nine neuropsychological tests (cognitive domains: global cognition, executive functioning, memory, and attention) and 10 exercise tests (physical domains: endurance capacity, muscle strength, balance, and mobility) were found. CONCLUSION: The Severe Impairment Battery, Mini Mental State Examination, and Alzheimer Disease Assessment Scale - cognitive subscale were recommended to measure global cognition. The Verbal Fluency Test Category/Letters, Clock Drawing Test, and Trail Making Test-B were recommended to measure executive functioning. No specific memory test could be recommended. The Digit Span Forward, Digit Span Backward, and Trail Making Test-A were recommended to measure attention. As physical exercise tests, the Timed Up and Go and Six Meter Walk for mobility, the Six Minute Walk Distance for endurance capacity, and the Tinetti Balance Scale were recommended.