UBC Faculty Research and Publications

Group-based exercise and cognitive-physical training in older adults with self-reported cognitive complaints:… Gregory, Michael A; Gill, Dawn P; Shellington, Erin M; Liu-Ambrose, Teresa; Shigematsu, Ryosuke; Zou, Guangyong; Shoemaker, Kevin; Owen, Adrian M; Hachinski, Vladimir; Stuckey, Melanie; Petrella, Robert J Jan 16, 2016

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STUDY PROTOCOL Open AccessGroup-based exercise and cognitive-physical training in older adults withself-reported cognitive complaints: TheMultiple-Modality, Mind-Motor (M4) studyprotocolMichael A. Gregory1,2, Dawn P. Gill2,3,4, Erin M. Shellington2,5, Teresa Liu-Ambrose6,7, Ryosuke Shigematsu8,Guangyong Zou9,10, Kevin Shoemaker5, Adrian M. Owen11, Vladimir Hachinski12, Melanie Stuckey13and Robert J. Petrella2,3,5,13,14*AbstractBackground: Dementia is associated with cognitive and functional deficits, and poses a significant personal,societal, and economic burden. Directing interventions towards older adults with self-reported cognitive complaintsmay provide the greatest impact on dementia incidence and prevalence. Risk factors for cognitive and functionaldeficits are multifactorial in nature; many are cardiovascular disease risk factors and are lifestyle-mediated. Evidencesuggests that multiple-modality exercise programs can provide cognitive and functional benefits that extend beyondwhat can be achieved from cognitive, aerobic, or resistance training alone, and preliminary evidence suggests thatnovel mind-motor interventions (i.e., Square Stepping Exercise; SSE) can benefit cognition and functional fitness.Nevertheless, it remains unclear whether multiple-modality exercise combined with mind-motor interventions canbenefit diverse cognitive and functional outcomes in older adults with cognitive complaints.Methods/Design: The Multiple-Modality, Mind-Motor (M4) study is a randomized controlled trial investigatingthe cognitive and functional impact of combined physical and cognitive training among community-dwellingadults with self-reported cognitive complaints who are 55 years of age or older. Participants are randomizedto a Multiple-Modality and Mind-Motor (M4) intervention group or a Multiple-Modality (M2) comparison group.Participants exercise for 60 minutes/day, 3-days/week for 24 weeks and are assessed at baseline, 24 weeks and52 weeks. The primary outcome is global cognitive function at 24 weeks, derived from the Cambridge BrainSciences computerized cognitive battery. Secondary outcomes are: i) global cognitive function at 52 weeks; ii)domain-specific cognitive function at 24 and 52 weeks; iii) mobility (gait characteristics under single and dual-taskconditions and balance); and 3) vascular health (blood pressure and carotid arterial measurements). We willanalyze data based on an intent-to-treat approach, using mixed models for repeated measurements.(Continued on next page)* Correspondence: petrella@uwo.ca2Lawson Health Research Institute, London, ON, Canada3Department of Family Medicine, Western University, London, ON, CanadaFull list of author information is available at the end of the article© 2016 Gregory et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Gregory et al. BMC Geriatrics  (2016) 16:17 DOI 10.1186/s12877-016-0190-9(Continued from previous page)Discussion: The design features of the M4 trial and the methods included to address previous limitations withincognitive and exercise research will be discussed. Results from the M4 trial will provide evidence of combinedmultiple-modality and cognitive training among older adults with self-reported cognitive complaints on cognitive,mobility-related and vascular outcomes.Trial Registration: ClinicalTrials.gov NCT02136368.Keywords: Multiple-modality, mind-motor, exercise, randomized controlled trial, older adults, cognitive complaints,cognition, mobility, vascular healthBackgroundCognitive impairment in agingWith the global population aging, there is a growing ur-gency to identify the most effective strategies to preventcognitive decline. Early prevention strategies may pro-vide the greatest impact on the incidence of cognitiveimpairment in aging [1]. With the goal of interveningearlier, it is of interest to examine non-demented olderadults with self-reported cognitive complaints, regardlessof whether they have objective evidence of impairment[2]. The estimated prevalence of cognitive complaints inolder adults ranges between 11 % and 56 % [3, 4]. Cogni-tive complaints have been associated with poorer scoreson objective cognitive assessments [5], as well as corticaland hippocampal atrophy [6], and each identified cogni-tive complaint increases the likelihood of cognitive im-pairment by approximately 20 % [5].Relationship between cognition and vascular diseaseVascular risk factors (e.g., hypertension, obesity) areconsidered the most readily modifiable risk factors fordementia [7]. These risk factors, especially elevationsin blood pressure (BP) and the associated arterialstiffening, reduce cerebrovascular reactivity and cere-bral blood flow, and predispose older adults to greaterrisk of hypoperfusion in the brain [8]. Sustainedhypertension and arterial stiffness are associated witha number of pathological changes in the brain [9],the occurrence of a stroke [10], the presence ofneurotropic markers of Alzheimer’s disease (AD) [11],poorer scores on objective cognitive testing [12], andclinical dementia [13]. Although there is an increasingconsensus on the role of vascular risk factors in cog-nitive impairment, few studies have investigated theeffects of modifying vascular risk factors on cognitivehealth in either healthy older adults, or in those withcognitive impairment [14].Relationship between cognition and mobilityGait dysfunction is frequently observed in older adultswith cognitive impairment [15], often precedes a diag-nosis of dementia [16], and has been suggested as apotentially modifiable risk factor for cognitive decline[16]. Specifically, reduced gait velocity and step length,and increased gait variability under usual (i.e., normalwalking) and dual-task (DT; i.e., walking while subtract-ing 7 s from 100) conditions, have been associated withimpaired executive functioning (EF) [17], underlyingcerebrovascular disease [18], and reduced prefrontaland parietal cortical volume [19] in cognitively healthyolder adults, as well as diffuse cortical atrophy [20] andabnormal neurochemical signatures within the primarymotor cortex [21], among those with mild cognitive im-pairment (MCI). Gait dysfunction has also been associ-ated with increased falls risk among cognitively healthyolder adults [22] and those with cognitive impairment[23], as well as an increased risk for institutionalizationover 5 years [24]. Interventions aimed at improving bothcognition and mobility may prove most effective at redu-cing the risk of both cognitive and functional decline.Non-pharmacological interventions to prevent cognitiveand functional declineExercise interventionsHealthy lifestyles, including vascular risk factor controlthrough the habitual participation in exercise, may be animportant strategy to prevent or slow the progression ofAD [25]. Previous meta-analyses have revealed positiveeffects of aerobic exercise on cognition, with the largesteffects on EF and global cognition in cognitively healthyolder adults [26] and those with objective cognitive im-pairment [27]. Despite this evidence, a recent Cochranereview found that there is insufficient evidence to con-clude that cognitive improvements are solely attributableto improved cardiovascular fitness [28]. Although moreresearch is needed, resistance training has been found toimpart cognitive benefits in older adults without cogni-tive impairment, including improvements in memoryand EF [29], as well as frontal lobe neurophysiology [30],and elevations in circulating neural growth factors [31].Exercise interventions aimed at improving balanceand mobility have also produced discrepant findings.A Cochrane review highlighted the paucity of evi-dence related to the effect of exercise on mobilityGregory et al. BMC Geriatrics  (2016) 16:17 Page 2 of 14outcomes (i.e., usual and DT gait) and concluded thatthe available evidence suggesting exercise can impartmoderate benefits on mobility outcomes is weak, andthat further rigorously developed randomized con-trolled trials (RCTs) are required [32].Multiple-modality exercise programs incorporate anumber of physical exercise training types (i.e., aerobic, re-sistance, flexibility, and balance) [33]. Combining multipleexercise modalities may lead to greater improvements incognition, vascular health, and functional outcomes, whencompared to programs that focus on a single modality(e.g. aerobic only or resistance only programs) [34]. Previ-ous meta-analyses in healthy older adults observed thataerobically-based, multiple-modality exercise programscan improve cognitive function, specifically EF [35] andinformation processing speed [36], to a greater extent thanaerobic exercise alone. Results from several RCTs sug-gest that similar results can be expected for thoseself-reporting cognitive complaints [37, 38] or withobjective cognitive impairment [39, 40].Participation in three months of multiple-modalitytraining or less has been associated with improved cog-nitive functioning [41], medial temporal lobe neuro-physiology [42], functional mobility [41], and usual andDT gait velocity [43] in cognitively healthy older adults.Further, improved cognitive functioning has been ob-served in older adults with self-reported cognitive com-plaints [37]. Longer duration interventions might bemore efficacious at improving cognition. Six months ofmultiple-modality exercise has been shown improveglobal cognition in older adults with self-reported cog-nitive complaints [38], as well as improve global cogni-tion and reduce cortical atrophy in older adults withobjective cognitive impairment [40], and these im-provements can be maintained for up to 12 months[38]. Further, 12 months of multiple-modality exercisecan improve global cognition, memory (immediate re-call), and verbal fluency in older adults with objectivecognitive impairment [39]. These observations suggestthat multiple-modality exercise programs can serve asan effective and multifaceted approach to benefit anumber of cognitive and functional outcomes in cogni-tively healthy older adults and in those at risk fordementia.“Traditional” cognitive training & innovative cognitive-physical(“Mind-Motor”) programsCognitive training requires the organization and dir-ection of a number of neurological processes, such asattention, perception, memory, and EF, and has beenshown to benefit cognition in aging [44]. A recentmeta-analysis revealed significant effects for cognitivetraining on EF, memory and global cognitive function-ing, when compared to active controls (e.g., groupsreceiving educational DVDs or health promotiontraining) [45]. Further, this meta-analysis suggestedsignificant effects for cognitive training on memoryand subjective cognition functioning when comparedto controls receiving no intervention [45]. Althoughthe initial observations related to the cognitive bene-fits of cognitive training are promising, the improve-ments in cognitive functioning that are garneredfollowing cognitive training are traditionally domain-specific [46].Square-Stepping Exercise (SSE) is a simple, low-cost,indoor, group-based exercise program for older adults[47]. This novel program can be best described as avisuospatial working memory task with a stepping re-sponse (i.e., “mind-motor” training) and requires partici-pants to memorize and execute progressively morecomplex foot placement patterns that involve forward,backward, lateral, and diagonal steps using a griddedfloor mat. Although SSE was originally designed to im-prove lower extremity mobility in at-risk fallers [47],pilot work suggests the potential for SSE to benefit cog-nition [48–50]. Improvements in global cognition, atten-tion, and mental flexibility were seen in cognitivelyhealthy older adults after a 16-week SSE program(40 min/day, 3 days/week) [48], and improved memoryand EF following a 26-week SSE program (1 day ofclass-based SSE/week for 50–60 min plus 10 min ofdaily SSE homework) [49]. Furthermore, improvementsin verbal learning and memory, verbal fluency and globalcognitive function were seen in older adults without de-mentia following a 6-month exercise plus DT trainingintervention (involving SSE) [50]. The available evidenceregarding the effects of SSE on cognition is still prelim-inary and has not been examined in regard to gait dys-function, and thus, future rigorously designed trials arerequired to determine the efficacy of SSE on cognitiveand functional outcomes.Rationale and study objectivesDespite these promising observations, several limita-tions related to our understanding of the cognitiveand functional benefits of exercise or cognitive train-ing remain. Questions regarding the frequency, inten-sity, time, and type of exercise that would provide thegreatest cognitive benefit are currently equivocal [51].Other external factors, including biological sex [34]and the severity of cognitive impairment [27] also ap-pear to modify the relationships of exercise with cog-nitive and physical functioning. The available evidencesuggests that aerobically-based exercise programs thatincorporate other exercise modalities (i.e., resistance,balance) and some form of cognitive training, mightimpart a significantly larger global cognitive benefitthan those that focus on a single strategy [34].Gregory et al. BMC Geriatrics  (2016) 16:17 Page 3 of 14Additional large-scale, rigorous RCTs are required to de-termine the impact of multiple-modality exercise pro-grams combined with novel cognitive training programs,on cognition and functional mobility outcomes, and to de-lineate the trajectory of these improvements as well as themaintenance of training effects after follow-up, in olderadults who may be at increased risk for future cognitivedecline [28, 51].The primary objective of this study is to determinewhether a group-based multiple-modality exercise pro-gram combined with mind-motor training [Multiple-Modality, Mind-Motor (M4)] can lead to improvedglobal cognitive functioning at 24 weeks, when com-pared to a multiple-modality exercise program alone[Multiple-Modality (M2)], among community-dwellingolder adults with self-reported cognitive complaints.The study hypothesis is that improvement in globalcognitive functioning will be observed in both groups;however, the improvement will be greater for M4 com-pared to M2. Secondary objectives include investigatingwhether M4 (when compared to M2) improves: i)global cognitive functioning at 52 weeks; ii) domain-specific cognitive functioning at 24 and 52 weeks; iii)mobility (gait characteristics under usual and DT condi-tions and balance) at 24 and 52 weeks; and iv) vascularhealth (BP and carotid arterial measurements) at 24and 52 weeks.Methods/designThis study is a two-arm, 24-week RCT with a 28-weekno-contact follow-up. Participants were randomly allo-cated (1:1) to either: 1) the intervention (M4) group; or2) the comparison (M2) group. This study is being runin four waves; the first wave commenced exercise classeson 10 February 2014 and the fourth and final wavebegan exercise classes on 30 March 2015. All study datacollection will be completed by April 2016. The designand reporting of this study follows the CONSORT(Consolidated Standards of Reporting Trials) 2010Statement for parallel group randomized trials [52].This RCT was registered with ClinicalTrials.gov on 29April 2014 (Identifier: NCT02136368).Ethics, consent and permissionsThe Western University Health Sciences Research EthicsBoard approved this study (Protocol #18858 and File#102434) and all participants provided written informedconsent prior to taking part in this study.SettingParticipants were recruited from the communities inand around Woodstock, ON, Canada. Screening visits,specific components of the measurement sessions, andthe exercises classes are held at community-basedlocations in Woodstock. Components of the measure-ment sessions that could not be completed within thecommunity take place at the Parkwood Institute inLondon, ON, Canada.Recruitment strategiesFormal recruitment commenced on 5 December 2013.Community-dwelling older adults were recruited via: 1)advertisements in the local newspapers and communitypartner publications; 2) posters at local businesses; 3)health fairs; 4) and word of mouth. Interested individualscontacted the study coordinator by phone, where theywere provided with a brief description of the study. Indi-viduals were then asked about their age, living statusand whether they had a cognitive concern. If responsessuggested study eligibility then interested individualswere invited to attend a formal in-person screening visit.ParticipantsOlder adults were eligible if they: 1) were aged55 years or older; 2) self-reported a cognitive com-plaint (i.e., answering “yes” to the question: “Do youfeel like your memory or thinking skills have gottenworse recently?”) and; 3) had preserved instrumentalactivities of daily living (based on the Lawton-BrodyInstrumental Activities of Daily Living scale) [53]. Ex-clusion criteria were: 1) probable dementia (i.e., self-reported diagnosis or Mini-Mental State Examinationscore < 24) [54]; 2) major depression [i.e., score ≥ 16on the Center for Epidemiologic Studies – DepressionScale combined with clinical judgment by the Princi-pal Investigator and study physician (R Petrella)]; 3)other neurological or psychiatric disorders; 4) recenthistory of severe cardiovascular conditions; 5) signifi-cant orthopaedic conditions; 6) BP unsafe for exercise(i.e., >180/100 mmHg and/or <100/60 mmHg) [55]; 7)severe sensory impairment; 8) unable to comprehendstudy letter of information; 9) unable to commit to atleast 80 % of exercise sessions over the 24-week inter-vention period; and 10) any other factors that couldpotentially limit the ability to fully participate in theintervention.InterventionsComparison group: Multiple-Modality (M2) exercise groupThe M2 group participated in 60-minute group-basedmultiple-modality exercise classes, 3 days per weekover 24 weeks. The class breakdown was as follows:1) 5-minute warm-up; 2) 20 minutes of moderate-to-vigorous-intensity aerobic exercise; 3) 5-minute aer-obic cool-down; 4) 10 minutes of resistance training;5) 15 minutes of balance training, range of motionand breathing exercises; and 6) 5 minutes of stretch-ing (see Table 1). The balance training, range ofGregory et al. BMC Geriatrics  (2016) 16:17 Page 4 of 14motion, and breathing exercises do not incorporatethe use of additional loading (e.g., hand weights orresistance bands), and were deemed as suitable con-trol exercises within the M2 group, as these exerciseshave not been found to impart cognitive benefits [56].Intervention group: Multiple-Modality and Mind-Motor (M4)exercise groupParticipants in the M4 group completed a similarmultiple-modality exercise class, with one exception; spe-cifically, 15 minutes of mind-motor exercise (i.e., progres-sive SSE) was substituted in place of the 15 minutes ofbalance, range of motion and breathing exercises. Thisway, participants in both groups were taking part in thesame amount of activity (60-minute classes; 3 days perweek for 24 weeks) and were receiving the same amountof social interaction and attention from the studypersonnel, with the only difference being the type of activ-ity that they received for 15 minutes during each class.The SSE was selected as the mind-motor trainingcomponent within this study. There are over 200 step-ping patterns that range in difficulty from beginner toadvanced. Participants progressed through SSE patternseach class (as a group), and started from the last suc-cessfully completed pattern performed during the previ-ous exercise session. The goal was to progress as far aspossible over the 24-week period. Participants watchedan instructor demonstrate a pattern and then attemptedto repeat the pattern (by memory) on the SSE mat(250 cm x 100 cm, partitioned in to 10 rows of 4 equal-sized squares (see Fig. 1). Participants worked in smallgroups with no more than 6 participants on an individ-ual SSE mat. In order to promote a positive social at-mosphere, participants were encouraged to assist eachother during this component of the class. In order toprogress to the next SSE pattern, at least 80 % of theparticipants had to successfully complete the pattern atleast four times in a reasonable period of time. If thegroup did not successfully complete a specific patternafter three classes then the group would progress to thenext pattern within the same difficulty level.Class size, compliance & intensityStudy-specific M2 and M4 exercise classes were heldduring morning time slots, with class sizes varying from8 to 23 participants (depending on the wave). Attend-ance at exercise classes was tracked and monitored on aregular basis. The final SSE pattern completed duringeach session was tracked, and used as the first pattern ateach subsequent training session. Participants were en-couraged to attend a minimum of 80 % of classes overthe course of the intervention period. During the no-Table 1 Description of M2 and M4 interventionsM2: Multiple-Modality Exercise Group (Comparison Group) M4: Multiple-Modality, Mind-Motor Exercise Group (Intervention Group)Warm-up (5 minutes)o Light aerobicso Dynamic range of motion of the major jointsWarm-up (5 minutes)o Light aerobicso Dynamic range of motion of the major jointsAerobic Exercise (20 Minutes)o Large rhythmical endurance activities (e.g., walking, marching,sequenced aerobics)o Keep HR continuously in target zone (i.e., not interval training)o Moderate to vigorous intensityo RPE: 5–8 on scale of 0–10o Participants to check HR ½ way through and at end of aerobic exercise.Aerobic Exercise (20 Minutes)o Large rhythmical endurance activities (e.g., walking, marching,sequenced aerobics)o Keep HR continuously in target zone (i.e., not interval training)o Moderate to vigorous intensityo RPE: 5–8 on scale of 0–10o Participants to check HR ½ way through and at end of aerobic exercise.Aerobic Cool Down (5 minutes)o Safely bringing heart rates downAerobic Cool Down (5 minutes)o Safely bringing heart rates downResistance Training (10 minutes)o Therabands, wall or chair exercises, core strengtheningo Day 1 – Upper body focuso Day 2– Lower body focuso Day 3 – Core focusResistance Training (10 minutes)o Therabands, wall or chair exercises, core strengtheningo Day 1 – Upper body focuso Day 2 – Lower body focuso Day 3– Core focusBalance, Range of Motion & Breathing(15 minutes)o Keep HR BELOW target zoneo Dynamic, static and functional balanceo Breathing and relaxation exerciseso Finger exerciseso Range of motion (e.g., arm circles)Mind-Motor Training (15 minutes)o Keep HR BELOW target zoneo Progressive, group-based, Square Stepping Exercise (SSE)Stretching (5 minutes) Stretching (5 minutes)TOTAL: 60 minutes60 minutes Multiple-Modality Exercise TOTAL: 60 minutes 45 minutes Multiple-Modality Exercise 15 minutesMind-Motor ExerciseAbbreviations: HR, heart rate; RPE, rating perceived exertionaNote: This table represents an individual session breakdown by group. Participants attended these structured 60-minute group-based exercise classes, 3 timesper week for 24 weeksGregory et al. BMC Geriatrics  (2016) 16:17 Page 5 of 14contact control period, participants in both groups wereencouraged to continue exercising; however, the studyteam did not provide the M4 group with SSE mats tocontinue SSE training or provide any additional inter-vention, and were not in contact with participants untiltheir final study visit.At the start of the study, each participant was providedwith an individualized training heart rate (65-85 % of es-timated maximum heart rate) determined via the StepTest and Exercise Prescription (STEP™) tool [57, 58].During the aerobic exercise section, participants wereencouraged to exercise at their training heart rate and/or at a rating of 5–8 on the 10-point modified BorgRating of Perceived Exertion (RPE) scale. During eitherthe balance/range-of-motion (M2 group) or the mind-motor (M4 group) components, participants wereencouraged to work at a comfortable pace with the goalof keeping heart rates below their training heart rate.Participants were instructed to record their heart rateand RPE both immediately following the aerobic exercisecomponent and then again following either the balance/range of motion (M2 group) or the mind-motor (M4group) component. In order to ensure progression inaerobic training over the 24-weeks, training heart ratesfor each participant were recalculated at the midpoint ofthe intervention (i.e., 12 weeks) via the STEP™ tool.Instructor trainingExercise classes were led by Seniors’ Fitness Instructors,certified through the Canadian Centre for Activity andAging [59]. Members from our research team underwentan in-person training session with one of the original de-velopers of the SSE program and study co-investigator(R Shigematsu). Our research team then developed theSSE protocol to be used as the mind-motor componentwithin the M4 group and conducted training with all in-structors on the M2 and M4 class exercise protocols, inorder to ensure standardized delivery of the programs.Outcome assessmentOutcomes are measured at baseline, 24 weeks (interven-tion endpoint) and 52 weeks (study endpoint) (see Fig. 2).Measurement sessions were conducted over 2 to 3 con-secutive days; training emphasizes strict adherence to allwritten study protocols. All participants, regardless ofFig. 1 Description of Square Stepping Exercise (SSE). Participants arerequired to progress across a gridded floor mat while completingsteps that are identical to a previously demonstrated foot placementpattern. As individuals progress, stepping pattern complexity iselevated in order to increase difficulty levels and match theindividuals progressed performance capacities. Examples ofbeginner, intermediate and advanced patterns are shownFig. 2 Study FlowGregory et al. BMC Geriatrics  (2016) 16:17 Page 6 of 14their compliance with the exercise intervention, are tele-phoned one month in advance to book appointments.Baseline dataBaseline measurements were obtained prior to rando-mization. In addition to the measurements describedbelow, the following were also collected: demographicand general health characteristics; medical history andmedications; anthropometric and fitness measure-ments; cognitive functioning using the Montreal Cog-nitive Assessment (MoCA) [60]; and current physicalactivity levels using the Phone-FITT physical activityinterview [61].Measurement protocolsCognition Global cognitive functioning, as well asdomain-specific cognitive functioning, is calculatedusing the Cambridge Brain Sciences (CBS) computerizedcognitive battery (www.cambridgebrainsciences.com).The CBS contains 12 non-verbal, culturally independenttests, which cover four broad cognitive domains (i.e.,memory, reasoning, concentration, planning or EF) [62](see Table 2). Six of the 12 tasks emphasize abstract rea-soning, planning and problem solving, and these taskswere specifically included since they correlate highlywith measures of general fluid intelligence [63]. TheCBS tasks are fully automated, and have been used to ef-fectively evaluate cognition in a several large-scale,population-based studies [46, 62]. The CBS cognitivebattery is a computerized adaptive testing platform thatrandomly generates novel versions of the tasks betweenindividual trials and can be administered in 60 minutes,thereby eliminating the potential to observe specific test-related practice effects or participant fatigue that arecommon to traditional paper-based cognitive assess-ments. The CBS tasks are conducted using laptop com-puters and a trackball mouse using authorized copiesthat have been obtained from one of the original devel-opers and study co-investigator (A Owen). The CBS isadministered on Day 1 of each measurement session forfamiliarization purposes only, in order to ensure partici-pants feel comfortable using the trackball mouse and alsoto prevent any learning effects [62]. On Day 2 of themeasurement session, the CBS testing session occurs.Composite scores for each cognitive domain will bederived using previously published methods [64] as fol-lows: i) calculating baseline group means and standarddeviations from each task; ii) for each task, convertingscores to standardized z scores (subtracting baselinegroup mean from raw score and dividing by baselinegroup SD); and then iii) within each domain, averagingtask standardized scores to create domain-specific stan-dardized scores. The four domain-specific standardizedscores will then be averaged to create a global cognitivefunctioning score.Ambulatory BP monitoring Participants are fitted witha 24-hour ambulatory BP monitor (Model 90207,Spacelabs Inc., Redmond, WA, USA). A total of 40readings are recorded over a 24-hour period, withone measurement obtained every half hour during theday (06:00–22:00), and once every hour during thenight (22:00–06:00). Participants are instructed torelax the arm and remain still during cuff inflationand deflation; in case of measurement error, themonitor performs an automatic repeat attempt twominutes later. Participants are instructed to keep thecuff on for the entire 24-hour period and to abstainfrom showering or water activities. An activity log isprovided to record any events that could affect BP,such as physical activity or stressful situations. Aminimum of 32 measurements (80 %) will be requiredfor statistical analysis. Systolic and diastolic ambulatoryBP will be averaged for day-time hours, night-time hours,and then over the entire 24-hour period [65].Common carotid arterial ultrasonography Participantsare instructed to avoid engaging in vigorous exercise ordrink alcohol for 24 hours, avoid caffeine and smokingfor 12 hours, and fast for 4 hours prior to the ultrasoundmeasurement. Participants are instrumented with astandard three lead electrocardiogram and undergo10 minutes of supine rest in a quiet, temperature con-trolled room. With the participant’s head turned ap-proximately 45 degrees towards the left, a 10Mhztransducer is placed longitudinally along the right ca-rotid artery, 1–2 cm proximal to the carotid sinus, toobtain two-dimensional B-mode ultrasound images(Vingmed System 5, GE Ultrasound A/S, Horton,Norway). Right common carotid arterial diameters aremeasured in triplicate from wall to wall, and from wallto intima media layer at end diastole and peak systole.Doppler ultrasound is used to collect pulse wave for60 seconds. Following acquisition of the ultrasound im-ages, carotid pulse pressure is inferred from supine bra-chial arterial BP (BPM-100, BPTru™ Medical Devices,Coquitlam, BC, Canada). Anatomic land marking is usedto ensure that all ultrasound images are obtained fromthe same portions of the carotid artery and to ensure ac-curate comparisons over time.Carotid arterial compliance (CAC) will be deter-mined using the following equation: CAC = [π(Dmax/2)2 – π(Dmin/2)2]/ΔP [66], where Dmax is the systoliccarotid arterial diameter, Dmin is the diastolic carotidarterial diameter, and ΔP is the automated supinebrachial pulse pressure. Carotid intima-media thick-ness (IMT) will be determined by subtracting theGregory et al. BMC Geriatrics  (2016) 16:17 Page 7 of 14Table 2 Description of Cambridge Brain Sciences cognitive batteryTask Name Cognitive Domain Brief Description Outcome Measure1. Monkey Ladder Memory Sets of numbered squares are displayed all at thesame time at random locations within aninvisible 5x5 grid. After a variable interval, thenumbers are removed leaving just the blanksquares visible. A tone cues the participant torespond by clicking on the squares in ascendingnumerical sequence.Maximum level achieved(Visuospatial working memory) The amount of squares presented increases ordecreases by 1 after each trial depending onwhether they responded correctly. The first trialcontains 4 numbered squares.2. Grammatical Reasoning Reasoning Problems of the form “The square is notencapsulated by the circle” are displayed on thescreen and the participant must indicate whetherthe statement correctly describes a pair ofobjects displayed in the centre of the screen.Total score(Verbal Reasoning) In order to achieve maximum points, theparticipant must solve as many problems aspossible within the given time. The total scoreincreases or decreases by 1 after each trialdepending on whether they responded correctly.3. Double Trouble Reasoning A coloured word is displayed at the top of thescreen (e.g., the word RED drawn in blue ink).Participants must indicate which of two colouredwords at the bottom of the screen describes thecolour that the word at the top of the screen isdrawn in. The colour word mappings may becongruent, incongruent, or doubly incongruent,depending on whether or not the colours that agiven word describes matches the colour that it isdrawn in.Total score(Colour-Word Remapping) To gain maximum points, the participant mustsolve as many problems as possible within thegiven time. The total score increases ordecreases by 1 after each trial depending onwhether they responded correctly.4. Odd One Out Reasoning A 3x3 grid of cells is displayed on the screen.Each cell contains a variable number of copies ofa coloured shape. The features that make up theobjects in each cell (colour, shape, number ofcopies) are related to each other according to aset of rules. The participant must deduce therules that relate the object features and selectthe one cell whose contents do not correspondto those rules.Total correct(Deductive Reasoning) To gain maximum points, the participant mustsolve as many problems as possible. If theresponse is correct, the total score increases byone point and the next problem is morecomplex. If the response is incorrect, the totalscore decreases by 1 point.5. Spatial Span Blocks Memory 16 squares are displayed in a 4x4 grid. A subsetof the squares flash in a random sequence at arate of 1 flash every 900 ms. Subsequently, themouse cursor is displayed and a tone cues theparticipant to repeat the sequence by clicking onthe squares in the same order in which theyflashed.Maximum level achieved(Spatial Span) To gain maximum points, the participant mustsolve as many problems as possible. If theresponse is correct, the number of illuminatedsquares increases by one. If the response isincorrect, the number of illuminated squaresdecreases by 1. The first trial contains 4illuminated squares.6. Rotations Concentration In this variant, 2 grids of coloured squares aredisplayed to either side of the screen with 1 ofthe grids rotated by a multiple of 90°. Whenrotated, the grids are either identical or differ bythe position of at least 1 square. In order to gainmaximum points, the participant must indicatewhether the grids are identical, solving as manyproblems as possible.Total score(Spatial Rotations) If the response is correct, the total scoreincreases by the number of squares in the gridand subsequent trials have more squares. If theresponse is incorrect, the total score decreasesby the number of squares in the grid andsubsequent trials have fewer squares. The firstgrids contain 4 coloured squares each.7. Feature Match Task Concentration Two grids are displayed on the screen, eachcontaining a set of abstract shapes. In half of thetrials the grids differ by just one shape. In orderto gain maximum points, the participant mustindicate whether or not the grid contents areidentical, solving as many problems as possible.Total scoreIf the response is correct, the total scoreincreases by the number of shapes in the gridand the number of shapes in subsequent trialsincreases. If the response is incorrect the totalscore decreases by the number of shapes in thegrid and subsequent trials have fewer shapes.The first grids contain four abstract shapes each.8. Digit Span Memory Participants view a sequence of digits thatappear on the screen one after another.Subsequently, participants are required to repeatthe sequence of numbers by using the mousecursor to click a series of numbered buttons thatappear along the bottom of the screen.Maximum level achievedIf the response is correct, the total length of thesequence increases by 1. If the response isincorrect, the total length of the sequencedecreases by 1. The first trial contains afour-digit sequence.Gregory et al. BMC Geriatrics  (2016) 16:17 Page 8 of 14carotid arterial lumen diameter from the arterial diameterat diastole. Two trained technicians are responsible forobtaining and analyzing all ultrasound images, with thesame technician performing all assessments on a givenparticipant whenever possible. Immediately following theultrasound measurement, all participants are offered astandardized snack.Gait Spatiotemporal gait characteristics are collectedusing a portable electronic walkway system with embed-ded pressure sensors [GAITRite® System; 580 x 90 x.63 cm (L x W x H), an active electronic surface area 792x 610 cm (L x W), with a total of 29,952 pressure sensors,scanning frequency of 60 Hz, Software version 4.7.1, CIRSystems, Peekskill, NY, USA]. The pressure exerted by thefeet during ambulation across the mat activates the em-bedded pressure sensors in order to sense and digitally re-construct the relative arrangement of footfall patternswithin a two-dimensional space. The GAITRite® is a validand reliable tool for gait analysis in healthy older adults[67] and in those with mobility impairments [68]. Partici-pant start and endpoints are positioned 1.5 metres fromeither end of the mat in order to avoid the recording of ac-celeration and deceleration phases of the gait cycle [68].Following the demonstration of a usual (i.e., standardgait with no DT demands) walk by the assessor,participants complete two usual walking trials at theirpreferred speed (i.e., a single habitualization trialfollowed by a single collected trial that is to be usedfor analysis). Participants then perform three separateDT walking conditions (counting backwards by ones;phonemic verbal fluency task; subtracting serial sevens) ata self-selected “usual” pace; for each condition, partici-pants will complete two trials (across the mat and thenback to the starting point). There will be no instruction toprioritize gait or responses to the cognitive tasks dur-ing the DT conditions. For the “counting backwardsby ones” condition and the serial subtraction condi-tion, participants are instructed to start from 100, 90,and 80 at baseline, 24 weeks and 52 weeks, respect-ively. For the phonemic verbal fluency condition, par-ticipants are instructed to name as many animals,vegetables, and countries, at baseline, 24 weeks, and52 weeks respectively.The gait performance from the two trials for each DTcondition will be combined and the average performancewithin specific gait parameters will be used for analysis.Under both usual and DT conditions, the following willbe examined: average gait velocity (cm/s), step length(cm), and stride time variability [coefficient of variation(CoV), expressed as a percentage = (SD/mean) x 100]. Inrecordings of the usual and DT walks, footfalls that doTable 2 Description of Cambridge Brain Sciences cognitive battery (Continued)9. Hampshire Tree Task Planning Nine numbered beads are positioned on a treeshaped frame. The participant repositions thebeads one-by-one so that they are configured inascending numerical order running from left toright and top to bottom of the tree.Total score(Spatial Planning) After each trial, the total score is incremented byadding the minimum number of movesrequired × 2 (the number of moves actuallymade), thereby rewarding efficient planning.10. Paired Associates Memory Boxes are displayed at random locations on aninvisible 5x5 grid. The boxes open one afteranother to reveal an enclosed object.Subsequently, the objects are displayed inrandom order in the centre of the grid and theparticipant must click on the boxes thatcontained them.Maximum level achievedIf the response is correct, the total number ofobjects increases by 1. If the response isincorrect, the total number of objects decreasesby 1, and subsequent trials have fewer objects.The first trial contains 4 objects.11. Polygons Concentration A pair of overlapping polygons is displayed onone side of the screen. In order to gainmaximum points, the participant must indicatewhether a polygon displayed on the other sideof the screen is identical to one of theinterlocking polygons, solving as many problemsas possible.Total score(Interlocking polygons) If responses are correct, the total score increasesby the difficulty level and the differencesbetween the polygons becomes increasinglysubtle.If the responses are incorrect, the total scoredecreases by the difficulty level and thedifference between the polygons become morepronounced.12. Spatial Search Planning Sets of boxes are displayed on the screen inrandom locations within an invisible 5x5 grid.Theparticipant must find a hidden “token” by clickingon the boxes one at a time to reveal theircontents. When the token is found, it is hiddenwithin another box.Maximum level achieved(Self-Ordered Search) If the response is correct, the total number ofboxes increases by 1. If the response is incorrect,the total number of boxes decreases by 1, andsubsequent trials have fewer boxes. The first trialcontains 5 boxes.Note: All tasks are performed for a total of 5 minutes; three 90-second blocks, separated by two 15-second rest periods. During the rest periods, the neuropsycho-logical tasks are hidden from view. Following each rest period, the task is returned to view, and participant continue from the last, correctly completed levelof difficultyGregory et al. BMC Geriatrics  (2016) 16:17 Page 9 of 14not entirely fall on the walkway at the start and the endwill be removed prior to analyses.Balance Balance is assessed using the Fullerton Ad-vanced Balance (FAB) Scale, a valid and reliable tool thatwas developed to identify emerging static and dynamicbalance issues in functionally independent older adults[69]. Individual performance across 10 separate balancetasks is evaluated and scored on a Likert Scale (rangingfrom 0–4) following strictly defined criteria. The individ-ual scores are summed to provide a total balance score,where higher scores reflect better balance performance(score ranges from 0 to 40).Other measurements Other measurements were takenin order to further describe the sample, help withexplaining study findings, and for planned sensitivityanalyses.The Phone-FITT: This interview can be administeredover the phone or in person, and is a valid and reliablemethod to evaluate both instrumental activities of dailyliving (household activity) and leisure time activities(recreational activity) [61]. The Phone-FITT evaluatesthe frequency of activities, the average duration of par-ticipation during a given bout of the activity, and theperceived intensity at which the activity was performed,during an average week in the past month. Summaryscores are calculated for household, recreational andtotal physical activity. In addition to being measured in-person as part of the measurement sessions, the Phone-FITT was also administered via telephone each monththroughout exercise intervention, in order to track otheractivity that participants were undertaking.Clinic BP. Following 5 minutes of seated rest, BP ismeasured in triplicate from the brachial artery using anautomated oscillometer (BPM-100, BPTru™ Medical De-vices, Coquitlam, BC, Canada), with each measure sepa-rated by a 2-minute rest period. Clinic BP will becalculated as the average of the last two measurements.Anthropometric measurements: Body weight (to thenearest kg) is measured with a standard weigh scale andheight (to the nearest cm) is measured with a stadiometer(Health-o-Meter, Continental Scale Corp., Chicago, Il,USA). Waist circumference (to the nearest cm) is alsomeasured following a normal exhalation at the mid-pointbetween the twelfth rib and the upper boarder of the iliaccrest [55].Fitness: Predicted maximal oxygen uptake (pVO2max)is calculated using the STEP™ tool [57, 58]. Partici-pants are instructed to step up and down a set oftwo steps (20 cm high), 20 times, at a comfortablepace. An algorithm using age, sex, time to completethe test, and post-test heart rate generates the pVO2-max. This tool is also used to provide participantswith a target heart rate for exercise at the start of thestudy and again at the mid-way point of the exerciseintervention (as described previously).Sample sizeThe sample size calculation is based on the primary out-come and analysis. To our knowledge, no study to datehas observed the effect of a 6-month multiple-modalityand mind-motor exercise intervention on global cogni-tive functioning in older adults with cognitive com-plaints. A meta-analysis on the impact of aerobic fitnesstraining on cognition in older adults suggested thatphysical exercise can improve cognition with an effectsize of d = 0.48 [35]. Although the CBS is grounded inwell-validated neuropsychological tests [46], it has notbeen used to date as an outcome in published exerciseintervention studies. For these reasons, sample size forthe proposed study must be approximated by using theeffect size approach, combined with feasibility and com-parisons to sample sizes used in other similar studies.With 52 participants per group, our study would have80 % power at the 5 % significance level to detect an ef-fect size (mean difference divided by SD) of 0.55, a mod-erate effect size. We estimated a dropout rate of 20 %during the 24-week period, which increased our calcula-tion to 65 participants per group. Thus, we proposedthat 130 participants (65 participants per group) is a rea-sonable sample size.The 20 % drop out rate is conservative since we ob-served a drop out rate of 16 % in a previous study[50]. This sample size may also be considered conser-vative since we will be using a variant of Analysis ofCovariance (ANCOVA) to perform data analysis forthe primary outcome. This proposed sample size isalso in line with two exercise intervention studies forolder adults with cognitive complaints; specifically,the MAX trial [37], where 126 individuals were en-rolled, and a trial by Lautenschlager et al. [38], where170 participants were enrolled.Randomization and allocation concealmentThe randomization sequence was computer-generated(1:1 in one block of 130) and concealed using envelopesuntil interventions were assigned. Following baselinemeasurement, the Research Coordinator (who was notinvolved in generating the randomization sequence)enrolled and allocated participants to either the M4or M2 group.BlindingThe CBS cognitive battery measurement will be blindedat 24 and 52 weeks. Additionally, wherever possible,study personnel conducting other aspects of the assess-ments will be blinded to group allocation. Due to theGregory et al. BMC Geriatrics  (2016) 16:17 Page 10 of 14nature of the intervention, neither participants nor theexercise instructors can be blinded to group allocation.The principal investigator and investigators conductingthe statistical analysis are also be blinded to groupallocation.Statistical methodsWe will analyze data based on an intent-to-treat ap-proach, using mixed models for repeated measure-ments, which encompasses ANCOVA as a specialcase [70]. Therefore, we will include all enrolled par-ticipants in analyses and analyze data according tothe randomization scheme. For our primary outcome,we will examine the difference between the M4 andM2 groups at 24 weeks in mean change of globalcognitive functioning. Our secondary analysis will includeexamining the difference between groups at 52 weeks inmean change of global cognitive functioning. Next, we willexamine differences between groups at 24 at 52 weeks oni) cognitive outcomes: memory, reasoning, concentrationand EF; ii) mobility-related outcomes: usual and DT gaitvelocity, step length and stride time variability, and totalFAB score; and iii) vascular outcomes: 24-hour systolicand diastolic BP, CAC, and carotid IMT.For our primary outcome, we will also conduct sensi-tivity analyses whereby: 1) we will additionally adjust forage, sex, and baseline cardiorespiratory fitness; and 2)we will only include participants who complete a 24-week assessment and attend at least 80 % of exerciseclasses (i.e., “all-completers analysis”). For our primaryanalysis, we will also examine interactions involving age,sex, and baseline cognitive functioning (via the MoCAscore). Two-sided P-values less than 0.05 will be claimedas statistically significant; however, interpretation ofstudy results will primarily be based on estimation andassociated 95 % confidence intervals [52].DiscussionThis study will evaluate the effects of a 24-weekmultiple-modality plus mind-motor exercise programon global cognitive functioning, as well as domain-specific cognitive functioning, indices of cardiovascu-lar health, and functional mobility in a sample ofcommunity-dwelling older adults with subjective cog-nitive complaints.With the aging population and increased life ex-pectancy, novel interventions aimed at preventing orslowing the onset of chronic diseases are needed. Thecognitive continuum in aging suggests that strategiesaimed at preventing or mitigating the progression ofcognitive impairment might be most effective whentargeting individuals who are within the earliest phasealong the pathological cognitive continuum (i.e., prior tothe establishment of objective cognitive impairment) [1].Improving cognition or reducing the risk of cognitive de-cline in individuals who report cognitive concerns mayhelp to reduce the future incidence of more serious formsof cognitive impairment [2].Physical and cognitive activities, social engagementand vascular risk factor modification have all been sug-gested as important strategies for the prevention ofcognitive decline [71]. Literature suggests that healthyolder adults [41], as well as those with MCI [39] haveimproved EF following multiple-modality exercise pro-grams. Further, initial research related to cognitivetraining has shown improvements in cognition, albeitdomain-specific improvements in healthy older adults[46]. Recent evidence continues to suggest that cogni-tive training interventions produce cognitive improve-ments that are reserved for the cognitive domains that areactively being trained [46] and unless there is significantprogression in task difficulty through the intervention,there are very little transfer effects encountered [34, 72].By combining exercise and cognitive training pro-grams, improvements in cognitive functioning may beadditive [34]. The combination of a cognitive trainingparadigm within a physical exercise program may be su-perior to interventions that deliver these training modal-ities in isolation [34, 72]. The mind-motor interventionused in this study, Square-Stepping Exercise (SSE), com-bines physical and cognitive tasks and also promotes so-cial engagement, which itself has been shown to benefitcognition [73]; thus, SSE might be a preferred cognitivetraining program for older adults compared to otheravailable options (i.e., computerized cognitive training).Combining group-based multiple-modality exercisetraining with mind-motor training may provide concur-rent and complementary cognitive and vascular benefits,while providing greater cognitive benefits than eitherintervention alone.The vascular benefits of aerobically-based exercisetraining are well documented; however, the impact ofaerobic exercise on cognition and brain health has yet tobe unequivocally discerned [28, 34]. Further, although anumber of studies have investigated the cognitive bene-fits of cognitive training, there remains very little evi-dence regarding the potential vascular benefits that canbe garnered through cognitive training. By combining amultiple-modality exercise program with mind-motortraining, we aim to reduce risk factor burden related toa number of chronic diseases and conditions, includingcardiovascular disease, mobility limitations, and cogni-tive impairment and dementia, in an attempt to providethe most effective strategy to promote active and suc-cessful aging [72].Limitations of the design and implementation of thestudy must also be considered. Participation was limitedto a group of motivated volunteers, available duringGregory et al. BMC Geriatrics  (2016) 16:17 Page 11 of 14daytime hours, who are able to commit to a 24-weekexercise program. In this study, we chose to use anactive control group (M2 exercise program) as ourcomparison group rather than including an inactivecontrol group. However, recent reviews [74] havedrawn attention to the limited number of investiga-tions on the effects of exercise in older adults withcognitive impairment that include an active controlgroup comparison, and have recommended that fu-ture studies address this issue. The inclusion of anactive control group allows for the control of otherfactors such as the social interaction associated withgroup exercise classes; however, there is evidence thatimplicates low intensity exercise interventions withimprovements in cognition and physical function [37].Future studies might consider also including usual-care control groups, in addition to an active compari-son group in their study design. The definition ofwhat classifies a “subjective cognitive complaint” hasyet to be elucidated in the literature. We chose touse a simple question to measure whether individualshad self-reported a cognitive complaint, following themethods used by Barnes and colleagues [37]. Futurestudies should consult the recently published concep-tual framework [75] in order to determine the mostappropriate methods to evaluate subjective cognitivedecline and accurately identify individuals who are atincreased risk for dementia [2].With the global population aging, there is growingurgency to identify the most effective methods to re-duce cardiovascular disease risk factor burden, theestablishment of functional limitations, and the devel-opment of cognitive impairment. The Multiple-Modality,Mind-Motor study has been designed to simultan-eously address these concerns and determine whethera multiple-modality exercise program combined withmind-motor training can improve cognition, vascularhealth, and mobility in older adults with cognitivecomplaints, to a greater extent than multiple-modalityexercise programs alone.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsMG participated in the study design and acquisition of data and helped todraft the manuscript. DG participated in the conception, design, andcoordination of the study and helped to draft the manuscript. ESparticipated in the acquisition of data and helped to draft the manuscript.TLA participated in the conception and design of the study. RS participatedin the design of the study. GZ participated in the design of the study. KSparticipated in the conception and design of the study. AO participated inthe design of the study. VH participated in the conception and design of thestudy. MS participated in the study design and acquisition of data andhelped to draft the manuscript. RP conceived the study, and participated inits design and coordination and helped to draft the manuscript. All authorsread and approved the final manuscript.Authors’ informationMichael A. Gregory and Dawn P. Gill Designates Co-First Authors.AcknowledgementsGraduate students and Research Assistants: John Bocti, Joe Decaria, AshleighDe Cruz, Amanda Deosaran, Noah Koblinsky, and Sam Titheridge. Seniors’Fitness Instructor Team: Lacy Bertin, Beth Munro, Sylvia Smith Nancy Scott,and other volunteers from South Gate Centre for Active Adults 50+ inWoodstock, Ontario. Community partners in Woodstock, Ontario: South GateCentre for Active Adults 50+ (Executive Director: Chris Cunningham);Woodstock Health & Fitness (President: Kapil Verma); Maranatha ChristianReformed Church; and Salvation Army Community Church. Funding wasprovided by: Canadian Institutes of Health Research (Grant #: MOP 130474);St. Joseph’s Health Care Foundation (Grant #: 048–1415); and Fellowships inthe Care of the Elderly Research, training awards through the Aging,Rehabilitation, and Geriatric Care Research Centre of the Lawson HealthResearch Institute in partnership with the St. Joseph’s Health CareFoundation (authors MG and DG).Author details1Health and Rehabilitation Sciences, Western University, London, ON, Canada.2Lawson Health Research Institute, London, ON, Canada. 3Department ofFamily Medicine, Western University, London, ON, Canada. 4Department ofEpidemiology, University of Washington, Seattle, WA, USA. 5School ofKinesiology, Western University, London, ON, Canada. 6Department ofPhysical Therapy, University of British Columbia, Vancouver, BC, Canada.7Djavad Mowafaghian Centre for Brain Health, Vancouver, BC, Canada.8Faculty of Education, Mie University, Tsu, Japan. 9Robarts Clinical Trials ofRobarts Research Institute, Western University, London, ON, Canada.10Department of Epidemiology and Biostatistics, Western University, London,ON, Canada. 11The Brain and Mind Institute, Western University, London, ON,Canada. 12Department of Clinical Neurological Sciences, Western University,London, ON, Canada. 13Canadian Centre for Activity and Aging, Faculty ofHealth Sciences, Western University, London, ON, Canada. 14Centre forStudies in Family Medicine, Western Centre for Public Health and FamilyMedicine, Second Floor, Western University, 1465 Richmond St., London, ONN6G 2M1, Canada.Received: 13 October 2015 Accepted: 6 January 2016References1. 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