Protocol for the Brain Health Support Program Study of the Canadian Therapeutic Platform Trial for Multidomain Interventions to Prevent Dementia (CAN-THUMBS UP): A Prospective 12-Month Intervention Study.

BACKGROUND/OBJECTIVES: CAN-THUMBS UP is designed as a comprehensive and innovative fully remote program to 1) develop an interactive and compelling online Brain Health Support Program intervention, with potential to positively influence dementia literacy, self-efficacy and lifestyle risk factors; 2) enroll and retain a community-dwelling Platform Trial Cohort of individuals at risk of dementia who will participate in the intervention; 3) support an open platform trial to test a variety of multidomain interventions that might further benefit individuals at risk of dementia. This manuscript presents the Brain Health Support Program Study protocol. DESIGN/SETTING: Twelve-month prospective multi-center longitudinal study to evaluate a fully remote web-based educational intervention. Participants will subsequently be part of a Platform Trial Cohort and may be eligible to participate in further dementia prevention clinical trials. PARTICIPANTS: Three hundred fifty older adults who are cognitively unimpaired or have mild cognitive impairment, with at least 1 well established dementia risk factor. INTERVENTION: Participants engage in the Brain Health Support Program intervention for 45-weeks and complete pre/post intervention measures. This intervention is designed to convey best available evidence for dementia prevention, consists of 181 chapters within 8 modules that are progressively delivered, and is available online in English and French. The program has been developed as a collaborative effort by investigators with recognized expertise in the program's content areas, along with input from older-adult citizen advisors. MEASUREMENTS: This study utilizes adapted remote assessments with accessible technologies (e.g. videoconferencing, cognitive testing via computer and mobile phone, wearable devices to track physical activity and sleep, self-administered saliva sample collection). The primary outcome is change in dementia literacy, as measured by the Alzheimer's Disease Knowledge Scale. Secondary outcomes include change in self-efficacy; engagement using the online program; user satisfaction ratings; and evaluation of usability and acceptance. Exploratory outcomes include changes in attitudes toward dementia, modifiable risk factors, performance on the Neuropsychological Test Battery, performance on self-administered online cognitive assessments, and levels of physical activity and sleep; success of the national recruitment plan; and the distribution of age adjusted polygenic hazard scores. CONCLUSIONS: This fully remote study provides an accessible approach to research with all study activities being completed in the participants' home environment. This approach may reduce barriers to participation, provide an easier and less demanding participant experience, and reach a broader geography with recruitment from all regions of Canada. CAN-THUMBS UP represents a Canadian contribution to the global World-Wide FINGERS program (alz.org/wwfingers).

Oxylipin profiling in endothelial cells in vitro - Effects of DHA and hydrocortisone upon an inflammatory challenge.

Omega-3 poly-unsaturated fatty acids have been shown to have beneficial effects on several inflammatory-driven endpoints such as cardiovascular diseases. The anti-inflammatory effects of docosahexaenoic acid (DHA) are largely mediated through various oxylipins. Yet, mechanistic insights are limited. Here, we measured 53 oxylipins using LC-MS/MS in an in vitro model of endothelial cell inflammation, and compared the changes induced by DHA to hydrocortisone, a well-established anti-inflammatory drug. DHA modified several oxylipins derived from different precursors such as DHA, AA, LA and EPA. In response to a TNFα and IL-1-ß challenge, DHA clearly reduced many COX-derived pro-inflammatory oxylipins, yet to a minor extent when compared to hydrocortisone. DHA also upregulated metabolites from the CYP and LOX pathways as opposed to hydrocortisone. Thus, DHA reduced pro-inflammation and enhanced pro-resolution, while hydrocortisone blunted both the pro- and anti-inflammatory pathways. Our results may fuel further research on the mitigation of corticosteroids adverse side-effects.

Incidence and risk factors for healthcare utilisation among patients discharged on outpatient parenteral antimicrobial therapy.

Outpatient parenteral antimicrobial therapy (OPAT) programmes facilitate hospital discharge, but patients remain at risk of complications and consequent healthcare utilisation (HCU). Here we elucidated the incidence of and risk factors associated with HCU in OPAT patients. This was a retrospective, single-centre, case-control study of adult patients discharged on OPAT. Cases (n = 63) and controls (n = 126) were patients that did or did not utilise the healthcare system within 60 days. Characteristics associated with HCU in bivariate analysis (P ≤ 0.2) were included in a multivariable logistic regression model. Variables were retained in the final model if they were independently (P < 0.05) associated with 60-day HCU. Among all study patients, the mean age was 55 ± 16, 65% were men, and wound infection (22%) and cellulitis (14%) were common diagnoses. The cumulative incidence of 60-day unplanned HCU was 27% with a disproportionately higher incidence in the first 30 days (21%). A statin at discharge (adjusted odds ratios (aOR) 0.23, 95% confidence intervals (CIs) 0.09-0.57), number of prior admissions in past 12 months (aOR 1.48, 95% CIs 1.05-2.10), and a sepsis diagnosis (aOR 4.62, 95% CIs 1.23-17.3) were independently associated with HCU. HCU was most commonly due to non-infection related complications (44%) and worsening primary infection (31%). There are multiple risk factors for HCU in OPAT patients, and formal OPAT clinics may help to risk stratify and target the highest risk groups.

Post-surgical mediastinitis due to carbapenem-resistant Enterobacteriaceae: Clinical, epidemiological and survival characteristics.

Invasive infections due to carbapenem-resistant Enterobacteriaceae (CRE), including polymyxin-resistant (PR-CRE) strains, are being increasingly reported. However, there is a lack of clinical data for several life-threatening infections. Here we describe a cohort of patients with post-surgical mediastinitis due to CRE, including PR-CRE. This study was a retrospective cohort design at a single cardiology centre. Patients with mediastinitis due to CRE were identified and were investigated for clinically relevant variables. Infecting isolates were studied using molecular techniques. Patients infected with polymyxin-susceptible CRE (PS-CRE) strains were compared with those infected with PR-CRE strains. In total, 33 patients with CRE mediastinitis were studied, including 15 patients (45%) with PR-CRE. The majority (61%) were previously colonised. All infecting isolates carried blaKPC genes. Baseline characteristics of patients with PR-CRE mediastinitis were comparable with those with PS-CRE mediastinitis. Of the patients studied, 70% received at least one agent considered active in vitro and most patients received at least three concomitant antibiotics. Carbapenem plus polymyxin B was the most common antibiotic combination (73%). Over 90% of patients underwent surgical debridement. Overall, in-hospital mortality was 33% and tended to be higher in patients infected with PR-CRE (17% vs. 53%; P=0.06). In conclusion, mediastinitis due to CRE, including PR-CRE, can become a significant challenge in centres with CRE and a high cardiac surgery volume. Despite complex antibiotic treatments and aggressive surgical procedures, these patients have a high mortality, particularly those infected with PR-CRE.

Gut microbial metabolism of polyphenols from black tea and red wine/grape juice is source-specific and colon-region dependent.

The colonic microbial degradation of a polyphenol-rich black tea extract (BTE) and red wine/grape juice extract (RWGE) was compared in a five-stage in vitro gastrointestinal model (TWINSHIME). Microbial metabolism of BTE and RWGE polyphenols in the TWINSHIME was studied subsequently in single- and continuous-dose experiments. A combination of liquid or gas chromatography with mass spectrometry (LC-MS or GC-MS) and NMR-based metabolic profiling was used to measure selected parent polyphenols, their microbial degradation into phenolic acids, and the production of short-chain fatty acids (SCFAs) in different colon compartments. Acetate production was increased by continuous feeding of BTE but not RWGE. During RWGE feeding, gallic acid and 4-hydroxyphenylpropionic acid remained elevated throughout the colon, while during BTE feeding, they were consumed in the distal colon, while 3-phenylpropionic acid was strongly produced. Gut microbial production of phenolics and SCFAs is dependent on colon location and polyphenol source, which may influence potential health benefits.

Learning to visually perceive the relative mass of colliding balls in globally and locally constrained task ecologies.

Novice observers differ from each other in the kinematic variables they use for the perception of kinetic properties, but they converge on more useful variables after practice with feedback. The colliding-balls paradigm was used to investigate how the convergence depends on the relations between the candidate variables and the to-be-perceived property, relative mass. Experiment 1 showed that observers do not change in the variables they use if the variables with which they start allow accurate performance. Experiment 2 showed that, at least for some observers, convergence can be facilitated by reducing the correlations between commonly used nonspecifying variables and relative mass but not by keeping those variables constant. Experiments 3a and 3b further demonstrated that observers learn not to rely on a particular nonspecifying variable if the correlation between that variable and relative mass is reduced.

Mortality and apolipoprotein E in Hispanic, African-American, and Caucasian elders.

To investigate whether mortality risk is influenced by apolipoprotein E (APOE) genotype and whether the risk differs by ethnicity, we compared the mortality risk in 2,112 individuals > or = 65 years of age residing in northern Manhattan in New York. Mortality risks associated with the APOE genotype, adjusted for sex, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides, differed significantly by ethnic group. Among Caucasian and Hispanics, the E2/E3 genotype was associated with the lowest mortality risk in the multivariate Cox proportional hazards modeling, adjusted for lipid levels, whereas mortality risk did not differ substantially between the E4/E3 and E3/E3 genotypes. Among African-Americans, the E2/E3 genotype was not associated with the lowest mortality risk, but the E4/E3 genotype was. Adjustment for heart disease, diabetes, and stroke reduced mortality risk associated with each genotype by about 50% for all ethnic groups, but the patterns remained the same. Although we cannot rule out the possibility of a healthy survival bias, our analyses designed to examine healthy survival by comparing risk of mortality in groups who were younger or older at entry do not support this possibility. Our findings suggest that the APOE genotype is associated with mortality and that the genotypic risks differ by ethnic group. Nearly 50% of the mortality risk associated with the APOE genotype appears to act through major chronic diseases, but those diseases only partially explain the mechanism by which the genotypic risk acts. To better understand the observed ethnic differences in mortality risk by genotype, a detailed prospective study is needed to examine the relationships among APOE, other candidate genes, health conditions, and eventual death.

Individual differences and the use of nonspecifying variables in learning to perceive distance and size: comments on McConnell, Muchisky, and Bingham (1998).

McConnell, Muchisky, and Bingham (1998) showed that observers are able to judge the distance and size of falling, rolling, and swinging balls and that performance improves after practice with feedback. They concluded that observers use information that specifies the spatial scales of the different event types--namely, event duration in combination with event-specific constants. The improvement was interpreted as the calibration of the event-specific constants. We argue that their analyses should have considered the use of optical variables that do not specify the to-be-perceived metrics and individual differences in variable use. Furthermore, we propose convergence on the more useful variables as an alternative explanation for the observed improvement. The viability of these arguments is demonstrated with an experiment in which participants are trained with feedback to judge the distance and size of freely falling balls.

Longitudinal study of quality of life in people with advanced Alzheimer's disease.

The authors examined three indicators of health-related quality of life in people with advanced Alzheimer's disease ([AD]; N=150): confinement to home, null activity, and null positive affect, as reported by patient proxies. Dementia severity predicted time-to-onset for all three disease milestones in models that controlled for sociodemographic indicators, nursing home status, and death in the follow-up period. Patients whose dementia worsened over follow-up were more likely to reach each milestone. These outcomes represent key milestones in the care of patients; they are sensitive to disease progression, and they are likely to be useful for studying treatment in advanced AD.

Cognitive correlates of mnemonics usage and verbal recall memory in old age.

OBJECTIVES: The objectives of this study were to determine whether minimizing requisite processing resources to learn a word list would differentially improve recall of older adults and to examine the associations between memory and nonmemory cognitive abilities. BACKGROUND: It has been hypothesized that a reduction in general processing resources contributes to age-related declines in memory and other cognitive abilities. METHODS: Twenty-four young adults and 47 older adults were administered two semantically related word lists, one list with words blocked into their categories and the other with categories intermixed. Tests of attention and working memory, language, and abstract reasoning were interspersed with the memory tasks. Participants were classified as young (age range: 17-30 years), young-old (age range: 65-73 years), and old-old (age range: 74-87 years) to compare the effects of list condition (i.e., blocked vs. unblocked) on recall performance. Correlation and regression analyses were used to examine the cognitive correlates of recall performance. RESULTS: Expected age differences in recall performance were observed. Based on the resource-reduction hypothesis of cognitive aging, we hypothesized that the blocked presentation of the to-be-remembered list would minimize processing demands and therefore differentially benefit recall in older elderly participants. Contrary to our prediction, however, the relative benefits of blocked list presentation on recall measures were comparable for young and older participants. Correlations and regression analyses revealed that recall performance was more strongly associated with word finding ability than with working memory or abstract reasoning skills. CONCLUSIONS: Results suggest that level of recall of a semantically related word list and use of semantic clustering as an encoding strategy are associated more strongly with general word finding skills than with processing capacity.

Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan.

OBJECTIVE: To compare the incidence rates for AD among elderly African-American, Caribbean Hispanic, and white individuals and to determine whether coincident cerebrovascular disease contributes to the inconsistency in reported differences among ethnic groups. METHODS: This was a population-based, longitudinal study over a 7-year period in the Washington Heights and Inwood communities of New York City. Annual incidence rates for AD were calculated and compared by ethnic group, and cumulative incidence adjusted for differences in education, diabetes, cardiovascular risk factors, and stroke was calculated. RESULTS: The age-specific incidence rate for probable and possible AD was 1.3% (95% CI, 0.8 to 1.7) per person-year between the ages of 65 and 74 years, 4.0% (95% CI, 3.2 to 4.8) per person-year between ages 75 and 84 years, and 7.9% (95% CI, 5.5 to 10.5) per person-year for ages 85 and older. Compared to white individuals, the cumulative incidence of AD to age 90 years was increased twofold among African-American and Caribbean Hispanic individuals. Adjustment for differences in number of years of education, illiteracy, or a history of stroke, hypertension, heart disease, or diabetes did not change the disproportionate risks among the three ethnic groups. CONCLUSION: The incidence rate for AD was significantly higher among African-American and Caribbean Hispanic elderly individuals compared white individuals. The presence of clinically apparent cardiovascular or cerebrovascular disease did not contribute to the increased risk of disease. Because the proportion of African-American and Caribbean Hispanic individuals reaching ages 65 and older in the United States is increasing more rapidly than the proportion of white individuals, it is imperative that this disparity in health among the elderly be understood.

A comparative single-use clinical study of the efficacy of two manual toothbrushes with angled bristles.

PURPOSE: To compare the safety and plaque removal efficacy of two angled-bristled toothbrushes. MATERIALS AND METHODS: The brushes were compared using a single-use, cross-over designed study, where healthy subjects from a normal population brushed their teeth with their assigned toothbrush for a timed 60 seconds. Pre- and post-brushing plaque levels were evaluated after disclosing, using the Proximal/Marginal Plaque Index. At the first visit, 100 subjects with a plaque index of > or = 2.20 after 23-25 hours of no oral hygiene were enrolled in the study. At the end of the study, data from 91 subjects were suitable for analysis. The two treatment sequence groups, X-Aktiv/CrossAction and CrossAction/X-Aktiv, were balanced for age and gender and, at each visit, pre-brushing plaque scores did not differ significantly between the two groups. Data from the two visits were pooled, after which plaque removal efficacies were compared. RESULTS: Both toothbrushes were found to be safe and both significantly reduced plaque levels (P< or = 0.0001), but the CrossAction was significantly more effective than the X-Aktiv for whole mouth and marginal sites, as well as the difficult-to-access approximal areas (P< or = 0.0008). For the whole mouth, the CrossAction was 11.8% more effective; for marginal sites the difference was 12.6%, and for approximal sites the difference was 11.4%. It is concluded that the Oral-B CrossAction toothbrush is significantly more effective with respect to plaque removal than the Dr. Best X-Aktiv.

Neuropsychological test performance: a study of non-Hispanic White elderly.

This study examined within-group differences in neuropsychological test performance between US versus foreign-born English-speaking White elders. Participants included 193 randomly selected English-speaking elderly community residents who self-identified as non-Hispanic White. Participants were classified as US (n = 106) or foreign-born (n = 87). All participants were independently diagnosed by a physician as nondemented. After controlling for years of education, participants born in the United States obtained significantly higher scores on measures of verbal abstract reasoning, naming, and fluency than foreign-born elders. These results suggest that although non-Hispanics White are often treated as a homogeneous group, performance differences exist even within this group. Effects of acculturation level and language use on cognitive styles may help explain these findings.

Academic practice groups: strategy for survival.

BACKGROUND: The mission of public academic health centers (puAHC) and their affiliated practice groups (APG) focuses on teaching, research, and the clinical care of at-risk populations. Resources to accomplish this mission, however, are becoming scarce. For puAHC to survive and remain competitive, innovative strategies will need to be developed by the APG. We hypothesized that the integration of a surgical academic practice of the APG with a nonacademic integrated health care delivery system (NAIDS) in a managed care environment would benefit all involved. METHODS: A surgical academic practice was integrated with a NAIDS in a 95% managed care market. Faculty alone provided care the first year, and third-year residents were added the following year. To assess outcome, we collected benefit and cost data for the 1-year period before integration and compared them with the two, 1-year periods after integration. RESULTS: In the second year of integration, revenues from the NAIDS referrals to the puAHC and APG increased 89% and 150%, respectively. The NAIDS' general surgical and endoscopy caseload increased by 25%. Additionally, there was a 92% reduction in operating room technician cost with no increase in operating time per case. Finally, the third-year resident experienced a caseload increase of 163%. CONCLUSIONS: In an environment where resources are diminishing and managed care consists of many large NAIDS that drive referrals and revenue, the integration of a surgical academic practice with a NAIDS benefits all shareholders. Academic practice groups that develop strategies that leverage their competitive advantage will have the best chance of surviving in today's turbulent health care market.

Source memory and encoding strategy in normal aging.

Of the memory deficits associated with aging, elders are most impaired at attributing the source to remembered information. Additionally, aging is marked by a decrease in the use of encoding strategies that are thought to enhance the acquisition and retention of information. We examined how manipulating the encoding strategy during acquisition affected item and source memory in 32 young and 68 elderly participants. Elderly participants were dichotomized into young-old and old-old based upon the median age (74 years). Memory was assessed using Word List A from the California Verbal Learning Test (CVLT) and its alternate form. Encoding strategy was manipulated by semantic clustering. For the Blocked List, words were presented grouped into their semantic categories, whereas for the Unblocked List categories were intermixed within the list. Item and source memory judgments were made 20 minutes after the final CVLT recall trial and again one week later. Results revealed a disproportionate decline in source, compared to item memory in the two older groups. Semantic blocking enhanced item memory for the elders, but not for the young. The amount of semantic clustering performed by the elders showed a decline with age and was positively related to source performance. Results also suggest that subtle age-related changes in semantic knowledge may be related to declines in semantic clustering and memory performance.

Endogenous estrogen levels and Alzheimer's disease among postmenopausal women.

BACKGROUND: Although several studies have suggested that hormone replacement therapy lowers the risk of AD among postmenopausal women, few studies have evaluated the relationship of endogenous estrogen levels and AD. The current study investigated whether serum estrone and estradiol levels were related to the presence of AD among postmenopausal women not currently taking hormone replacement therapy. METHODS: Using a case-control design, we examined an ethnically diverse sample of postmenopausal women who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD (n = 50) and nondemented controls (n = 93). All women were participants in a study of aging and dementia and were seen consecutively between August 1997 and October 1998. RESULTS: Patients with AD had lower estradiol (F[1,141] = 8.3, p = 0.005) levels than did normal controls. Patients also had lower estrone levels; however, this comparison did not quite meet significance criteria (F[1,141] = 3.6, p = 0.06). Compared to estradiol levels >20 pg/mL, women with AD were four to six times more likely to have levels <20 pg/mL after adjusting for age, years of education, presence of an APOE-epsilon4 allele, ethnicity, and body mass index. There were no significant differences in frequency of AD among women within different quartiles of estrone after adjusting for potential confounds. CONCLUSIONS: The results of this preliminary case-control study suggest that estradiol levels may decline significantly in women in whom AD develops.

Learning to perceive the relative mass of colliding balls: the effects of ratio scaling and feedback.

The theory of direct perception holds that competent observers are able to detect optical patterns that specify the relative mass of colliding balls. Heuristic theorists, on the other hand, claim that judgments of relative mass are based on variables that do not specify relative mass. We contrasted these views with an experiment in which participants were given feedback on their ratio-scaled estimates of the relative mass of simulated colliding balls. Correlations between judged relative mass and various kinetic and kinematic measures of the collisions revealed that (1) judgments of relative mass become more accurate with feedback, (2) different observers use different variables, (3) during training, many observers change which variables they use, (4) before training, observers tend to use nonspecifying variables or combinations thereof, (5) after a minimal amount of training, at least some observers seem to detect mass-specifying information, and (6) the judgments do not support a generalization of the heuristic model of Gilden and Proffitt (1989, 1994). These findings suggest that direct perception of relative mass is a skill that can be developed through appropriate training.

An advanced toothbrush with improved plaque removal efficacy.

PURPOSE: To compare the plaque removal efficacy and safety of a new advanced manual toothbrush, the Oral-B CrossAction, with seven other toothbrushes. MATERIALS AND METHODS: Seven independent, cross-over design clinical studies were conducted using the same examiner who was blind to the identity of the test products and treatment assignments. In each study, approximately 75 healthy adult subjects from a general population brushed with their randomly assigned toothbrush (CrossAction or comparison brush) at Visit 1 for 1 min without supervision or instruction in brushing technique. Subjects returned after a 1-week washout period and brushed with the alternate toothbrush (Visit 2). Plaque was evaluated before and after brushing using the Rustogi Modified Navy Plaque Index. Statistical analyses were conducted by an independent statistician who remained blind to the identity of all test products. RESULTS: Each of the toothbrushes tested provided significant (P < or = 0.0001) reductions in plaque scores after a single brushing. In each of the studies, the CrossAction toothbrush removed significantly (P < or = 0.0001) greater amounts of whole mouth, gingival margin, and approximal plaque than the compared toothbrush. All toothbrushes were found to be safe, with no changes in oral tissues or restorations observed over the course of each study. The results from these studies were consistent, demonstrating that the CrossAction toothbrush significantly enhances the ability of subjects to remove more plaque during normal brushing compared to seven other toothbrushes.

A comparative clinical investigation of a novel toothbrush designed to enhance plaque removal efficacy.

PURPOSE: To investigate the safety and efficacy of a new toothbrush with a novel brush head design (Oral-B CrossAction) in comparison with seven leading manual brushes. MATERIALS AND METHODS: Seven independent clinical studies, each involving approximately 100 healthy subjects from a general population, were carried out using a crossover design. In each study, the Oral-B CrossAction toothbrush was compared with an alternative brush for plaque removal efficacy. Plaque was evaluated before and after brushing for 60 s using the Proximal/Marginal Plaque Index. Subjects were randomly assigned to the two brushes in each study and after brushing at visit 1 they returned after a further 2 weeks to repeat the procedure with the second brush. RESULTS: All toothbrushes in the seven studies significantly reduced levels of plaque from their pre-brushing values and were found to be safe with no evidence of oral soft tissue trauma. In each of the studies, the CrossAction was found to be significantly (P < 0.05) more effective than the comparison brush for whole mouth plaque scores, as well as for plaque scores at the gingival margin and proximal surfaces. Advantages in favor of the CrossAction ranged from 9.8% to 23.2% for whole mouth plaque, from 5.3% to 20.6% for the gingival margin and from 12.8% to 24.5% for proximal surfaces. It was concluded that the novel brush head design of the CrossAction toothbrush provides enhanced plaque removal, especially from proximal surfaces, and that this toothbrush is significantly more effective than all seven toothbrushes tested.