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The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams.
The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here.
The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020.
Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.
CVD and associated metabolic diseases are linked to chronic inflammation, which can be modified by diet. The objective of the present study was to determine whether there is a difference in inflammatory markers, blood metabolic and lipid panels and lymphocyte gene expression in response to a high-fat dairy food challenge with or without milk fat globule membrane (MFGM). Participants consumed a dairy product-based meal containing whipping cream (WC) high in saturated fat with or without the addition of MFGM, following a 12 h fasting blood draw. Inflammatory markers including IL-6 and C-reactive protein, lipid and metabolic panels and lymphocyte gene expression fold changes were measured using multiplex assays, clinical laboratory services and TaqMan real-time RT-PCR, respectively. Fold changes in gene expression were determined using the Pfaffl method. Response variables were converted into incremental AUC, tested for differences, and corrected for multiple comparisons. The postprandial insulin response was significantly lower following the meal containing MFGM (P < 0·01). The gene encoding soluble epoxide hydrolase (EPHX2) was shown to be more up-regulated in the absence of MFGM (P = 0·009). Secondary analyses showed that participants with higher baseline cholesterol:HDL-cholesterol ratio (Chol:HDL) had a greater reduction in gene expression of cluster of differentiation 14 (CD14) and lymphotoxin β receptor (LTBR) with the WC+MFGM meal. The protein and lipid composition of MFGM is thought to be anti-inflammatory. These exploratory analyses suggest that addition of MFGM to a high-saturated fat meal modifies postprandial insulin response and offers a protective role for those individuals with higher baseline Chol:HDL.
In the current opioid epidemic, identifying high-risk patients among those with substance and opioid use may prevent deaths. The objective of this study was to determine whether frequent emergency department (ED) use and degree of frequent use are associated with mortality among ED patients with substance and opioid use.
This cohort study used linked population-based ED (National Ambulatory Care Reporting System) and mortality data from Alberta. All adults ≥ 18 years with substance or opioid use-related visits based on diagnostic codes from April 1, 2012, to March 31, 2013, were included (n = 16,389). Frequent use was defined by ≥ 5 visits in the previous year. Outcomes were unadjusted and adjusted (for age, sex, income) mortality within 90 days (primary), and 30 days, 365 days, and 2 years (secondary). To examine degree, frequent use was subcategorized into 5–10, 11–15, 16–20, and > 20 visits.
Frequent users were older, lower income, and made lower acuity visits than non-frequent users. Frequent users with substance use had higher mortality at 365 days (hazard ratio [HR] 1.36 [1.04, 1.77]) and 2 years (HR 1.32 [1.04, 1.67]), but not at 90 or 30 days. Mortality did not differ for frequent users with opioid use overall. By degree, patients with substance use and > 20 visits/year and with opioid use and 16–20 visits/year demonstrated a higher 365-day and 2-year mortality.
Among patients with substance use, frequent ED use and extremely frequent use (> 20 visits/year) were associated with long-term but not short-term mortality. These findings suggest a role for targeted screening and preventive intervention.
We aim to evaluate the effect of caloric restriction (CR) in cognition by comparing performance in neuropsychological tests for working memory between a group of non-obese healthy subjects doing CR for 2 years with another consuming ad libitum diet (AL).
This study was part of a larger multicenter trial called CALERIE that consisted of a randomized clinical trial with parallel-group comparing 2 years of 25% CR and AL in 220 volunteers with a BMI between 22 and 28 kg/m2, across 3 sites. The cognitive tests used were the Cambridge Neuropsychological Tests Automated Battery (CANTAB) for Spatial Working Memory (SWM) including the total number of errors (SWMTE) and strategy (SWMS). Included as possible moderators were sleep quality, mood states, perceived stress, and energy expenditure. Analyses were performed at baseline and months 12 and 24.
After adjustments, there was a significantly greater improvement in working memory assessed by the SWM for CR individuals, compared to AL. At month 24, it was related mostly to lower protein intake, compared to other macronutrients. Changes in SWM were moderated by changes in sleep quality, physical activity, and energy expenditure.
On the long term, CR in healthy individuals seems to have a slightly positive effect on working memory. The study of brain CR targets opens new possibilities to prevent and treat cognitive deficits.
A new proportional counter x-ray detector with application for powder diffractometry has been developed. The new detector collects virtually the entire diffraction spectrum simultaneously with good efficiency and angular resolution. Thus, the powder spectrum of a small sample can be obtained much faster than with film or a conventional powder diffractometer. The detector read-out is digital and is interfaced to a dedicated minicomputer. A description of the detector system is discussed and preliminary results are presented.
To characterize the association of longitudinal changes in maternal anthropometric measures with neonatal anthropometry and to assess to what extent late-gestational changes in maternal anthropometry are associated with neonatal body composition.
In a prospective cohort of pregnant women, maternal anthropometry was measured at six study visits across pregnancy and after birth, neonates were measured and fat and lean mass calculated. We estimated maternal anthropometric trajectories and separately assessed rate of change in the second (15–28 weeks) and third trimester (28–39 weeks) in relation to neonatal anthropometry. We investigated the extent to which tertiles of third-trimester maternal anthropometry change were associated with neonatal outcomes.
Women were recruited from twelve US sites (2009–2013).
Non-obese women with singleton pregnancies (n 2334).
A higher rate of increase in gestational weight gain was associated with larger-birth-weight infants with greater lean and fat mass. In contrast, higher rates of increase in maternal anthropometry measures were not associated with infant birth weight but were associated with decreased neonatal lean mass. In the third trimester, women in the tertile of lowest change in triceps skinfold (−0·57 to −0·06 mm per week) had neonates with 35·8 g more lean mass than neonates of mothers in the middle tertile of rate of change (−0·05 to 0·06 mm per week).
The rate of change in third-trimester maternal anthropometry measures may be related to neonatal lean and fat mass yet have a negligible impact on infant birth weight, indicating that neonatal anthropometry may provide additional information over birth weight alone.
During the past two decades, it has been amply documented that neuropsychiatric disorders (NPDs) disproportionately account for burden of illness attributable to chronic non-communicable medical disorders globally. It is also likely that human capital costs attributable to NPDs will disproportionately increase as a consequence of population aging and beneficial risk factor modification of other common and chronic medical disorders (e.g., cardiovascular disease). Notwithstanding the availability of multiple modalities of antidepressant treatment, relatively few studies in psychiatry have primarily sought to determine whether improving cognitive function in MDD improves patient reported outcomes (PROs) and/or is cost effective. The mediational relevance of cognition in MDD potentially extrapolates to all NPDs, indicating that screening for, measuring, preventing, and treating cognitive deficits in psychiatry is not only a primary therapeutic target, but also should be conceptualized as a transdiagnostic domain to be considered regardless of patient age and/or differential diagnosis.
Field research was conducted in 2012 and 2013 in Georgia, New York, and North Carolina to evaluate the effect of trifluralin PPI on turnip root production. Treatments included trifluralin PPI at 0, 0.42, 0.56, 0.84, 1.12, 1.68, 2.24, and 3.36 kg ai ha−1. Aboveground injury to turnip varied by location and increased from 0% to 85% as trifluralin rate increased from 0.42 to 3.36 kg ha−1. Trifluralin at 0.42 to 0.84 kg ha−1 caused ≤7% injury, except at Clayton, NC, and Freeville, NY, where injury ≤32%. Trifluralin at 0.42 to 0.84 kg ha−1 reduced turnip root yield ≤11% at all locations, except Clinton, NC, where yield was reduced 29% and 43% by 0.56 and 0.84 kg ha−1, respectively. Turnip roots were not injured internally by trifluralin. Our research results suggest that up to 0.84 kg ha−1 trifluralin PPI is safe to use in turnip roots.
Cognitive dysfunction is a symptomatic domain identified across many mental disorders. Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational and functional disability. Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD. Most antidepressants have not been developed and/or evaluated for their ability to directly and independently ameliorate cognitive deficits. Multiple interacting neurobiological mechanisms (eg, neuroinflammation) are implicated as subserving cognitive deficits in MDD. A testable hypothesis, with preliminary support, posits that improving performance across cognitive domains in individuals with MDD may improve psychosocial function, workplace function, quality of life, and other patient-reported outcomes, independent of effects on core mood symptoms. Herein we aim to (1) provide a rationale for prioritizing cognitive deficits as a therapeutic target, (2) briefly discuss the neurobiological substrates subserving cognitive dysfunction, and (3) provide an update on current and future treatment avenues.
Although relapse in psychosis is common, a small proportion of patients will not relapse in the long term. We examined the proportion and predictors of patients who never relapsed in the 10 years following complete resolution of positive symptoms from their first psychotic episode.
Patients who previously enrolled in a 12-month randomized controlled trial on medication discontinuation and relapse following first-episode psychosis (FEP) were followed up after 10 years. Relapse of positive symptoms was operationalized as a change from a Clinical Global Impression scale positive score of <3 for at least 3 consecutive months to a score of ⩾3 (mild or more severe). Baseline predictors included basic demographics, premorbid functioning, symptoms, functioning, and neurocognitive functioning.
Out of 178 first-episode patients, 37 (21%) never relapsed during the 10-year period. Univariate predictors (p ⩽ 0.1) of patients who never relapsed included a duration of untreated psychosis (DUP) ⩽30 days, diagnosed with non-schizophrenia spectrum disorders, having less severe negative symptoms, and performing better in logical memory immediate recall and verbal fluency tests. A multivariate logistic regression analysis further suggested that the absence of any relapsing episodes was significantly related to better short-term verbal memory, shorter DUP, and non-schizophrenia spectrum disorders.
Treatment delay and neurocognitive function are potentially modifiable predictors of good long-term prognosis in FEP. These predictors are informative as they can be incorporated into an optimum risk prediction model in the future, which would help with clinical decision making regarding maintenance treatment in FEP.
Although school-based programmes for the identification of children and young people (CYP) with mental health difficulties (MHD) have the potential to improve short- and long-term outcomes across a range of mental disorders, the evidence-base on the effectiveness of these programmes is underdeveloped. In this systematic review, we sought to identify and synthesise evidence on the effectiveness and cost-effectiveness of school-based methods to identify students experiencing MHD, as measured by accurate identification, referral rates, and service uptake.
Electronic bibliographic databases: MEDLINE, Embase, PsycINFO, ERIC, British Education Index and ASSIA were searched. Comparative studies were included if they assessed the effectiveness or cost-effectiveness of strategies to identify students in formal education aged 3–18 years with MHD, presenting symptoms of mental ill health, or exposed to psychosocial risks that increase the likelihood of developing a MHD.
We identified 27 studies describing 44 unique identification programmes. Only one study was a randomised controlled trial. Most studies evaluated the utility of universal screening programmes; where comparison of identification rates was made, the comparator test varied across studies. The heterogeneity of studies, the absence of randomised studies and poor outcome reporting make for a weak evidence-base that only generate tentative conclusions about the effectiveness of school-based identification programmes.
Well-designed pragmatic trials that include the evaluation of cost-effectiveness and detailed process evaluations are necessary to establish the accuracy of different identification models, as well as their effectiveness in connecting students to appropriate support in real-world settings.
The Main Karoo Basin of South Africa contains a near-continuous sequence of continental deposition spanning ~80 Myr from the mid-Permian to the Early Jurassic. The terrestrial vertebrates of this sequence provide a high-resolution stratigraphic record of regional origination and extinction, especially for the mid–late Permian. Until now, data have only been surveyed at coarse stratigraphic resolution using methods that are biased by nonuniform sampling rates, limiting our understanding of the dynamics of diversification through this important time period. Here, we apply robust methods (gap-filler and modified gap-filler rates) for the inference of patterns of species richness, origination rates, and extinction rates to a subset of 1321 reliably-identified fossil occurrences resolved to approximately 50 m stratigraphic intervals. This data set provides an approximate time resolution of 0.3–0.6 Myr and shows that extinction rates increased considerably in the upper 100 m of the mid-Permian Abrahamskraal Formation, corresponding to the latest part of the Tapinocephalus Assemblage Zone (AZ). Origination rates were only weakly elevated in the same interval and were not sufficient to compensate for these extinctions. Subsampled species richness estimates for the lower part of the overlying Teekloof Formation (corresponding to the Pristerognathus and Tropidostoma AZs) are low, showing that species richness remained low for at least 1.5–3 million years after the main extinction pulse. A high unevenness of the taxon abundance–frequency distribution, which is classically associated with trophically unstable postextinction faunas, in fact developed shortly before the acme of elevated extinction rates due to the appearance and proliferation of the dicynodont Diictodon. Our findings provide strong support for a Capitanian (“end-Guadalupian”) extinction event among terrestrial vertebrates and suggest that further high-resolution quantitative studies may help resolve the lack of consensus among paleobiologists regarding this event.
The term ‘mood stabiliser’ is ill-defined and lacks clinical utility. We propose a framework to evaluate medications and effectively communicate their mood stabilising properties – their acute and prophylactic efficacy across the domains of mania and depression. The standardised framework provides a common definition to facilitate research and clinical practice.
Declaration of interest
The Treatment Algorithm Group (TAG) was supported logistically by Servier who provided financial assistance with travel and accommodation for those TAG members travelling interstate or overseas to attend the meeting in Sydney (held on 18 November 2017). None of the committee were paid to participate in this project and Servier have not had any input into the content, format or outputs from this project.
Ondansetron is increasingly administered to children suffering from concussion-associated nausea/vomiting. We examined the association between ondansetron administration and post-concussion symptoms in children at 1 week and 1 month following the concussion.
This was a secondary analysis of data collected prospectively in a cohort study conducted in nine pediatric emergency departments (EDs) (5P study). Participants were children ages between 5 and 17.99 years who sustained a concussion in the previous 48 hours. For the current study, only 5P participants who reported nausea and/or vomiting in the ED were eligible. The exposure of interest was ondansetron administration; the comparison group included all other participants. The primary outcome was an increase in at least three symptoms of the Post-Concussion Symptom Inventory score at 1 week and 1 month following trauma.
Among the 3,063 children included in the 5P study, 1805 (59%) reported nausea and provided data at 1 week and/or 1 month. Among them, 132 (7%) received ondansetron. Multivariable logistic regression adjusted for confounders did not show an association between ondansetron use and the risk of persistent post-concussion symptoms at 1 week (OR: 1.13 [95% CI: 0.86-1.49]), but it was associated with a higher risk at 1 month (OR: 1.33 [95% CI: 1.05-1.97]).
In children presenting to the ED with an acute concussion, ondansetron use was associated with a higher risk of persistent post-concussion symptoms at 1 month. Although this may be related to the limitations of the design, it highlights the importance of evaluating this association using a randomized clinical trial.
OBJECTIVES/SPECIFIC AIMS: To develop a KL2 curriculum on the science and art of drug formulation. METHODS/STUDY POPULATION: Develop training materials for KL2 scholars that outline the art of formulation development. Materials will include syllabi, reading materials, and course work. RESULTS/ANTICIPATED RESULTS: This will enhance the training of KL2 scholars by incorporating formulation development concepts into their human health enhancing research projects. DISCUSSION/SIGNIFICANCE OF IMPACT: For new chemical entities, formulation goals must be realistic and move along in a step-wise manner from the laboratory bench, through toxicology studies, and on to Phase 1 studies. By training scholars in phase-specific formulation goals, their interactions with funding agencies, formulation scientists, and regulators will be more efficient, productive, and successful. For those scholars who are working to improve existing treatments, introducing the concept of formulation improvements that can create new indications, or improve efficacy, safety and patient compliance will open up more possibilities for creative product development.