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Objectives: Evidence suggests that workers exposed to psychosocial stressors at work from the effort-reward imbalance (ERI) model are at increased risk for type 2 diabetes mellitus (T2DM). However, evidence about the effect of ERI on prediabetes is scarce. This study aimed to examine the association between effort-reward imbalance at work, glycated hemoglobin level and the prevalence of prediabetes in women and men from a prospective cohort study., Methods: This study was conducted among 1354 white-collar workers followed for an average of 18 years. Effort-reward imbalance at work was measured in 1999 to 2001 using a validated instrument. Glycated hemoglobin was assessed at follow-up (2015 to 2018). Differences in mean glycated hemoglobin levels were estimated with linear models. Prediabetes prevalence ratios (PRs) were computed using robust Poisson regression models., Results: In women, those exposed to effort-reward imbalance at work at baseline had a higher prevalence of prediabetes (PR = 1.60, 95% confidence interval: 1.02-2.49) at follow-up following adjustment for sociodemographic, lifestyle-related, clinical, and other occupational risk factors. There was no difference in mean glycated hemoglobin levels., Conclusion: Among women, effort-reward imbalance at work at midlife was associated with the prevalence of prediabetes, at older age. Preventive workplace interventions aiming to reduce the prevalence of effort-reward imbalance at work may be effective to reduce the prevalence of prediabetes among women., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Objectives: To develop a web-based food frequency questionnaire (FFQ) measuring intake of plant-based protein foods (PBPs) among older adults from the province of Quebec, Canada., Design: The questionnaire was adapted from an existing self-administered FFQ and first underwent expert panel evaluation for face and content validity. Then, three phases of cognitive testing were conducted in French, using the probe and think aloud approaches. Between each phase, the questionnaire was modified based on participants' feedback to improve the clarity and comprehension of the questions., Setting: Quebec City, Quebec, Canada., Participants: Twenty adults aged 65 years and older. Purposive sampling was used to maximize variation in sociodemographic characteristics, including gender, age, education level, and PBP consumption., Results: The expert panel found the 28-item questionnaire to be a comprehensive measure of PBP intake and suggested minor changes to improve its clarity. The cognitive interviews showed that our PBP-FFQ was generally well understood and identified issues requiring modifications to improve comprehension and accuracy., Discussion: Our FFQ provides a comprehensive measure of PBP intake, is well understood by older adults in Québec, and will support rigorous assessment of PBP intake in this population, but requires further validation to confirm validity and reproducibility.

Background: Musculoskeletal pain (MSP) is the leading contributor to disability, limiting mobility and dexterity. As research on the determinants of MSP is evolving, biomarkers can probably play a significant role in understanding its causes and improving its clinical management. This scoping review aimed to provide an overview of the associations between biomarkers and MSP., Methods: This study followed Arksey and O'Malley and PRISMA-ScR recommendations. Keywords related to biomarkers, association, and MSP were searched on PubMed, Embase, Cochrane, and Web of Science databases from inception to September 28th, 2023. Data were systematically retrieved from the retained articles. A narrative synthesis approach - but no quality assessment - was used to map the core themes of biological markers of MSP that emerged from this work., Results: In total, 81 out of 25,165 identified articles were included in this scoping review. These studies were heterogeneous in many aspects. Overall, vitamin D deficiency, dyslipidemia (or hypercholesterolemia), and cytokines (high levels) were the most studied biomarkers with regards to MSP and were most often reported to be associated with non-specific MSP. Cadmium, calcium, C-reactive protein, collagen, creatinine, hormones, omega-3 fatty acids, sodium, tumor necrosis factor-alpha, and vitamin C were also reported to be associated with MSP syndromes, but the evidence on these associations was sketchier. No conclusions could be drawn as to age and sex., Conclusions: Our findings suggest that some biomarkers are associated with specific MSP syndromes, while others would be associated with non-specific syndromes. Among all candidate markers, the evidence seems to be more consistent for vitamin D, cytokines and lipids (total cholesterol, triglycerides, low- and high-density lipoproteins). High-quality studies, stratified by age and sex, are needed to advance our understanding on biomarkers of MSP., Competing Interests: All authors declare that they have no conflicts of interest to report in this work., (© 2024 Djade et al.)

Purpose: Major changes were made to Canada's Food Guide (CFG) in 2019. This study aimed to understand the perceptions of older adults toward this newest version. Methods: Older adults were invited to participate via newsletters sent to older adults and retirees' organizations in the Province of Quebec. Participants completed an online survey about their baseline familiarity with the 2019 CFG using a 5-point Likert scale and took part in an individual semi-structured online interview, which explored their perceptions toward the 2019 CFG. A thematic qualitative analysis of the interview transcripts was performed. Results: Fifty-eight older adults (>65 years, 30 women, 28 men, including 19 consumers and 39 non-consumers of plant-based protein (PBP) foods) participated in the study. Older adults were mostly familiar with the 2019 CFG and had a positive perception of its features. They appreciated the design, proposed recipes, and healthy eating recommendations. Perceptions about the three food groups were mixed, mainly regarding the decreased emphasis on dairy products. Some appreciated that animal proteins were less prominent, while others raised issues on how to integrate PBP into their diet. Perceptions appeared to be influenced by sex and PBP consumption. Conclusion: Older adults in the Province of Quebec view most of the 2019 CFG recommendations positively. Our observations may be useful to dietitians and public health practitioners when developing strategies to improve adherence.

The COVID-19 pandemic precipitated the implementation of extended interval immune checkpoint inhibitors (ICIs) in an effort to limit hospital visits, but few studies have examined their safety. This study aimed to compare in oncology outpatients, immune-mediated adverse events (IMAEs) in terms of total number, incidence, severity, and time to occurrence, based on exposure to standard or extended interval ICIs. A retrospective cohort study was conducted in patients who received at least one dose of an ICI between 2015 and 2021. Data were collected from patient records and pharmacy software. Adjusted logistic, Poisson, and Cox regression models were estimated. A total of 310 patients with a mean age of 67.1 years were included, 130 of whom had the extended interval. No statistically significant differences were observed between the groups. With the standard and extended intervals, the mean total number of IMAE per participant was 1.02 and 1.18, respectively; the incidence of an IMAE was 62% and 64%. Of the 147 IMAE episodes in the standard interval group, 14 (9.5%) were grade 3 or higher, while there were 15 (12.4%) among the 121 IMAE episodes in the extended interval group. Compared with standard interval, the use of extended interval did not increase the risk of having a first IMAE (adjusted hazard ratio 0.92 (95% CI 0.67-1.26)). This study suggests that the administration of an ICI according to extended interval is as safe as the administration according to standard interval in oncology outpatients., (© 2024. Crown.)

A cell's ability to secrete extracellular vesicles (EVs) for communication is present in all three domains of life. Notably, Gram-negative bacteria produce a specific type of EVs called outer membrane vesicles (OMVs). We previously observed the presence of OMVs in human blood, which could represent a means of communication from the microbiota to the host. Here, in order to investigate the possible translocation of OMVs from the intestine to other organs, the mouse was used as an animal model after OMVs administration. To achieve this, we first optimized the signal of OMVs containing the fluorescent protein miRFP713 associated with the outer membrane anchoring peptide OmpA by adding biliverdin, a fluorescence cofactor, to the cultures. The miRFP713-expressing OMVs produced in E. coli REL606 strain were then characterized according to their diameter and protein composition. Native- and miRFP713-expressing OMVs were found to produce homogenous populations of vesicles. Finally, in vivo and ex vivo fluorescence imaging was used to monitor the distribution of miRFP713-OMVs in mice in various organs whether by intravenous injection or oral gavage. The relative stability of the fluorescence signals up to 3 days post-injection/gavage paves the way to future studies investigating the OMV-based communication established between the different microbiotas and their host.

Introduction: The objective of this study was to examine whether a healthy lifestyle composite score of social engagement, physical activity, and Mediterranean diet adherence moderates the association between psychological distress and global cognitive decline among cognitively healthy older adults (67+ years of age at baseline)., Methods: A total of 1,272 cognitively intact older adults (Mage = 74.1 ± 4.1 years, 51.9% female) in the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge) completed a series of self-reported questionnaires to measure psychological distress and lifestyle behaviors, and the Modified Mini-Mental Examination (3MS) to assess cognitive performance at baseline and annually over 3 years., Results: Controlling for sociodemographic and health-related characteristics, greater psychological distress was associated with steeper cognitive decline over time among males (B = -0.07, 95% CI: [-0.12, -0.02]), but not females (B = 0.008, 95% CI: [0.03, 0.04]). Although a healthy lifestyle composite score did not statistically significantly moderate the distress-cognition relationship (B = -0.005, 95% CI: [-0.02, 0.01]), there was an association between higher psychological distress and greater cognitive decline at low levels of social engagement (B = -0.05, 95% CI: [-0.09, -0.006]), but not at high levels of social engagement (B = 0.02, 95% CI: [-0.03, 0.07])., Conclusion: This study suggests that the potentially harmful impact of stress on cognitive function may be malleable through specific healthy lifestyle behaviors and emphasizes the importance of taking a sex-based approach to cognitive aging research., (© 2024 S. Karger AG, Basel.)

Background: The effect of marine omega-3 PUFAs on risk of stroke remains unclear., Methods: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome., Results: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P <0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P <0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P =0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P =0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD., Conclusions: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke., Competing Interests: Disclosures Dr O’Keefe reports major ownership interest in Cardiotabs. Dr Harris reports minor ownership interest in Omegaquant Analytics, LLC. Dr Sala-Vila reports travel and grant support from California Walnut Commission. Dr Mora reports compensation for consultant services from Quest Diagnostics. Dr Murphy reports compensation from Pharmavite for consultant services. Dr Bork reports grants from Karen Elise Jensens Fond. Dr Ärnlöv reports compensation from Astellas Pharma for other services; compensation from Boehringer Ingelheim for consultant services; compensation from AstraZeneca for other services; and compensation from Novartis for other services. Dr Geleijnse reports grants from National Institutes of Health to other; grants from Upfield Europe BV to other; and grants from The Dutch Heart Foundation to other. Dr Manson reports grants from National Institutes of Health and compensation from National Institutes of Health for other services. Dr Mora reports compensation from Pfizer for consultant services; employment by Brigham and Women’s Hospital; grants from National Institute of Diabetes and Digestive and Kidney Diseases; and grants from National Heart, Lung, and Blood Institute. Dr Melo van Lent reports grants from National Institutes of Health and grants from Alzheimer’s Association. Dr Mozaffarian reports grants from Rockefeller Foundation; compensation from Beren Therapeutics for other services; stock holdings in HumanCo; compensation from January Inc. for other services; compensation from Filtricine for other services; compensation from Perfect Day for other services; compensation from Tiny Organics for other services; grants from Bill and Melinda Gates Foundation; compensation from Calibrate for other services; grants from Vail Innovative Global Research; grants from Kaiser Permanente Fund at East Bay Community Foundation; compensation from DayTwo for other services; compensation from Instacart health for other services; compensation from Season Health for other services; grants from National Institutes of Health; compensation from Barilla for consultant services; stock holdings in Calibrate; compensation from Kaiser Permanente Fund for other services; compensation from HumanCo for other services

Malnutrition is correlated with poor cognition; however, an understanding of the association between nutrition risk, which precedes malnutrition, and cognition is lacking. This study aimed to determine if nutrition risk measured with the SCREEN-8 tool is associated with cognitive performance among cognitively healthy adults aged 55+, after adjusting for demographic and lifestyle covariates. Sex- and age-stratified analyses were also explored. Baseline data from the Canadian Longitudinal Study on Aging was used. Cognition was determined using a 6-measure composite score based on four executive functions and two memory tasks, taking into account age, sex, and education. Multivariable linear regression was performed while adjusting for body mass index (BMI), lifestyle, and health covariates in the entire sample ( n  = 11 378) and then stratified by sex and age. Approximately half of participants were female (54.5%) aged 65+ (54.1%). Greater nutrition risk was associated with poorer cognitive performance in the entire sample ( F [1, 11 368]  = 5.36, p  = 0.021) and among participants aged 55-64 ( n  = 5227; F [1, 5217]  = 5.45, p  = 0.020). Sex differences in lifestyle and health factors associated with cognition were apparent, but nutrition risk was not associated with cognition in sex-stratified models. Based on this analysis, there may be an association between nutrition risk and cognitive performance in older adults. When screening for either cognitive impairment or nutrition risk, complementary assessments for these conditions is warranted, as early intervention may provide benefit., Competing Interests: VT and HK received funding from the Canadian Consortium on Neurodegeneration in Aging (CCNA) for this current manuscript. HK has received grants/contracts from Abbott Laboratories and payment or honoraria from Nestle Health Sciences and ICEBM. SCREEN-8 instrument was used in the CLSA to determine nutrition risk. GF reports consulting fees from LuciLab Inc. and payment or honoraria for presentations from RésoSanté Colombie Britanique (presentation). NDA, AJF, and DL have no competing interests to disclose.

Introduction: Cardiovascular disease risk factors (CVRFs) contribute to the development of cognitive impairment and dementia., Methods: This study examined the associations between circulating CVRF biomarkers and cognition in 386 cognitively healthy older adults (mean age = 78 ± 4 years, 53% females) selected from the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge). Memory, executive function, and processing speed were assessed at baseline and 2-year follow-up. CVRF biomarkers included total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides, glucose, insulin, high sensitivity C-reactive protein (hs-CRP), homocysteine, protein carbonyls, and cortisol. Linear mixed models were used to determine associations between individual CVRF biomarkers and cognition at both time points., Results: HDL-C was most consistently associated with cognition with higher values related to better performance across several domains. Overall, stronger and more consistent relationships between CVRF biomarkers and cognition were observed in females relative to males., Discussion: Findings suggest that increases in the majority of circulating CVRFs are not associated with worse cognition in cognitively healthy older adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. SB, AJF, and PG declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Koblinsky, Carmichael, Belleville, Fiocco, Gaudreau, Greenwood, Kergoat, Morais, Presse, Laurin and Ferland.)

Background: Psychosocial stressors at work, like job strain and effort-reward imbalance (ERI), can increase coronary heart disease (CHD) risk. ERI indicates an imbalance between the effort and received rewards. Evidence about the adverse effect of combined exposure to these work stressors on CHD risk is scarce. This study examines the separate and combined effect of job strain and ERI exposure on CHD incidence in a prospective cohort of white-collar workers in Quebec, Canada., Methods: Six thousand four hundred sixty-five white-collar workers without cardiovascular disease (mean age, 45.3±6.7) were followed for 18 years (from 2000 to 2018). Job strain and ERI were measured with validated questionnaires. CHD events were retrieved from medico-administrative databases using validated algorithms. Marginal Cox models were used to calculate hazard ratios (HR) stratified by sex. Multiple imputation and inverse probability weights were applied to minimize potential threats to internal validity., Results: Among 3118 men, 571 had a first CHD event. Exposure to either job strain or ERI was associated with an adjusted 49% CHD risk increase (HR, 1.49 [95% CI, 1.07-2.09]). Combined exposure to job strain and ERI was associated with an adjusted 103% CHD risk increase (HR, 2.03 [95% CI, 1.38-2.97]). Exclusion of early CHD cases and censoring at retirement did not alter these associations. Among 3347 women, 265 had a first CHD event. Findings were inconclusive (passive job HR, 1.24 [95% CI, 0.80-1.91]; active job HR, 1.16 [95% CI, 0.70-1.94]; job strain HR, 1.08 [95% CI, 0.66-1.77]; ERI HR, 1.02 [95% CI, 0.72-1.45])., Conclusions: In this prospective cohort study, men exposed to job strain or ERI, separately and in combination, were at increased risk of CHD. Early interventions on these psychosocial stressors at work in men may be effective prevention strategies to reduce CHD burden. Among women, further investigation is required., Competing Interests: Disclosures Drs Talbot, Gilbert-Ouimet, Vézina, Trudel, Milot, and Brisson reported receiving grants from the Canadian Institute of Health Research during the conduct of the study. M. Lavigne-Robichaud was supported by a PhD grant from les Fonds de Recherche du Québec en santé. Dr Talbot is supported by a research career award from the Fonds de Recherche du Québec en Santé. The other authors report no conflicts.

The identification of modifiable factors that could maintain cognitive function is a public health priority. It is thought that some work-related psychosocial factors help developing cognitive reserve through high intellectual complexity. However, they also have well-known adverse health effects and are considered to be chronic psychosocial stressors. Indeed, these stressors could increase low-grade inflammation and promote oxidative stress associated with accelerated telomere shortening. Both low-grade inflammation and shorter telomeres have been associated with a cognitive decline. This study aimed to evaluate the total, direct, and indirect effects of work-related psychosocial factors on global cognitive function overall and by sex, through telomere length and an inflammatory index. A random sample of 2219 participants followed over 17 years was included in this study, with blood samples and data with cognitive function drawn from a longitudinal study of 9188 white-collar workers (51% female). Work-related psychosocial factors were evaluated according to the Demand-Control-Support and the Effort-Reward Imbalance (ERI) models. Global cognitive function was evaluated with the validated Montreal Cognitive Assessment (MoCA). Telomere length and inflammatory biomarkers were measured using standardised protocols. The direct and indirect effects were estimated using a novel mediation analysis method developed for multiple correlated mediators. Associations were observed between passive work or low job control, and shorter telomeres among females, and between low social support at work, ERI or iso-strain, and a higher inflammatory index among males. An association was observed with higher cognitive performance for longer telomeres, but not for the inflammatory index. Passive work overall, and low reward were associated with lower cognitive performance in males; whereas, high psychological demand in both males and females and high job strain in females were associated with a higher cognitive performance. However, none of these associations were mediated by telomere length or the inflammatory index. This study suggests that some work-related psychosocial factors could be associated with shorter telomeres and low-grade inflammation, but these associations do not explain the relationship between work-related psychosocial factors and global cognitive function. A better understanding of the biological pathways, by which these factors affect cognitive function, could guide future preventive strategies to maintain cognitive function and promote healthy aging.

The bone marrow niche plays an increasing role in the pathophysiogenesis of myelodysplastic syndromes. More specifically, mesenchymal stromal cells, which can secrete extracellular vesicles and their miRNA contents, modulate the fate of hematopoietic stem cells leading to leukemogenesis. Extracellular vesicles can mediate their miRNA and protein contents between nearby cells but also in the plasma of the patients, being potent tools for diagnosis and prognostic markers in MDS. They can be targeted by antisense miRNA or by modulators of the secretion of extracellular vesicles and could lead to future therapeutic directions in MDS.

The purpose of immune checkpoint inhibitor (ICI)-based therapies is to help the patient's immune system to combat tumors by restoring the immune response mediated by CD8+ cytotoxic T cells. Despite impressive clinical responses, most patients do not respond to ICIs. Therapeutic vaccines with autologous professional antigen-presenting cells, including dendritic cells, do not show yet significant clinical benefit. To improve these approaches, we have developed a new therapeutic vaccine based on an allogeneic plasmacytoid dendritic cell line (PDC*line), which efficiently activates the CD8+ T-cell response in the context of melanoma. The goal of the study is to demonstrate the potential of this platform to activate circulating tumor-specific CD8+ T cells in patients with lung cancer, specifically non-small-cell lung cancer (NSCLC). PDC*line cells loaded with peptides derived from tumor antigens are used to stimulate the peripheral blood mononuclear cells of NSCLC patients. Very interestingly, we demonstrate an efficient activation of specific T cells for at least two tumor antigens in 69% of patients irrespective of tumor antigen mRNA overexpression and NSCLC subtype. We also show, for the first time, that the antitumor CD8+ T-cell expansion is considerably improved by clinical-grade anti-PD-1 antibodies. Using PDC*line cells as an antigen presentation platform, we show that circulating antitumor CD8+ T cells from lung cancer patients can be activated, and we demonstrate the synergistic effect of anti-PD-1 on this expansion. These results are encouraging for the development of a PDC*line-based vaccine in NSCLC patients, especially in combination with ICIs.

The revised Canada's food guide released in 2019 promotes the consumption of plant-based protein foods (PBP). Yet, older adults consume little of them. This qualitative study aimed to identify older adults' beliefs about consuming PBP and to assess differences in beliefs by gender and baseline PBP consumption. Recruitment was done to obtain an equal number of men and women, 20 PBP-consumers and 40 non-consumers. Each participant completed an online questionnaire collecting sociodemographic data and took part in an individual semi-structured interview based on the Theory of Planned Behavior. A thematic analysis was performed using the Nvivo software. Health benefits, good taste and protecting the environment were perceived as advantages of consuming PBP, whereas difficulty digesting and not liking the taste were reported as disadvantages. Family members were frequently named as people who would approve and/or disapprove the consumption of PBP. Having more knowledge about PBP would facilitate consumption, while lack of motivation to change eating habits and lack of knowledge on how to prepare PBP meals were perceived barriers. Several differences in beliefs by gender and baseline PBP consumption were observed. Future interventions should focus on the beliefs that were identified as important to older adults (i.e., health benefits and food preparation skills), and should be tailored to their gender and PBP consumption., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The perplex interrelation between circulating extracellular vesicles (cEVs) and amyloid-β (Aβ) deposits in the context of Alzheimer's disease (AD) is poorly understood., Objective: This study aims to 1) analyze the possible cross-linkage of the neurotoxic amyloid-β oligomers (oAβ) to the human cEVs, 2) identify cEVs corona proteins associated with oAβ binding, and 3) analyze the distribution and expression of targeted cEVs proteins in preclinical participants converted to AD 5 years later (Pre-AD)., Methods: cEVs were isolated from 15 Pre-AD participants and 15 healthy controls selected from the Canadian Study of Health and Aging. Biochemical, clinical, lipid, and inflammatory profiles were measured. oAβ and cEVs interaction was determined by nanoparticle tracking analysis and proteinase K digestion. cEVs bound proteins were determined by ELISA., Results: oAβ were trapped by cEVs and were topologically bound to their external surface. We identified surface-exposed proteins functionally able to conjugate oAβ including apolipoprotein J (apoJ), apoE and RAGE, with apoJ being 30- to 130-fold higher than RAGE and apoE, respectively. The expression of cEVs apoJ was significantly lower in Pre-AD up to 5 years before AD onset., Conclusion: Our findings suggest that cEVs might participate in oAβ clearance and that early dysregulation of cEVs could increase the risk of conversion to AD.

Virus-like particles (VLPs) are versatile protein-based platforms that can be used as a vaccine platform mainly in infectiology. In the present work, we compared a previously designed, non-infectious, adenovirus-inspired 60-mer dodecahedric VLP to display short epitopes or a large tumor model antigen. To validate these two kinds of platforms as a potential immuno-stimulating approach, we evaluated their ability to control melanoma B16-ovalbumin (OVA) growth in mice. A set of adjuvants was screened, showing that polyinosinic-polycytidylic acid (poly(I:C)) was well suited to generate a homogeneous cellular and humoral response against the desired epitopes. In a prophylactic setting, vaccination with the VLP displaying these epitopes resulted in total inhibition of tumor growth 1 month after vaccination. A therapeutic vaccination strategy showed a delay in grafted tumor growth or its total rejection. If the "simple" epitope display on the VLP is sufficient to prevent tumor growth, then an improved engineered platform enabling display of a large antigen is a tool to overcome the barrier of immune allele restriction, broadening the immune response, and paving the way for its potential utilization in humans as an off-the-shelf vaccine., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Extracellular vesicles (EVs) are critical elements of cell-cell communication. Here, we characterized the outer membrane vesicles (OMVs) released by specific clones of Escherichia coli isolated from the Long-Term Evolution Experiment after 50,000 generations (50K) of adaptation to glucose minimal medium. Compared with their ancestor, the evolved clones produce small OMVs but also larger ones which display variable amounts of both OmpA and LPS. Tracking ancestral, fluorescently labelled OMVs revealed that they fuse with both ancestral- and 50K-evolved cells, albeit in different proportions. We quantified that less than 2% of the cells from one 50K-evolved clone acquired the fluorescence delivered by OMVs from the ancestral strain but that one cell concomitantly fuses with several OMVs. Globally, our results showed that OMV production in E. coli is a phenotype that varies along bacterial evolution and question the contribution of OMVs-mediated interactions in bacterial adaptation.

Virus-like particles constitute versatile vectors that can be used as vaccine platforms in many fields from infectiology and more recently to oncology. We previously designed non-infectious adenovirus-inspired 60-mer dodecahedric virus-like particles named ADDomers displaying on their surface either a short epitope or a large tumor/viral antigen. In this work, we explored for the first time the immunogenicity of ADDomers exhibiting melanoma-derived tumor antigen/epitope and their impact on the features of human dendritic cell (DC) subsets. We first demonstrated that ADDomers displaying tumor epitope/antigen elicit a strong immune-stimulating potential of human DC subsets (cDC2s, cDC1s, pDCs), which were able to internalize and cross-present tumor antigen, and subsequently cross-prime antigen-specific T-cell responses. To further limit off-target effects and enhance DC targeting, we engineered specific motifs to de-target epithelial cells and improve DCs' addressing. The improved engineered platform making it possible to display large antigen represents a tool to overcome the barrier of immune allele restriction, broadening the immune response, and paving the way to its potential utilization in humans as an off-the-shelf vaccine.

The microbiota constitutes an important part of the holobiont in which extracellular vesicles (EVs) are key players in health, especially regarding inter- and intra-kingdom communications. Analysis of EVs from the red blood cell concentrates of healthy donors revealed variable amounts of OmpA and LPS in 12 of the 14 analyzed samples, providing indirect experimental evidence of the presence of microbiota EVs in human circulating blood in the absence of barrier disruption. To investigate the role of these microbiota EVs, we tracked the fusion of fluorescent Escherichia coli EVs with blood mononuclear cells and showed that, in the circulating blood, these EVs interacted almost exclusively with monocytes. This study demonstrates that bacterial EVs constitute critical elements of the host-microbiota cellular communication. The analysis of bacterial EVs should thus be systematically included in any characterization of human EVs.

Background: Omega-3 (n-3) PUFAs are suggested to play a role in the prevention of cognitive decline. The evidence may be inconsistent due to methodologic issues, including interrelations with other long-chain (14 or more carbons) fatty acids (LCFAs) and use of sex as a confounding factor rather than an effect modifier., Objectives: This study evaluated the association between serum n-3 PUFAs and performance across 4 cognitive domains, overall and by sex, while controlling for other LCFAs., Methods: In total, 386 healthy older adults (aged 77.4 ± 3.8 y; 53% females) from the Quebec Longitudinal Study on Nutrition and Successful Aging underwent a cognitive evaluation and blood sampling. Verbal and nonverbal episodic memory, executive functioning, and processing speed were evaluated. Serum LCFA concentrations were measured by gas chromatography. LCFAs were grouped according to standard fatty acid classes and factor analysis using principal component analysis (FA-PCA). Multivariate linear regression models were performed, including unadjusted and adjusted models for other LCFAs., Results: Higher n-3 PUFA concentrations were associated with better nonverbal memory and processing speed in fully adjusted models not including other LCFAs (βs of 0.21 and 0.19, respectively). The magnitude of these associations varied when other LCFAs were entered in the model (βs of 0.27 and 0.32, respectively) or when FA-PCA factors were considered (βs of 0.27 and 0.21, respectively). Associations with verbal episodic memory were limited to higher concentrations of EPA, whereas there was no association between n-3 PUFAs and executive functioning. Higher n-3 PUFAs were associated with better verbal and nonverbal episodic memory in females and with better executive functioning and processing speed in males., Conclusions: These results suggest that other LCFAs should be considered when evaluating the association between n-3 PUFAs and cognitive performance in healthy older adults. Sex differences across cognitive domains warrant further investigation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objectives: This study was an in-depth exploration of unique data from a nationally representative sample of adults living in the United States to identify biomarkers associated with musculoskeletal pain., Methods: We performed secondary analyses of 2003-2004 NHANES data. After a first screening of 187 markers, analyses of 31 biomarkers were conducted on participants aged ≥20 years identified in all counties using the 2000 Census Bureau data (n = 4,742). To assess the association of each biomarker with each pain outcome (acute, subacute and chronic low back, neck, and shoulder pain), analyses were carried out using multivariable logistic regression with adjustments for sex, age and body mass index. Biomarkers were considered as continuous variables and categorized at the median of their distributions., Results: Pain at any site for ≥24 hours during the past month was reported by 1,214 participants. Of these, 779 mentioned that the pain had lasted for ≥3 months ("chronic pain"). α-carotene, ascorbic acid, β-carotene, mercury and total protein had a statistically significant, inverse association with ≥2 chronic pain sites. Acrylamide, alkaline phosphatase, cadmium, cotinine, glycidamide, homocysteine, retinol, triglycerides and white blood cell count were positively associated with ≥2 chronic pain sites. Few biological markers were associated with acute and subacute pain., Conclusions: This study identified some biomarkers that were strongly and consistently associated with musculoskeletal pain. These results raise new hypotheses and could have tremendous implications for advancing knowledge in the field. Research on musculoskeletal pain needs to put more effort on the biological dimension of the biopsychosocial model of pain., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The aim of this study was to check if self-reported smoking is still associated with back pain above and beyond its association with cotinine, to test the hypothesis that the association of self-reported cigarette smoking with back pain is due to residual confounding., Methods: Secondary analyses of population-based cross-sectional data pertaining to 4470 adults were conducted. In multivariate analyses examining the associations of self-reported smoking with several spinal pain outcomes (neck pain, low back pain, low back pain with pain below knee, self-reported diagnosis of arthritis/rheumatism, and related limitations), further adjustment for serum cotinine concentrations was made., Results: Self-reported cigarette smoking was associated with neck pain (adjusted Odds Ratio ( a OR) Regular smokers vs. Non-smokers: 1.44; 95% Confidence Interval (CI): 1.14-1.82), low back pain ( a OR: 1.48; 95% CI: 1.24-1.78), low back pain with pain below knee ( a OR: 1.98; 95% CI: 1.42-2.76), as well as arthritis/rheumatism ( a OR: 1.33; 95% CI: 1.03-1.71), and related functional limitations (P < .05). Further adjustment for serum cotinine concentrations brought about little change in the ORs or beta coefficients., Conclusions: These results do not support the hypothesis that serum cotinine concentrations explain the well-known relationship between cigarette smoking and spinal pain., (Copyright © 2021. Published by Elsevier Inc.)

Transcription factors (TFs) are key players in the control of gene expression and consequently all major cellular process, ranging from cell fate determination to cell cycle control and response to the environment.In particular cases, their ectopic expression has shown great promise in cell reprogramming for regenerative medicine, ontogenesis studies, and cell modeling. The current reprogramming methods mainly rely on gene transfer, therefore require technological improvements to limit genetic imprinting and improve safety. Direct protein delivery could represent an attractive alternative. Cell-penetrating peptides (CPPs) fused to recombinant TFs or other proteins involved in the epigenetic definition of cells have great potential in this context. We have thus developed the direct vectorization of Oct4, Sox2, or Nanog TFs and the posttranscriptional regulatory RNA-binding protein Lin28a by using the minimal transduction domain (MD 11 ) of Epstein-Barr virus ZEBRA protein.This section describes the molecular cloning and production of different TFs fused to ZEBRA MD 11 domain in the E. coli expression system. We also include the optimized purification conditions for each recombinant protein. The treatment of primary fibroblasts as well as cord blood-derived hematopoietic stem cells is also described. Finally, the transcriptional activation of the target genes following the transfer of TFs analyzed by quantitative PCR is presented.Our work primarily finds applications for advanced medicinal products, an area that requires novel therapy designs and delivery systems devoid of genetic material transfer to improve safety., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Deprescribing, a relatively recent concept, has been proposed as a promising solution to the growing issues of polypharmacy and use of medications of questionable benefit among older adults. However, little is known about the health outcomes of deprescribing interventions., Objective: This paper presents the protocol of a study that aims to contribute to the knowledge on deprescribing by addressing two specific objectives: (1) describe the impact of deprescribing in adults ≥60 years on health outcomes or quality of life; and (2) determine the characteristics of effective interventions in deprescribing., Methods: Primary studies targeting three concepts (older adults, deprescribing, and health or quality of life outcomes) will be included in the review. The search will be performed using key international databases (MEDLINE, EMBASE, CINAHL, Ageline, PsycInfo), and a special effort will be made to identify gray literature. Two reviewers will independently screen the articles, extract the information, and evaluate the quality of the selected studies. If methodologically feasible, meta-analyses will be performed for groups of intervention studies reporting on deprescribing interventions for similar medications, used for similar or identical indications, and reporting on similar outcomes (eg, benzodiazepines used against insomnia and studies reporting on quality of sleep or quality of life). Alternatively, the results will be presented in bottom-line statements (objective 1) and a matrix outlining effective interventions (objective 2)., Results: The knowledge synthesis may be limited by the availability of high-quality clinical trials on deprescribing and their outcomes in older adults. Additionally, analyses will likely be affected by studies on the deprescribing of different types of molecules within the same indication (eg, different pharmacological classes and medications to treat hypertension) and different measures of health and quality of life outcomes for the same indication. Nevertheless, we expect the review to identify which deprescribing interventions lead to improved health outcomes among seniors and which of their characteristics contribute to these outcomes., Conclusions: This systematic review will contribute to a better understanding of the health outcomes of deprescribing interventions among seniors., Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42015020866; https://www.crd.york.ac.uk/prospero/display&#95;record.php?ID=CRD42015020866., International Registered Report Identifier (irrid): PRR1-10.2196/25200., (©Zoë Tremblay, David Mumbere, Danielle Laurin, Caroline Sirois, Daniela Furrer, Lise Poisblaud, Pierre-Hugues Carmichael, Barbara Farrell, André Tourigny, Anik Giguere, Isabelle Vedel, José Morais, Edeltraut Kröger. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 09.12.2021.)

Objectives: Psychosocial stressors at work have been proposed as modifiable risk factors for mild cognitive impairment (MCI). This study aimed to evaluate the effect of cumulative exposure to psychosocial stressors at work on cognitive function., Methods: This study was conducted among 9188 white-collar workers recruited in 1991-1993 (T1), with follow-ups 8 (T2) and 24 years later (T3). After excluding death, losses to follow-up and retirees at T2, 5728 participants were included. Psychosocial stressors at work were measured according to the Karasek's questionnaire. Global cognitive function was measured with the Montreal Cognitive Assessment. Cumulative exposures to low psychological demand, low job control, passive job and high strain job were evaluated using marginal structural models including multiple imputation and inverse probability of censoring weighting., Results: In men, cumulative exposures (T1 and T2) to low psychological demand, low job control or passive job were associated with higher prevalences of more severe presentation of MCI (MSMCI) at T3 (Prevalence ratios (PRs) and 95% CIs of 1.50 (1.16 to 1.94); 1.38 (1.07 to 1.79) and 1.55 (1.20 to 2.00), respectively), but not with milder presentation of MCI. In women, only exposure to low psychological demand or passive job at T2 was associated with higher prevalences of MSMCI at T3 (PRs and 95% CI of 1.39 (0.97 to 1.99) and 1.29 (0.94 to 1.76), respectively)., Conclusions: These results support the deleterious effect of a low stimulating job on cognitive function and the cognitive reserve theory. Psychosocial stressors at work could be part of the effort for the primary prevention of cognitive decline., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chronic low-grade inflammation has been associated with high risk of several chronic diseases such as cardiovascular diseases, diabetes, depression, and dementia. As low-grade inflammation could be present long before the apparition of the disease, identifying modifiable risk factors could allow to act upstream. Psychosocial stressors at work have been suggested as modifiable risk factors of low-grade inflammation, but few longitudinal studies have evaluated the association between these stressors and inflammatory biomarkers, such as C-reactive protein (CRP) and interleukin-6 (IL-6)., Objective: This longitudinal study evaluate the associations between exposure to psychosocial stressors at work and CRP and IL-6, separately and combined into an inflammatory index., Methods: Data came from a cohort of 9188 white-collar workers recruited in 1991-1993 (T1) and followed-up after 8 (T2, 1999-2000) and 24 (T3, 2015-2018) years. Participants included in this study were randomly selected at T3 for serum biomarkers studies (n = 2557). CRP and IL-6 were measured using standardized protocols. Psychosocial stressors at work were assessed at T2 according to recognized models: Karasek's Demand-Control-Support model and Siegrist's Effort-Reward Imbalance (ERI) model, using validated questionnaires. High job strain was defined by an exposure to high psychological demand combined with low job control, and iso-strain was defined by an exposure to high job strain combined with low social support at work. ERI was defined by an imbalance between psychological demand and social, economic, and organizational reward. Several covariates were considered including sociodemographic, anthropometric, and lifestyle characteristics, and comorbidities. Prevalence ratios (PRs) and 95% confidence interval (CI) for the highest quartile of CRP, IL-6 and inflammatory index at T3 according to psychosocial stressors at work measured at T2 were calculated using generalized estimating equations. Multiple imputation and inverse probability of censoring weighting were done., Results: In men, an association was observed between exposure to iso-strain and the inflammatory index (PR of 1.42 (95% CI: 1.06;1.90)), mainly among men aged less than 65 years (PR of 2.00 (95% CI: 1.37;2.92)). In this same age group, associations with inflammatory biomarkers were also observed among men with exposure to ERI, and among women with exposure to low reward at work or moderate social support at work., Conclusion: These results suggest that psychosocial stressors at work may increase low-grade inflammation. However, further studies are needed to corroborate these results and to clarify the potential differences between men and women. As these stressors are frequent and modifiable, their reduction is important for public health and could play a role in the primary prevention of chronic diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Bisphosphonates are used to treat osteoporosis. Despite their benefits on bone mineral density (BMD) and fractures, they have shown adverse effects, sometimes severe, during chronic use. Taken for several years, they achieve long-term bone retention, making deprescribing feasible. This review aimed to synthesize evidence on the success and health outcomes of deprescribing of bisphosphonates in seniors, aged over 60 years., Methods: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including articles in English, French, or German published before July 2020. Eligible studies included seniors having discontinued bisphosphonates and reported on health outcomes; some allowed meta-analyses on fracture risk., Results: The review included 9 RCTs and 9 cohort studies of moderate quality. Bisphosphonates were discontinued after 2 to 7 years of use, and BMD or fractures were assessed during follow-up of 0.5 to 5 years. A significant reduction in BMD after discontinuation was observed in 9 of 10 studies. Results on fracture risk after discontinuation are mitigated: 6 RCT extensions showed no increase in the risk of any osteoporotic fractures after discontinuation. Meta-analyses including 4 RCTs showed an increased odds ratio of vertebral fractures of 2.04 (95% CI, 1.39-2.99) among discontinuers. Results from 2 large cohort studies showed no increased risks of any osteoporotic or vertebral fractures, while 2 studies found increased fracture risks., Conclusion: Bisphosphonates have successfully been discontinued low overall fracture risk after at least 3 years of use, but a risk for decreased BMD and increased vertebral fractures remained., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Introduction: The substantial link between apolipoprotein E ( APOE ) ε4 allele and oxidative stress may underlie enhanced Alzheimer's disease (AD) risk. Here, we studied the impact of APOE ε4 on the level of apolipoproteins with antioxidant activities along with oxidative markers in circulating extracellular vesicles (cEVs) and plasma from cognitively impaired-not demented (CIND) individuals converted to AD (CIND-AD)., Methods: Apolipoproteins E, J, and D and antioxidant response markers were determined in cEVs and plasma using immunoblotting, electrochemical examination, and spectrofluorimetry., Results: Total antioxidant capacity and apolipoprotein D levels in cEVs, as judged by regression analysis and cognitive performance correlations, allowed us to differentiate CIND APOE ε4 carriers from controls and to predict their progression to AD 5 years later., Discussion: Our findings support the pathological redox linkage between APOE ε4 and AD onset and suggest the use of cEVs oxidative signature in early AD diagnosis., Competing Interests: The authors report that they have no conflicts of interest to disclose., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

[Figure: see text].

It is now well established that adjusting for pure predictors of the outcome, in addition to confounders, allows unbiased estimation of the total exposure effect on an outcome with generally reduced standard errors (SEs). However, no analogous results have been derived for mediation analysis. Considering the simplest linear regression setting and the ordinary least square estimator, we obtained theoretical results showing that adjusting for pure predictors of the outcome, in addition to confounders, allows unbiased estimation of the natural indirect effect (NIE) and the natural direct effect (NDE) on the difference scale with reduced SEs. Adjusting for pure predictors of the mediator increases the SE of the NDE's estimator, but may increase or decrease the variance of the NIE's estimator. Adjusting for pure predictors of the exposure increases the variance of estimators of the NIE and NDE. Simulation studies were used to confirm and extend these results to the case where the mediator or the outcome is binary. Additional simulations were conducted to explore scenarios featuring an exposure-mediator interaction as well as the relative risk and odds ratio scales for the case of binary mediator and outcome. Both a regression approach and an inverse probability weighting approach were considered in the simulation study. A real-data illustration employing data from the Canadian Study of Health and Aging is provided. This analysis is concerned with the mediating effect of vitamin D in the effect of physical activity on dementia and its results are overall consistent with the theoretical and empirical findings., (© 2021 The Authors. Statistics in Medicine published by John Wiley & Sons, Ltd.)

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

Objectives: This study examined the effect of dietary patterns and engagement in cognitive stimulating lifestyle (CSL) behaviors on the trajectory of global cognition, executive function (EF), and verbal episodic memory (VEM)., Methods: Western and prudent dietary patterns were empirically derived using food frequency questionnaire responses from 350 community-dwelling older adults (mean age: 73.7 years) participating in the Quebec Longitudinal Study on Nutrition and Successful Aging. CSL was represented by a binary composite indicator based on education, occupational complexity, and social engagement. Global cognition, EF, and VEM were assessed prospectively., Results: Primary effect models revealed an association between higher Western dietary pattern score and a greater rate of decline in global cognition and EF. Higher Western dietary pattern adherence was also associated with poorer baseline VEM. Primary effect models also revealed that CSL was independently associated with baseline global cognition and EF. Effect modification models suggested an interactive effect between Western dietary pattern and CLS on global cognition only. No associations were found for prudent dietary pattern score., Discussion: Contributing to existing research supporting the negative impact of consuming an unhealthy diet on cognitive function, the current study suggests increased vulnerability among older adults who do not engage in a CSL. These findings can inform the development of lifestyle intervention programs that target brain health in later adulthood., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: In brain, extracellular vesicles (EVs) play an essential role in the neuron-glia interface and ensure the crosstalk between the brain and the periphery. Some studies now link the pathway dysfunction of the EVs to apolipoprotein E gene variant ( APOE ε4) and the risk of progression to Alzheimer's disease (AD). To better understand the role of APOE ε4 in pre-clinical AD, we have determined levels of pathogenic, neurotrophic and inflammatory proteins in peripheral EVs (pEVs) and in plasma from cognitively impaired, no dementia (CIND) participants stratified upon the absence ( APOE ε4 - ) or the presence ( APOE ε4 + ) of the ε4 allele of APOE ., Methods: Levels of 15 neurodegenerative, neurotrophic and neuroinflammatory proteins were quantified in pEVs and compared to their plasma levels from cognitively normal and CIND participants., Results: Levels of neurotrophic and inflammatory markers were reduced in pEVs from APOE ε4 + . The pentraxin-2/α-synuclein ratio measured in pEVs was able to predict AD 5 years before the onset among APOE ε4 + -CIND individuals., Discussion: Our findings suggest an alteration of the endosomal pathway in APOE ε4 + and that pEVs pentraxin-2/α-synuclein ratio could serve as a useful early biomarker for AD susceptibility., Competing Interests: The authors report that they have no conflict of interest to disclose., (© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Intensive systemic chemotherapy is the gold standard of acute myeloid leukemia (AML) treatment and is associated with considerable off-target toxicities. Safer and targeted delivery systems are thus urgently needed. In this study, we evaluated a virus-like particle derived from the human type 3 adenovirus, called the adenoviral dodecahedron (Dd) to target AML cells. The vectorization of leukemic cells was proved very effective at nanomolar concentrations in a time- and dose-dependent manner, without vector toxicity. The internalization involved clathrin-mediated energy-dependent endocytosis and strongly correlated with the expression of α V β 3 integrin. The treatment of healthy donor peripheral blood mononuclear cells showed a preferential targeting of monocytes compared to lymphocytes and granulocytes. Similarly, monocytes but also AML blasts were the best-vectorized populations in patients while acute lymphoid leukemia blasts were less efficiently targeted. Importantly, AML leukemic stem cells (LSCs) could be addressed. Finally, Dd reached peripheral monocytes and bone marrow hematopoietic stem and progenitor cells following intravenous injection in mice, without excessive spreading in other organs. These findings reveal Dd as a promising myeloid vector especially for therapeutic purposes in AML blasts, LSCs, and progenitor cells., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)

Importance: Mental health problems are associated with considerable occupational, medical, social, and economic burdens. Psychosocial stressors at work have been associated with a higher risk of mental disorders, but the risk of sickness absence due to a diagnosed mental disorder, indicating a more severe condition, has never been investigated in a systematic review and meta-analysis., Objective: To synthesize the evidence of the association of psychosocial stressors at work with sickness absence due to a diagnosed mental disorder among adult workers., Data Sources: Seven electronic databases (MEDLINE, Embase, PsycInfo, Web of Science, CINAHL, Sociological Abstracts, and International Bibliography of the Social Sciences), 3 gray literature databases (Grey Literature Report, WHO-IRIS and Open Grey), and the reference lists of all eligible studies and reviews were searched in January 2017 and updated in February 2019., Study Selection: Only original prospective studies evaluating the association of at least 1 psychosocial stressor at work from the 3 most recognized theoretical models were eligible: the job demand-control-support model, including exposure to job strain (high psychological demands with low job control); effort-reward imbalance model; and organizational justice model. Study selection was performed in duplicate by blinded independent reviewers. Among the 28 467 citations screened, 23 studies were eligible for systematic review., Data Extraction and Synthesis: This meta-analysis followed the PRISMA and MOOSE guidelines. Data extraction and risk of bias evaluation, using the Risk of Bias in Nonrandomized Studies-Interventions tool, were performed in duplicate by blinded independent reviewers. Data were pooled using random-effect models., Main Outcomes and Measures: Sickness absence due to a mental disorder with a diagnosis obtained objectively., Results: A total of 13 studies representing 130 056 participants were included in the 6 meta-analyses. Workers exposed to low reward were associated with a higher risk of sickness absence due to a diagnosed mental disorder compared with nonexposed workers (pooled risk ratio [RR], 1.76 [95% CI, 1.49-2.08]), as were those exposed to effort-reward imbalance (pooled RR, 1.66 [95% CI, 1.37-2.00]), job strain (pooled RR, 1.47 [95% CI, 1.24-1.74]), low job control (pooled RR, 1.25 [95% CI, 1.02-1.53]), and high psychological demands (pooled RR, 1.23 [95% CI, 1.04-1.45])., Conclusions and Relevance: This meta-analysis found that workers exposed to psychosocial stressors at work were associated with a higher risk of sickness absence due to a mental disorder. A better understanding of the importance of these stressors could help physicians when evaluating their patients' mental health and work capacity.

Background: Consumption of a prudent dietary pattern rich in healthy nutrients is associated with enhanced cognitive performance in older adulthood, while a Western dietary pattern low in healthy nutrients is associated with poor age-related cognitive function. Sex differences exist in dietary intake among older adults; however, there is a paucity of research examining the relationship between sex-specific dietary patterns and cognitive function in later life., Methods: The current study aimed to investigate sex differences in the relationship between sex-specific dietary pattern adherence and global cognitive function at baseline and over a 3-year follow-up in 1268 community-dwelling older adults (M age  = 74 years, n = 664 women, n = 612 men) from the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge). A 78-item Food Frequency Questionnaire was used to estimate dietary intake over the previous year. Sex-specific dietary pattern scores were derived using principal component analysis. Global cognition was assessed using the Modified Mini-Mental State Examination (3MS)., Results: Adjusted linear mixed effects models indicated that a healthy, prudent dietary pattern was not associated with baseline cognitive performance in men or women. No relationship was found between Western dietary pattern adherence and baseline cognitive function in women. Among men, adherence to an unhealthy, Western dietary pattern was associated with poorer baseline cognitive function (β = - 0.652, p = 0.02, 95% CI [- 1.22, - 0.65]). No association was found between prudent or Western dietary patterns and cognitive change over time in men or women., Conclusions: These findings highlight the importance of conducting sex-based analyses in aging research and suggest that the relationship between dietary pattern adherence and cognitive function in late life may be sex-dependent.

Objective: Vitamin D could prevent cognitive decline because of its neuroprotective, anti-inflammatory and antioxidant properties. This study aimed to evaluate the associations of plasma 25-hydroxyvitamin D (25(OH)D) concentrations with global cognitive function and incident dementia, including Alzheimer's disease (AD)., Methods: The Canadian Study of Health and Aging is a 10-year cohort study of a representative sample of individuals aged 65 years or older. A total of 661 subjects initially without dementia with frozen blood samples and follow-up data were included. Global cognitive function was measured using the validated Modified Mini-Mental State (3MS) examination. A consensus diagnosis of all-cause dementia and AD was made between the physician and the neuropsychologist according to published criteria. Cognitive decline for a 5-year increase in age at specific 25(OH)D concentrations was obtained using linear mixed models with repeated measures. Hazard ratios of incident dementia and AD were obtained using semi-parametric proportional hazards models with age as time scale., Results: Over a mean follow-up of 5.4 years, 141 subjects developed dementia of which 100 were AD. Overall, no significant association was found between 25(OH)D and cognitive decline, dementia or AD. Higher 25(OH)D concentrations were associated with an increased risk of dementia and AD in women, but not in men., Conclusion: This study does not support a protective effect of vitamin D status on cognitive function. Further research is needed to clarify the relation by sex.

Red Blood Cell (RBC) transfusion dependence is a prevalent consequence of anaemia in patients with lower risk Myelodysplastic Syndromes (MDS). These patients have shorter survival compared to patients responding to Erythropoiesis-stimulating agents (ESA), raising the question of potential negative effects of chronic RBC transfusions on MDS prognosis, independently of IPSS-R. Besides commonly identified complications of transfusions like iron toxicity or cardiac events, oxidative stress could be a risk factor for ineffective haematopoiesis. Recently, physicochemical changes of RBC during storage have been described. These changes called storage lesions could play a role in immunomodulation in vivo. We review the currently identified sources of potential impact on transfusion-associated effects in MDS patients and we discuss the unexplored potential role of erythrocyte-derived-extracellular vesicles. They could amplify impairment of haematopoiesis in addition to the negative intrinsic effects underlying the pathology in MDS. Thus, chronic RBC transfusions appear to potentially impact the outcome of MDS., Competing Interests: Declaration of Competing Interest Sophie Park has received research grants from Novartis, Pfizer and Celgene for investigation in fields involving ESA, transfusion questions and therapies in MDS. This article has not been supported by the pharmaceutical industry., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The use of benzodiazepines in relation to cognitive decline remains an area of controversy in aging populations. Objective: This study aims to evaluate the risk of cognitive impairment-not dementia (CIND), Alzheimer disease (AD), and all-cause dementia with benzodiazepine use. The effect modification by sex was also investigated. Methods: Data come from the Canadian Study of Health and Aging, a 10-year multicentric study involving 10 263 participants randomly selected, 65 years and older, living in the community and in institutions. Current exposure to benzodiazepines was assessed in a face-to-face interview or self-reported in a questionnaire. Cox proportional hazard regression models, using age as time scale, were conducted to estimate hazard ratios, with adjustment for sex, education, smoking, alcohol intake, depression, physical activity, nonsteroidal anti-inflammatory drug use, and vascular comorbidities. Results: Data sets included 5281 participants for dementia as the outcome, 5015 for AD, and 4187 for CIND. Compared with nonusers, current use of benzodiazepines was associated with an increased risk of CIND (hazard ratio = 1.36; 95% CI = 1.08-1.72) in the simplest model. Results remained similar in the fully adjusted model (hazard ratio = 1.32; 95% CI = 1.04-1.68). There was no association between benzodiazepine use and the risk of dementia or AD. All these effects were similar between men and women. Conclusion and Relevance: Benzodiazepine use in older people from the general population is related to subsequent occurrence of cognitive dysfunction but not implicated in the pathogenesis of dementia or AD. Caution should be exercised when prescribing benzodiazepines to preserve global cognitive function.

Introduction: Depression is a common and disabling health problem that contributes to an important social and economic burden, particularly among the working age population. The deleterious effect of psychosocial work factors on depression has been documented. However, the most recent systematic reviews had restrictive eligibility criteria and, since their publications, several original studies have been published. The proposed systematic review aims to update, evaluate and synthesise the effect of psychosocial work factors from three recognised theoretical models, the demand-control-support, effort-reward imbalance and organisational justice models, on the risk of depression among workers., Method and Analysis: A systematic literature search will be conducted in seven academic databases (Medline, Embase, CINAHL, Web of Science, PsycInfo, Sociological abstracts and IBSS) as well as three grey literature databases. The search strategy was first run on January 2017, updated in October 2017 and will be updated 6 months prior to submission for publication. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations, study selection will be carried out using a rigorous multistep screening process in duplicate by independent reviewers. Prospective studies evaluating the effect of at least one psychosocial work factor from the three theoretical models on depression or antidepressant medication use among working adults will be included. Extracted data will be used for evidence synthesis as well as to assess risk of bias and methodological quality. Meta-estimates will be provided after considering homogeneity and number of studies., Ethics and Dissemination: This study will only draw from published studies and grey literature available in electronic databases; ethics approval is not required. The results of this review will be published in a peer review journal and presented at relevant conferences. Given that psychosocial work factors are frequent and modifiable, the results can help reduce the social and economic burden of depression and support public policy-makers to improve occupational health standards., Prospero Registration Number: CRD42018107666., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The objective of this study was to develop and validate a short, self-administered questionnaire to assess diet quality in clinical settings, using the Alternative Healthy Eating Index (AHEI) as reference., Methods: A total of 1040 men and women (aged 44.6 ± 14.4 y) completed a validated web-based food frequency questionnaire (webFFQ) and had their height and weight measured (development sample). Participants were categorized arbitrarily according to diet quality (high: AHEI score ≥ 65/110, low: AHEI score < 65/110) based on dietary intake data from the webFFQ. The Brief Diet Quality Assessment Tool was developed using a classification and regression tree (CART) approach and individual answers to the webFFQ among participants considered to have a plausible energy intake (ratio of reported energy intake to basal metabolic rate ≥ 1.2 and < 2.4; n = 1040). A second sample of 3344 older adults (aged 66.5 ± 6.4 y) was used to test the external validity of the Brief Diet Quality Assessment Tool (external validation sample)., Results: The decision tree included sequences of 3 to 6 binary questions, yielding 21 different pathways classifying diet quality as being high or low. In the development sample, the area under the receiver operating characteristic (ROC) curve of the predictive model was 0.92, with sensitivity, specificity and agreement values of 89.5, 83.9 and 87.2%. Compared with individuals having a low-quality diet according to the Brief Diet Quality Assessment Tool (mean AHEI 56.7 ± 11.4), individuals classified as having a high-quality diet (mean AHEI 71.3 ± 11.0) were significantly older, and had lower BMI, percent body fat and waist circumference, and had lower blood pressure, triglycerides, cholesterol/HDL ratio and fasting insulin as well as higher HDL-cholesterol concentrations (all P < 0.05). Similar results were observed in the external validation sample, although overall performance of the Brief Diet Quality Assessment Tool was slightly lower than in the development sample, with an area under the ROC curve of 0.79 and sensitivity, specificity and agreement values of 73.0, 69.0 and 71.3%, respectively., Conclusion: The CART approach yielded a simple and rapid Brief Diet Quality Assessment Tool that identifies individuals at risk of having a low-quality diet. Further studies are needed to test the performance of this tool in primary care settings.

Dietary patterns, or the combination of foods and beverages intake, have been associated with better cognitive function in older persons. To date, no study has investigated the link between a posteriori nutrient patterns based on food intake, and cognitive decline in longitudinal analyses. The aim of this study was to evaluate the relationship between nutrient patterns and cognitive function and decline in two longitudinal cohorts of older persons from France and Canada. The study sample was composed of participants from the Three-City study (3C, France) and the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge, Quebec, Canada). Both studies estimated nutritional intakes at baseline, and carried out repeated measures of global cognitive function for 1,388 and 1,439 individuals, respectively. Nutrient patterns were determined using principal component analysis methodology in the two samples, and their relation with cognitive function and decline was estimated using linear mixed models. In 3C, a healthy nutrient pattern, characterized by higher intakes of plant-based foods, was associated with a higher global cognitive function at baseline, as opposed to a Western nutrient pattern, which was associated with lower cognitive performance. In NuAge, we also found a healthy nutrient pattern and a Western pattern, although no association was observed with either of these patterns in the Canadian cohort. No association between any of the nutrient patterns and cognitive decline was observed in either cohort. There is a need for longitudinal cohorts focusing on nutrient patterns with substantial follow-up, in order to evaluate more accurately associations between nutrition and cognition in older persons.

Peripheral biomarkers have shown significant value in predicting brain health and may serve as a useful proxy measurement in the assessment of evidence-based lifestyle behavior modification programs, including physical activity and nutrition programs, that aim to maintain cognitive function in late life. The aim of this systematic review was to elucidate which peripheral biomarkers are robustly associated with cognitive function among relatively healthy non-demented older adults. Following the standards for systematic reviews (PICO, PRIMSA), and employing MEDLINE and Scopus search engines, 222 articles were included in the review. Based on the review of biomarker proxies of cognitive health, it is recommended that a comprehensive biomarker panel, or biomarker signature, be developed as a clinical end point for behavior modification trials aimed at enhancing cognitive function in late life. The biomarker signature should take a multisystemic approach, including lipid, immune/inflammatory, and metabolic biomarkers in the biological signature index of cognitive health., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Chronic myelomonocytic leukemia (CMML) is a myeloid hematological malignancy with overlapping features of myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). The knowledge of the role of the tumor microenvironment (TME), particularly mesenchymal stromal cells (MSCs), in MDS pathogenesis is increasing. Generally, cancer is associated with a procoagulant state participating in tumor development. Monocytes release procoagulant, tissue factor (TF)-bearing microparticles. We hypothesized that MSCs and clonal monocytes release procoagulant extracellular vesicles (EVs) within the CMML TME, inducing a procoagulant state that could modify hematopoietic stem cell (HSC) homeostasis. We isolated and cultured MSCs and monocytes from CMML patients and MSCs from healthy donors (HDs). Their medium EVs and small EVs (sEVs) were collected after iterative ultracentrifugations and characterized by nanoparticle tracking analysis. Their impact on hemostasis was studied with a thrombin generation assay and fibrinography. CMML or HD HSCs were exposed to sEVs from either CMML or HD MSCs. CMML MSC sEVs increased HD HSC procoagulant activity, suggesting a transfer of TF from the CMML TME to HD HSCs. The presence of TF on sEVs was shown by electron microscopy and western blot. Moreover, CMML monocyte EVs conferred a procoagulant activity to HD MSCs, which was reversed by an anti-TF antibody, suggesting the presence of TF on the EVs. Our findings revealed a procoagulant "climate" within the CMML environment related to TF-bearing sEVs secreted by CMML MSCs and monocytes., (© 2019 by The American Society of Hematology.)

Background: Little attention has been paid to neurotoxicants on the risk of dementia. Exposure to known neurotoxicants such as polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides is suspected to have adverse cognitive effects in older populations., Objective: To assess whether plasma concentrations of PCBs and OC pesticides are associated with the risk of cognitive decline, Alzheimer's disease (AD) and of all-cause dementia in the Canadian older population., Methods: Analyses were based on data from the Canadian Study of Health and Aging, a 3-phase, 10-year population-based study of individuals aged 65+ years. Analyses included 669 clinically assessed subjects, of which 156 developed dementia including 108 incident cases of AD. Subjects were screened at each phase with the 100-point Modified Mini-Mental State Examination (3MS), a measurement of global cognitive function. Statistical analyses included Cox proportional hazards model when the outcome was dementia or AD, and a repeated-measure mixed model when the outcome was the 3MS score., Results: No association of PCB and OC pesticides with the risk of dementia and AD was observed. Elevated concentrations of PCB congeners nos 118, 153, 156, 163, and OC pesticides 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT) and its metabolite 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) were significantly associated with cognitive decline as assessed with the 3MS. A posteriori analyses suggested that only p,p'-DDE was significantly related to a higher cognitive decline in time based on the 3MS among incident cases of dementia compared to subjects remaining nondemented., Conclusion: PCB and OC pesticide plasma concentrations were not related to the incident diagnosis of neither dementia, nor AD. Using the 3MS scores as the outcome, higher concentrations of four PCB congeners and two OC pesticides were associated with lower cognitive performances in subjects. The association of p,p'-DDE with cognitive decline in time in incident cases of dementia merits further investigation.

Introduction: Mental health problems (MHPs) are frequent and disabling and are the first or second leading cause of certified sickness absences from work in industrialised countries. They are generally long lasting and generate a considerable human and socioeconomic burden. The deleterious effect of adverse psychosocial work factors on MHP has been documented. However, the evidence regarding the effect of these factors on absences from work for an MHP has not been synthesised since 2007. The proposed systematic review aims to synthesise the effect of adverse psychosocial work factors from three validated theoretical models (the demand-control-support, effort-reward-imbalance and organisational justice models) on the risk of certified absences from work for diagnosed MHP among workers., Method and Analysis: A systematic search strategy will be conducted in seven databases: Medline, Embase, CINAHL, Web of Science, PsycInfo, Sociological abstracts and IBSS. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations, a multistep screening process by independent reviewers will lead to study selection. The search strategy was first run in 16 January 2017 and will be updated in October 2018. Only quantitative, prospective studies evaluating the effect of at least one psychosocial work factor from the validated theoretical models on certified absence from work for a diagnosed MHP will be considered for inclusion. Extracted data will be used for quantitative and qualitative evidence synthesis as well as to assess risk of bias and methodological quality. Meta-estimates will be provided for high-quality studies and by each psychosocial work factor, after considering homogeneity and number of studies., Ethics and Dissemination: As this study will be based only on published studies, ethics approval is not required. Given that psychosocial works factors are frequent and modifiable, the results of this systematic review may provide evidence to support prevention strategies that can help to reduce the human social and economic burden associated with medically certified absences from work for an MHP., Prospero Registration Number: CRD42018091632., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

One of the major factors limiting the effectiveness of cancer chemotherapy is inefficient drug delivery. Systems enabling efficient delivery and enhanced intracellular uptake appear particularly promising in this respect. Virus-like particle, adenoviral dodecahedron (Dd), employs receptor-mediated endocytosis for cell penetration and is able to deliver intracellularly dozens of cargo molecules attached to one particle. We focused on studying Dd properties in the context of cancer treatment, showing that intratumoral injection of Dd, assessed in mouse xenograft model, results in vector accumulation in tumor without spreading in off-target organs. Moreover, we demonstrated that Dd is a promising vector targeting leukocytes and drug-resistant cancer cells. Dd uptake by human blood cells analyzed in vitro indicated the preference for leukocytes in comparison to red blood cells and platelets. Furthermore, internalization of Dd-doxorubicin conjugate by drug-resistant cells leads to increased nuclear accumulation of doxorubicin and significant enhancement of cytotoxicity against target cancer cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)