ObjectiveAlthough adaptive e-learning environments (AEEs) can provide personalised instruction to health professional and students, their efficacy remains unclear. Therefore, this review aimed to ...identify, appraise and synthesise the evidence regarding the efficacy of AEEs in improving knowledge, skills and clinical behaviour in health professionals and students.DesignSystematic review and meta-analysis.Data sourcesCINAHL, EMBASE, ERIC, PsycINFO, PubMed and Web of Science from the first year of records to February 2019.Eligibility criteriaControlled studies that evaluated the effect of an AEE on knowledge, skills or clinical behaviour in health professionals or students.Screening, data extraction and synthesisTwo authors screened studies, extracted data, assessed risk of bias and coded quality of evidence independently. AEEs were reviewed with regard to their topic, theoretical framework and adaptivity process. Studies were included in the meta-analysis if they had a non-adaptive e-learning environment control group and had no missing data. Effect sizes (ES) were pooled using a random effects model.ResultsFrom a pool of 10 569 articles, we included 21 eligible studies enrolling 3684 health professionals and students. Clinical topics were mostly related to diagnostic testing, theoretical frameworks were varied and the adaptivity process was characterised by five subdomains: method, goals, timing, factors and types. The pooled ES was 0.70 for knowledge (95% CI −0.08 to 1.49; p.08) and 1.19 for skills (95% CI 0.59 to 1.79; p<0.00001). Risk of bias was generally high. Heterogeneity was large in all analyses.ConclusionsAEEs appear particularly effective in improving skills in health professionals and students. The adaptivity process within AEEs may be more beneficial for learning skills rather than factual knowledge, which generates less cognitive load. Future research should report more clearly on the design and adaptivity process of AEEs, and target higher-level outcomes, such as clinical behaviour.PROSPERO registration numberCRD42017065585
Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of ...alcohol's effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date.
Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip.
After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders.
These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.
Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared with the general population. We sought to evaluate the impact of mosaic chromosomal alterations (mCA) on death of ...CVD causes, coronary artery disease (CAD) causes, and of any cause in patients with a cancer diagnosis.
The study was a prospective cohort analysis of 48,919 UK Biobank participants with a cancer diagnosis. mCAs were characterized using DNA genotyping array intensity data and long-range chromosomal phase inference. Multivariable Cox regression models were used to ascertain the associations of mCAs. Exploratory endpoints included various incident cardiovascular phenotypes.
Overall, 10,070 individuals (20.6%) carried ≥ 1 mCA clone. In adjusted analyses, mCA was associated with an increased risk of death of CAD causes HR, 1.37; 95% confidence interval (CI), 1.09-1.71; P = 0.006. In sub-analyses, we found that carriers of mCAs diagnosed with kidney cancer had an increased risk of death of CVD causes (HR, 2.03; 95% CI, 1.11-3.72; P = 0.022) and CAD causes (HR, 3.57; 95% CI, 1.44-8.84; P = 0.006). Women diagnosed with breast cancer who carried a mCA also had a higher risk of death of CAD causes (HR, 2.46; 95% CI, 1.23-4.92; P = 0.011).
Among cancer survivors, carriers of any mCA are at an increased risk of CAD death compared with noncarriers. Mechanistic studies should be considered to better ascertain the biological mechanisms underneath the observed associations between mCAs and cardiovascular events for specific cancer types.
There may be clinical relevance in considering mCAs in patients diagnosed with cancer and undergoing treatment.
Females present a higher risk of adverse drug reactions. Sex‐related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation ...of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex‐related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross‐sectional studies. Participants were self‐described “White” adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age‐ and dose‐adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age‐adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10−4). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype‐inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose‐adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex‐specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.
Abstract
Aims
Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis ...in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.
Methods and results
We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.
Conclusion
The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
Graphical Abstract
rs10754555 associates with higher NLRP3 mRNA expression and NLRP3 inflammasome activation, which induces the release of IL-1β and IL-18. This leads to systemic inflammation, higher risk for coronary artery disease, and cardiovascular mortality.
Childhood maltreatment is associated with shorter leukocyte telomere length (LTL). However, the influence of cardiac vagal control on this relation is unknown. We examined whether cardiac vagal ...control at rest and in response to stress moderates or cross-sectionally mediates the relationship between childhood maltreatment and LTL.
Participants were 1179 men and women (aged 65 7.2 years) suffering from coronary artery disease or non-cardiovascular chronic disease. They completed a childhood maltreatment questionnaire and underwent a stress protocol while electrocardiogram was monitored. High-frequency heart rate variability (HF-HRV) measures were obtained at rest, during stress, and after stress in absolute and normalized units (nu). LTL was measured using quantitative polymerase chain reaction. Mediation and moderation analyses were performed.
HF-HRV and HF-HRV in normalized units (HFnu) measures did not mediate the childhood maltreatment-LTL relation. However, baseline HFnu ( p = .027) and HFnu reactivity ( p = .051) moderated the relation. Specifically, maltreatment was associated with significantly lower LTL among those with baseline HFnu at ( b = -0.059, p = .003) or below the mean ( b = -0.103, p < .001), but not among those with higher baseline HFnu. It was also associated with significantly lower LTL among participants who showed either blunted ( b = -0.058, p = .004) or increased HFnu ( b = -0.099, p = .001) responses to stress but not in those with large decreases in HFnu.
Childhood maltreatment was associated with lower LTL in those who showed a distinct cardiac vagal profile at baseline and in response to stress. The mechanisms and implications remain to be determined.
Heart failure (HF) is a complex disease, almost as common in women as in men. Nonetheless, HF clinical presentation, prognosis, and aetiology vary by sex. This review summarizes the current state of ...sex‐sensitive issues related to HF drugs included in treatment guidelines and suggests future directions for improved care. Heart failure presentation differs between female and male patients: females more often show with hypertensive aetiology and the preserved ejection fraction phenotype, while men more often show ischaemic aetiology and the reduced ejection fraction phenotype. Yet the HF clinical guidelines in Europe, the United States, and Canada do not reflect the sexual dimorphism. Further, in randomized clinical trials of HF medication, women are largely underrepresented, typically consisting of ≥70% men. Given the knowledge that some adverse drug reactions, such as torsade de pointes and angiotensin‐converting enzyme inhibitor‐induced cough, occur more frequently in women, we emphasize the need to test medications thoroughly in both sexes and explore sexual dimorphisms. To better represent all of the targeted patient population and provide better care for all, two kinds of change must come about: recruitment methods to randomized clinical trial samples need to evolve and the participation needs to seem more attractive to women.
BackgroundChildhood maltreatment can result in lifelong psychological and physical sequelae, including coronary artery disease (CAD). Mechanisms leading to increased risk of illness may involve ...emotional dysregulation and shortened leukocyte telomere length (LTL).MethodsTo evaluate whether (1) childhood maltreatment is associated with shorter LTL among older adults with CAD or other chronic illnesses; (2) sex and/or CAD status influence these results; and (3) symptoms of anxiety, depression, and stress moderate or mediate the association between childhood maltreatment and LTL, men and women (N = 1247; aged 65 ± 7.2 years) with and without CAD completed validated questionnaires on childhood maltreatment, symptoms of depression, anxiety, and perceived stress. LTL was measured using quantitative polymerase chain reaction. Analyses included bivariate correlations, hierarchical regressions, and moderation/mediation analyses, controlling for sociodemographic and lifestyle variables.ResultsChildhood maltreatment was associated with significantly shorter LTL (r = −0.059, p = 0.038, b = −0.016, p = 0.005). This relation was not moderated by depression, anxiety, nor perceived stress, though there was mitigated evidence for absence of a maltreatment-LTL relation in men with CAD. Stress perception (but not anxiety or depression) partially mediated the relation between childhood maltreatment and LTL Indirect effect, b = −0.0041, s.e. = 0.002, 95% CI (−0.0085 to −0.0002).ConclusionsChildhood maltreatment was associated with accelerated biological aging independently of patient characteristics. Emotional dysregulation resulting in chronic stress may contribute to this process. Whether stress management or other interventions may help prevent or slow premature aging in those who have suffered maltreatment requires study.
•A predictive model for COVID-19 hospitalization or death was developed.•This model was based on 7 risk factors for COVID-19.•This model identified high-risk subjects who could benefit from ...colchicine therapy.
A predictive model for hospitalization due to COVID-19 or death was developed in the placebo group (N=2,084) from a large clinical trial of colchicine in COVID-19 patients (N = 4,159).
The 7 variables retained in the predictive model were age, gender, body-mass index, history of respiratory disease, use of diabetes drugs, use of anticoagulants, and use of oral steroids at the time of randomization. An optimal threshold value identified from the predictive model was used to classify high-risk patients (those with a predicted probability above the optimal threshold) and low-risk patients (those with a predicted probability below the optimal threshold). The number needed to treat to prevent 1 hospitalization or death with colchicine treatment decreased from 71 in the whole study population (N = 4,159) to 29 in the high-risk subgroup (N=1,692).
This model could serve to identify high-risk subjects who will particularly benefit from early colchicine therapy.
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