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The inaugural Anatomy Education Research Institute (AERI 2017) was held in Bloomington, Indiana in July of 2017. This workshop style conference paired experienced educational researchers (invited speakers) with individuals interested in learning more about the field (accepted applicants). In 2017, AERI was held over a five-day period and entailed plenary style presentations, break-out sessions, and specific times for small group mentorship. All participants (applicants and invited speakers) completed a pre-conference survey at the beginning of the institute and a post-conference survey at the end of the institute. Both surveys included categorical and Likert scale questions as well as open-ended questions for participant feedback. Quantitative and qualitative analyses indicate that both applicants and speakers increased their knowledge of anatomy education research, but that additional obstacles remain. Funding, time, and a lack of respect for the field remain problematic for faculty that wish to complete educational research. Mentorship and a community of practice also emerged as major themes necessary for educational research to be successful.

Abstract Background Mental health conditions represent one of the major groups of non-transmissible diseases. Physical activity (PA) and sedentary time (ST) have been shown to affect mental health outcomes in opposite directions. In this study, we use accelerometery-derived measures of PA and ST from the UK Biobank (UKB) and depression, anxiety and well-being data from the UKB mental health questionnaire as well as published summary statistics to explore the causal associations between these phenotypes. Methods We used MRlap to test if objectively measured PA and ST associate with mental health outcomes using UKB data and summary statistics from published genome-wide association studies. We also tested for bidirectional associations. We performed sex stratified as well as sensitivity analyses. Results Genetically instrumented higher PA was associated with lower odds of depression (OR = 0.92; 95% CI: 0.88, 0.97) and depression severity (beta = − 0.11; 95% CI: − 0.18, − 0.04), Genetically instrumented higher ST was associated higher odds of anxiety (OR = 2.59; 95% CI: 1.10, 4.60). PA was associated with higher well-being (beta = 0.11, 95% CI: 0.04; 0.18) and ST with lower well-being (beta = − 0.18; 95% CI: − 0.32, − 0.03). Similar findings were observed when stratifying by sex. There was evidence for a bidirectional relationship, with higher genetic liability to depression associated with lower PA (beta = − 0.25, 95% CI: − 0.42; − 0.08) and higher well-being associated with higher PA (beta = 0.15; 95% CI: 0.05, 0.25). Conclusions We have demonstrated the bidirectional effects of both PA and ST on a range of mental health outcomes using objectively measured predictors and MR methods for causal inference. Our findings support a causal role for PA and ST in the development of mental health problems and in affecting well-being.

Abstract Falls represent a huge health and economic burden. Whilst many factors are associated with fall risk (e.g. obesity and physical inactivity) there is limited evidence for the causal role of these risk factors. Here, we used hospital and general practitioner records in UK Biobank, deriving a balance specific fall phenotype in 20,789 cases and 180,658 controls, performed a Genome Wide Association Study (GWAS) and used Mendelian Randomisation (MR) to test causal pathways. GWAS indicated a small but significant SNP-based heritability (4.4%), identifying one variant (rs429358) in APOE at genome-wide significance (P

Abstract Background Major depressive disorder (MDD) has a significant impact on global burden of disease. Complications in clinical management can occur when response to pharmacological modalities is considered inadequate and symptoms persist (treatment-resistant depression (TRD)). We aim to investigate inflammation, proxied by C-reactive protein (CRP) levels, and body mass index (BMI) as putative causal risk factors for depression and subsequent treatment resistance, leveraging genetic information to avoid confounding via Mendelian randomisation (MR). Methods We used the European UK Biobank subcohort ( $$n=451,025$$ n = 451 , 025 ), the mental health questionnaire (MHQ) and clinical records. For treatment resistance, a previously curated phenotype based on general practitioner (GP) records and prescription data was employed. We applied univariable and multivariable MR models to genetically predict the exposures and assess their causal contribution to a range of depression outcomes. We used a range of univariable, multivariable and mediation MR models techniques to address our research question with maximum rigour. In addition, we developed a novel statistical procedure to apply pleiotropy-robust multivariable MR to one sample data and employed a Bayesian bootstrap procedure to accurately quantify estimate uncertainty in mediation analysis which outperforms standard approaches in sparse binary outcomes. Given the flexibility of the one-sample design, we evaluated age and sex as moderators of the effects. Results In univariable MR models, genetically predicted BMI was positively associated with depression outcomes, including MDD ( $$\beta$$ β ( $$95\%$$ 95 % CI): 0.133(0.072, 0.205)) and TRD (0.347(0.002, 0.682)), with a larger magnitude in females and with age acting as a moderator of the effect of BMI on severity of depression (0.22(0.050, 0.389)). Multivariable MR analyses suggested an independent causal effect of BMI on TRD not through CRP (0.395(0.004, 0.732)). Our mediation analyses suggested that the effect of CRP on severity of depression was partly mediated by BMI. Individuals with TRD ( $$n=2199$$ n = 2199 ) observationally had higher CRP and BMI compared with individuals with MDD alone and healthy controls. Discussion Our work supports the assertion that BMI exerts a causal effect on a range of clinical and questionnaire-based depression phenotypes, with the effect being stronger in females and in younger individuals. We show that this effect is independent of inflammation proxied by CRP levels as the effects of CRP do not persist when jointly estimated with BMI. This is consistent with previous evidence suggesting that overweight contributed to depression even in the absence of any metabolic consequences. It appears that BMI exerts an effect on TRD that persists when we account for BMI influencing MDD.

BackgroundThough rates of tobacco smoking have decreased consistently over the past 3 decades, cigarette use remains the top preventable cause of premature death in North America. The Clinical Effort Against Secondhand Smoke Exposure (CEASE) is a medical clinic-based intervention that systematically screens parents for tobacco use and offers them direct access to evidence-based smoking cessation services. While the effectiveness of CEASE for parents who smoke has already been demonstrated in the United States, the CEASE model has not yet been tested in Canada, among parents who use e-cigarettes, or among adolescents who use cigarettes and e-cigarettes. ObjectiveWe aim to demonstrate the feasibility and evaluate the preliminary effectiveness of the CEASE program for parental smoking cessation and its adapted version for adolescent smoking cessation and adolescent and parental vaping cessation. MethodsWe will approach parents or guardians of children aged between 0 and 17 years, as well as adolescent patients aged between 14 and 17 years, from a tertiary care pediatric hospital in Montreal, Quebec, Canada, for participation in this single-blinded, pilot randomized controlled trial. Eligible participants are those who report using tobacco cigarettes or e-cigarettes at least once in the last 7 days and present to an outpatient pediatric clinic for a scheduled appointment. Our recruitment target is 100 participants: 50 parents or guardians of children aged 17 years or younger, and 50 adolescents aged between 14 and 17 years. The feasibility of implementation of the CEASE model will be measured by recruitment and retention rates for all 4 participant groups (stratified as follows: parents who use cigarettes, parents who use e-cigarettes exclusively, adolescents who use cigarettes, and adolescents who use e-cigarettes exclusively). Parent and adolescent participants within each group are randomized to the intervention and control groups using a 1:1 ratio through a computer-generated randomization list. Preliminary effectiveness outcomes include self-reported smoking and e-cigarette cessation, use of cessation resources, changes in smoking and e-cigarette use, motivation to quit, and quit attempts among participants. Participants complete electronic questionnaires on a tablet in the clinic at baseline as well as electronic follow-up questionnaires at 1, 3, and 6 months. Individuals reporting successful quit attempts are invited to provide a urine sample for cotinine testing to biochemically confirm quit. Analyses include descriptive statistics as well as exploratory trajectory analyses of smoking, e-cigarette use, and motivation to quit. ResultsResearch activities began in June 2022. Participant enrollment and data collection began in February 2023 and are expected to be completed in 15 months. ConclusionsThere is a strong need for effective and cost-effective smoking and vaping cessation interventions for parents and adolescents. If successful, this study will help inform the preparation of a fully powered randomized controlled trial of CEASE in Canada in these populations. Trial RegistrationClinicaltrials.gov NCT05366790; https://www.clinicaltrials.gov/study/NCT05366790 International Registered Report Identifier (IRRID)DERR1-10.2196/47978

Abstract Background Extensive evidence links higher body mass index (BMI) to higher odds of depression in people of European ancestry. However, our understanding of the relationship across different settings and ancestries is limited. Here, we test the relationship between body composition and depression in people of East Asian ancestry. Methods Multiple Mendelian randomisation (MR) methods were used to test the relationship between (a) BMI and (b) waist-hip ratio (WHR) with depression. Firstly, we performed two-sample MR using genetic summary statistics from a recent genome-wide association study (GWAS) of depression (with 15,771 cases and 178,777 controls) in people of East Asian ancestry. We selected 838 single nucleotide polymorphisms (SNPs) correlated with BMI and 263 SNPs correlated with WHR as genetic instrumental variables to estimate the causal effect of BMI and WHR on depression using the inverse-variance weighted (IVW) method. We repeated these analyses stratifying by home location status: China versus UK or USA. Secondly, we performed one-sample MR in the China Kadoorie Biobank (CKB) in 100,377 participants. This allowed us to test the relationship separately in (a) males and females and (b) urban and rural dwellers. We also examined (c) the linearity of the BMI-depression relationship. Results Both MR analyses provided evidence that higher BMI was associated with lower odds of depression. For example, a genetically-instrumented 1-SD higher BMI in the CKB was associated with lower odds of depressive symptoms [OR: 0.77, 95% CI: 0.63, 0.95]. There was evidence of differences according to place of residence. Using the IVW method, higher BMI was associated with lower odds of depression in people of East Asian ancestry living in China but there was no evidence for an association in people of East Asian ancestry living in the USA or UK. Furthermore, higher genetic BMI was associated with differential effects in urban and rural dwellers within China. Conclusions This study provides the first MR evidence for an inverse relationship between BMI and depression in people of East Asian ancestry. This contrasts with previous findings in European populations and therefore the public health response to obesity and depression is likely to need to differ based on sociocultural factors for example, ancestry and place of residence. This highlights the importance of setting-specific causality when using genetic causal inference approaches and data from diverse populations to test hypotheses. This is especially important when the relationship tested is not purely biological and may involve sociocultural factors.

Abstract Background The Anatomy Education Research Institute (AERI) was held in Bloomington, Indiana in July of 2017. Previous research has shown that AERI was successful in meeting Kirkpatrick’s first two levels of evaluation via positive initial reactions and learning gains identified at the end of AERI. This manuscript demonstrates continued success in Kirkpatrick levels two and three via six-month and thirty-month follow-up surveys and nine-month follow-up focus groups and interviews. Methods Quantitative analyses were completed using Microsoft Excel (2019) and SPSS version 26 while qualitative analyses were completed for both survey responses and focus groups/interviews using thematic analyses. Results Results demonstrate that the learning gains seen immediately post-AERI 2017 were sustained for all participants (accepted applicants and invited speakers). Qualitative results continued to demonstrate positive reactions to AERI 2017. Both quantitative and qualitative results demonstrated that the main obstacle to educational research for most participants is time, while collaboration, IRB, institutional roadblocks, and devaluing of educational research were also identified as obstacles. Conclusions The research presented here indicates positive outcomes to Kirkpatrick Levels 1, 2, & 3 of evaluation following AERI 2017. However, substantial obstacles still exist for researchers in medical education. The need for a sustained community of practice for educational researchers was suggested as a potential buffer against these obstacles and multiple options for providing that community are discussed.

Abstract We documented changes in depressive and anxiety symptoms from before to during the COVID-19 pandemic among young adults and investigated whether changes differed across participant characteristics. Data were available in an investigation of 1294 grade 7 students recruited in 1999–2000. For this analysis, we used data collected pre-pandemically in 2017–20 (mean (SD) age = 30.6 (1.0)) and during the pandemic in 2020–21 (mean (SD) age = 33.6 (0.6)). 673 participants with data in both cycles were retained for analysis. Symptoms were measured using the Major Depression Inventory (MDI) and the Generalized Anxiety Disorder-7 (GAD-7) scale. Standardized mean differences (SMD) of changes in MDI and GAD-7 values between cycles were calculated across participant characteristics. On average, MDI scores increased by 2.1 (95%CI 1.4, 2.8) points during the pandemic from mean 10.5; GAD-7 scores increased by 1.2 (0.8, 1.5) points from mean 4.7. The SMD was 0.24 (0.14, 0.33) for MDI, and 0.24 (0.13, 0.34) for GAD-7. No differences in MDI change scores were observed across participant characteristics. Differences in GAD-7 change scores were observed by mood/anxiety disorder (SMD − 0.31 (− 0.58, − 0.05)), household income (0.24 (0.02, 48)), living with young children (− 0.56 (− 1.23,− 0.05)), and adherence to public health recommendations 0.58 (0.19, 1.03)). Increases in depressive and anxiety symptoms were observed 10–16 months into the COVID-19 pandemic among adults age 32–36.

Purpose The COVID-19 pandemic has had significant health, social and economic impacts around the world. We established a national, population-based longitudinal cohort to investigate the immediate and longer-term physical, psychological and economic impacts of COVID-19 on affected people in Aotearoa New Zealand (Aotearoa), with the resulting evidence to assist in designing appropriate health and well-being services for people with COVID-19.Participants All people residing in Aotearoa aged 16 years or over, who had a confirmed or probable diagnosis of COVID-19 prior to December 2021, were invited to participate. Those living in dementia units were excluded. Participation involved taking part in one or more of four online surveys and/or in-depth interviews. The first wave of data collection took place from February to June 2022.Findings to date By 30 November 2021, of 8735 people in Aotearoa aged 16+ who had COVID-19, 8712 were eligible for the study and 8012 had valid addresses so were able to be contacted to take part. A total of 990 people, including 161 Tāngata Whenua (Māori, Indigenous peoples of Aotearoa) completed one or more surveys; in addition, 62 took part in in-depth interviews. Two hundred and seventeen people (20%) reported symptoms consistent with long COVID. Key areas of adverse impacts were experiences of stigma, mental distress, poor experiences of health services and barriers to healthcare, each being significantly more pronounced among disabled people and/or those with long COVID.Future plans Further data collection is planned to follow-up cohort participants. This cohort will be supplemented by the inclusion of a cohort of people with long COVID following Omicron infection. Future follow-ups will assess longitudinal changes to health and well-being impacts, including mental health, social, workplace/education and economic impacts of COVID-19.

Understanding the underpinnings of e-cigarette use among young adults is critical to addressing increasing uptake. We identified predictors of past-year e-cigarette use among young adults in Montreal, Canada. Data on potential predictors were available for 714 young adults participating in the ongoing Nicotine Dependence in Teens Study at age 20 in 2007–08. Past-year e-cigarette use was measured at age 30 in 2017–20. Each potential predictor was studied in a separate multivariable logistic regression model controlling for age, sex, and educational attainment. Male sex, friends who smoke, cigarette smoking, use of other tobacco products, alcohol use, use of marijuana, and impulsivity predicted past-year e-cigarette use. Higher educational attainment and very good/excellent self-rated health were protective. Program and policy makers will need to consider these predictors of e-cigarette use in the design of clinical and public health interventions targeting e-cigarette use in young adults.

Abstract The compatibility of forestry and koala conservation is a controversial issue. We used a BACIPS design to assess change in koala density after selective harvesting with regulations to protect environmental values. We also assessed additional sites heavily harvested 5–10 years previously, now dominated by young regeneration. We used replicate arrays of acoustic sensors and spatial count modelling of male bellowing to estimate male koala density over 3600 ha. Paired sites in nearby National Parks served as controls. Naïve occupancy was close to 100% before and after harvesting, indicating koalas were widespread across all arrays. Average density was higher than expected for forests in NSW, varying between arrays from 0.03–0.08 males ha−1. There was no significant effect of selective harvesting on density and little change evident between years. Density 5–10 years after previous heavy harvesting was equivalent to controls, with one harvested array supporting the second highest density in the study. Within arrays, density was similar between areas mapped as selectively harvested or excluded from harvest. Density was also high in young regeneration 5–10 years after heavy harvesting. We conclude that native forestry regulations provided sufficient habitat for koalas to maintain their density, both immediately after selective harvesting and 5–10 years after heavy harvesting.

We examined change in walking, moderate-to-vigorous physical activity (MVPA) and meeting MVPA guidelines from before to during the COVID-19 pandemic, and identified factors associated with newly meeting and no longer meeting MVPA guidelines during the pandemic. Complete data were available for 614 young adults participating in the ongoing Nicotine Dependence in Teens (NDIT) study pre-pandemically in 2010–12 and 2017–20, and during the pandemic in 2020–21. Change in physical activity was examined in four sub-groups (i.e., stable inactive, newly met MVPA guidelines, no longer met MVPA guidelines, stable active). Factors associated with newly and no longer met MVPA guidelines were identified in multivariable logistic regression. While walking and MVPA changed little from 2010-2 to 2017–20, both declined during the pandemic (median for both = -30 min/week). 63.3% of participants reported no change in meeting MVPA guidelines during the pandemic, 11.4% newly met MVPA guidelines and 25.2% no longer met MVPA guidelines. Male sex, not university-educated, amotivated to engage in physical activity reported pre-pandemic, and endorsing physical activity as a COVID-19 coping strategy were associated with newly met MVPA guidelines. Male sex, not university-educated, higher problem-focused coping scores and endorsing physical activity as a COVID-19 coping strategy were protective of no longer met MVPA guidelines. Increased understanding of why some participants increased or decreased MVPA during the pandemic is needed to inform physical activity-related policy during pandemics.

Abstract Impacts of invasive species are often difficult to quantify, meaning that many invaders are prioritised for management without robust, contextual evidence of impact. Most impact studies for invasive plants compare heavily invaded with non-invaded sites, revealing little about abundance–impact relationships. We examined effects of increasing cover and volume of the non-native herbaceous groundcover Tradescantia fluminensis on a temperate rainforest community of southern Australia. We hypothesised that there would be critical thresholds in T. fluminensis abundance, below which the native plant community would not be significantly impacted, but above which the community’s condition would degrade markedly. We modelled the abundance–impact relationship from 83 plots that varied in T. fluminensis abundance and landscape context and found the responses of almost all native plant indicators to invasion were non-linear. Native species richness, abundance and diversity exhibited negative exponential relationships with increasing T. fluminensis volume, but negative threshold relationships with increasing T. fluminensis cover. In the latter case, all metrics were relatively stable until cover reached between 20 and 30%, after which each decreased linearly, with a 50% decline occurring at 75–80% invader cover. Few growth forms (notably shrubs and climbers) exhibited such thresholds, with most exhibiting negative exponential relationships. Tradescantia fluminensis biomass increased dramatically at > 80% cover, with few native species able to persist at such high levels of invasion. Landscape context had almost no influence on native communities, or the abundance–impact relationships between T. fluminensis and the plant community metrics. Our results suggest that the diversity of native rainforest community can be maintained where T. fluminensis is present at moderate-to-low cover levels.

SARS-CoV-2 infection in children produces mild respiratory symptoms or no symptoms at all in most cases. Some pediatric patients develop a severe complication associated with high mortality, the multisystem inflammatory syndrome in children (MIS-C). In both scenarios, there are reports of neurological manifestations. This article aims to review the cases of pediatric patients with severe neurological issues and a coexisting positive SARS-CoV-2 test. A literature search was performed between March 2020 and May 2021. The results included the data from 41 studies, with 159 children with severe neurological manifestations, within an age range from 24 h to 17 years. The neurological disorders included 38 cases with stroke, 32 with encephalitis, 22 with encephalopathy, and 10 with Guillain–Barre syndrome. Sixty-five out of 159 cases with severe neurological manifestations were diagnosed with MIS-C. Direct neuroinvasion and the exaggerated immune response in some patients seem to be the most critical factors triggering these manifestations. Further research in the ongoing pandemic is needed to elucidate the precise mechanism.

Background: Venous, arterial, diabetic and pressure ulcers, collectively known as chronic wounds, negatively impact individuals across psychological, social and financial domains. Chronic wounds can be painful and the nature, frequency and impact of pain can differ depending on wound aetiology, wound state and on numerous patient factors. While systemic pharmaceutical agents have some effect in managing pain, there is a need to examine topical agents applied to the wound bed for pain relief. The objective of this study is to examine and synthesise existing literature on the effectiveness of topical agents in managing pain in venous, diabetic, pressure, arterial and mixed venous/arterial ulcers. Methods: We will use Cochrane Systematic Review methodology to identify and synthesise eligible randomised controlled trials (RCTs) evaluating the effectiveness of topical agents in reducing pain in chronic wounds. Embase, Medline, PubMed, CENTRAL, CINAHL, Scopus and Web of Science will be searched from inception to end of June 2022 without language limits. We will independently extract data on the pharmaceutical agent, participant demographics, aetiology, condition of the wound, and type, nature and frequency of pain using a pre-designed data extraction form. Subgroup and sensitivity analysis will be performed to address heterogeneity across studies if appropriate. Further stratification and analyses will be based on included study variables and outcomes. Discussion: Wound pain is primarily managed via systemic pharmaceutical agents. However, patients express reluctance regarding systemic analgesic drugs, fearing addiction. Additionally, persons with chronic wounds have co-morbidities including hypertension, diabetes, or cardiovascular disease and are already taking multiple medications. Topical analgesia can potentially mitigate some of the perceived disadvantages of systemic agents but the available range of these agents and their effectiveness in managing pain in chronic wounds is not so well understood. This review will focus on such agents across a range of the most common chronic wounds.

Laminin N-terminus α31 (LaNt α31) is an alternative splice isoform derived from the laminin α3 gene. The LaNt α31 protein is enriched around the terminal duct lobular units in normal breast tissue. In the skin and cornea the protein influences epithelial cell migration and tissue remodelling. However, LaNt α31 has never been investigated in a tumour environment. Here we analysed LaNt α31 in invasive ductal carcinoma and determined its contribution to breast carcinoma invasion. LaNt α31 expression and distribution were analysed by immunohistochemistry in human breast tissue biopsy sections and tissue microarrays covering 232 breast cancer samples. This analysis revealed LaNt α31 to be upregulated in 56% of invasive ductal carcinoma specimens compared with matched normal tissue, and further increased in nodal metastasis compared with the tumour mass in 45% of samples. 65.8% of triple negative cases displayed medium to high LaNt α31 expression. To study LaNt α31 function, an adenoviral system was used to induce expression in MCF-7 and MDA-MB-231 cells. 2D cell migration and invasion into collagen hydrogels were not significantly different between LaNt α31 overexpressing cells and control treated cells. However, LaNt α31 overexpression reduced the proliferation rate of MCF-7 and MDA-MB-231 cells. Moreover, LaNt α31 overexpressing MDA-MB-231 cells displayed a striking change in their mode of invasion into laminin-containing Matrigel; changing from multicellular streaming to individual cellular-invasion. In agreement with these results, 66.7% of the tumours with the highest LaNt α31 expression were non-cohesive. Together these findings indicate that breast cancer-associated changes in LaNt α31 expression could contribute to the processes involved in tumour invasion and may represent a new therapeutic target.

ObjectiveRobust evidence exists for the health-enhancing benefits of social support in adults. Inflammatory processes are thought to be an important mechanism linking social support and health risk. Less is known about the relation between social support and chronic inflammation during childhood and adolescence, or when the association emerges during the lifespan.MethodData from the population-representative 1999 Quebec Child and Adolescent Health and Social (QCAHS) survey were analyzed. Youth aged 9, 13, and 16 years (N = 3613) and their parents answered questions about social support. A subsample (n = 2186) completed a fasting blood draw that was assayed for C-reactive protein (CRP).FindingsHigher social support was significantly associated with lower hs-CRPlog, after controlling for age, sex, body mass index (BMI Z-score), medication use, puberty, ethnoracial status (French-Canadian), smoking, household income, and parental education (F = 25.88, p = < .001, Total R2adj = 10.2%). The association was largely similar for boys and girls, and strengthened with age.ConclusionGreater social support was linked to lower chronic low-grade inflammation in a large sample of children and adolescents. Effect sizes were small and consistent with prior findings in the adult literature. Importantly, these findings provide evidence that the relation between social support and inflammation emerges early in the lifespan. Future work should consider broader, more encompassing conceptualizations of social support, the role of social media, and prospective trajectories of social support and inflammatory markers.

BackgroundDementia is the most feared disease associated with aging. Prolonged fears about memory loss and dementia can have harmful consequences even in the absence of cognitive decline. Fear of dementia is associated with poorer health outcomes and psychological well-being and increased memory failures in older adults. ObjectiveWe will conduct a randomized controlled trial to determine the feasibility of a tailored, web-based mindfulness program to reduce fear of memory loss and increase quality of life in older adults experiencing heightened fear. MethodsEighty participants will be recruited and divided into 2 groups (40 in each group). One group will receive psychoeducation plus mindfulness training. A second group will receive psychoeducation, mindfulness training, and additional modules targeting maladaptive behavioral avoidance (ie, social and cognitive withdrawal). ResultsOur recent etiological model posits that maladaptive behavioral avoidance strategies critically underlie psychosocial dysfunction associated with fear of memory loss. Thus, we predict better outcomes in the second group, including reduced fear of memory loss (primary outcome), Alzheimer disease, anxiety, and subjective memory failures, and increased quality of life (secondary outcomes). Outcome measures will be applied at 5 time points (before, baseline, interim, and after the intervention, and at 3-month follow-up). Data will be analyzed using mixed models and correlations. ConclusionsResults from this study will contribute to the current literature on dementia-related fear and improve our understanding of how to effectively address and reduce these fears. Trial RegistrationClinicalTrials.gov NCT04821960; https://clinicaltrials.gov/ct2/show/NCT04821960. International Registered Report Identifier (IRRID)PRR1-10.2196/30514

Abstract Background Given the benefits of physical activity for health and survival, clinicians are seeking opportunities for cancer patients to become more active independent of rehabilitation programs that are small, time-limited, and location specific. This proof-of-concept study evaluated a community-based physical activity program (Curves™) for increasing physical activity among women diagnosed and treated for breast cancer. Methods Women were recruited from a breast cancer clinic through physician chart review. In study 1, women (n = 14) received the community physical activity memberships (Curves™), guidelines, and a pedometer. This group was compared to women (n = 16) who received physical activity guidelines and a pedometer on changes in physical activity. In study 2, women (n = 66) completed self-report questionnaires after Curves™ memberships expired to evaluate the program. Study 3 was a qualitative study exploring the benefits and barriers of the physical activity program among women (n = 6) who attended Curves™ regularly. Results Provision of memberships to a community-based physical activity program did not improve physical activity levels beyond educational and information resources. However, there are a number of advantages to community-based physical activity programs, and the women offer a number of suggestions for improvements for community physical activity opportunities aimed at breast cancer survivors. Conclusions Women-only community-based physical activity programs may be a viable option to help introduce women to get active after treatment. Trial registration ISRCTN, ISRCTN14747810. Registered on 18 October 2017—Retrospectively registered, https://doi.org/10.1186/ISRCTN14747810

Abstract Objective The Wilson Central Terminal (WCT) is an artificially constructed reference for surface electrocardiography, which is assumed to be near zero and steady during the cardiac cycle; namely it is the simple average of the three recorded limbs (right arm, left arm and left leg) composing the Einthoven triangle and considered to be electrically equidistant from the electrical center of the heart. This assumption has been challenged and disproved in 1954 with an experiment designed just to measure and minimize WCT. Minimization was attempted varying in real time the weight resistors connected to the limbs. Unfortunately, the experiment required a very cumbersome setup and showed that WCT amplitude could not be universally minimized, in other words, the weight resistors change for each person. Taking advantage of modern computation techniques as well as of a special ECG device that aside of the standard 12-lead Electrocardiogram (ECG) can measure WCT components, we propose a software minimization (genetic algorithm) method using data recorded from 72 volunteers. Result We show that while the WCT presents average amplitude relative to lead II of 58.85% (standard deviation of 30.84%), our minimization method yields an amplitude as small as 7.45% of lead II (standard deviation of 9.04%).

This report describes how stakeholder groups informed a web-based care planning tool’s development for addressing root causes of poor health. Stakeholders included community members (n = 6), researchers (n = 6), community care providers (n = 9), and patients (n = 17). Feedback was solicited through focus groups, semi-structured interviews, and user experience observations and then qualitatively analyzed to identify themes. Each group contributed a unique perspective. Researchers wanted evidence-based content; community members and providers focused on making goals manageable; patients wanted care team support and simple action-oriented language. Our findings highlight the benefits of stakeholder input. Blending perspectives from multiple groups results in a more robust intervention design.

Genetic studies have identified several epithelial-derived genes associated with airway diseases. However, techniques used to study gene function frequently exceed the proliferative potential of primary human bronchial epithelial cells (HBECs) isolated from patients. Increased expression of the polycomb group protein BMI-1 extends the lifespan of HBECs while maintaining cell context plasticity. Herein we aimed to assess how BMI-1 expression impacted cellular functions and global mRNA expression. HBECs from six donors were transduced with lentivirus containing BMI-1 and cells were characterised, including by RNA sequencing and impedance measurement. BMI-1-expressing HBECs (B-HBECs) have a proliferative advantage and show comparable in vitro properties to low passage primary HBECs, including cell attachment/spreading and barrier formation. The B-HBEC mRNA signature was modestly different to HBECs, with only 293 genes differentially expressed (5% false discovery rate). Genes linked to epithelial mesenchymal transition and cell cycle were enriched in B-HBECs. We investigated the expression of genes implicated in asthma from genetic and expression studies and found that 97.6% of genes remained unaltered. We have shown that increased BMI-1 expression in HBECs delays lung epithelial cell senescence by promoting cell cycle progression and highlighted the flexible utility for B-HBECs as an important platform for studying airway epithelial mechanisms.

Iron reduction and sulfate reduction are two of the major biogeochemical processes that occur in anoxic sediments. Microbes that catalyze these reactions are therefore some of the most abundant organisms in the subsurface, and some of the most important. Due to the variety of mechanisms that microbes employ to derive energy from these reactions, including the use of soluble electron shuttles, the dynamics between iron- and sulfate-reducing populations under changing biogeochemical conditions still elude complete characterization. Here, we amended experimental bioreactors comprised of freshwater aquifer sediment with ferric iron, sulfate, acetate, and the model electron shuttle AQDS (9,10-anthraquinone-2,6-disulfonate) and monitored both the changing redox conditions as well as changes in the microbial community over time. The addition of the electron shuttle AQDS did increase the initial rate of FeIII reduction; however, it had little effect on the composition of the microbial community. Our results show that in both AQDS- and AQDS+ systems there was an initial dominance of organisms classified as Geobacter (a genus of dissimilatory FeIII-reducing bacteria), after which sequences classified as Desulfosporosinus (a genus of dissimilatory sulfate-reducing bacteria) came to dominate both experimental systems. Furthermore, most of the ferric iron reduction occurred under this later, ostensibly "sulfate-reducing" phase of the experiment. This calls into question the usefulness of classifying subsurface sediments by the dominant microbial process alone because of their interrelated biogeochemical consequences. To better inform models of microbially-catalyzed subsurface processes, such interactions must be more thoroughly understood under a broad range of conditions.

This study sought to determine patterns of multimorbidity and quantify their impact on use of primary health services in the presence and absence of anxiety and depression among a cohort of urban community-dwelling men in Australia. The analytic sample consisted of men ( n = 2039; age 38–85) from the follow-up wave of a prospective cohort study of all participants of the Florey Adelaide Male Ageing Study (FAMAS; Stage 2 [2007–2010]) and age-matched men from the North-West Adelaide Health Study (NWAHS; Stage 3 [2008–2010]). Self-reported data and linkage with a national universal health coverage scheme (Medicare) provided information on the prevalence of eight chronic conditions and health service utilization information (including annual GP visits). Obesity and cardiovascular disease (CVD) were associated with the highest number of comorbid conditions. Two nonrandom multimorbidity “clusters” emerged: “CVD, Obesity, Diabetes” and “CVD, Obesity, Osteoarthritis.” Participants with conditions comorbid with CVD were more likely to have 10 or more annual GP visits, compared to multimorbidity involving other conditions. In comparison to participants without CVD, the presence of CVD increased the chance of having 10 or more annual GP visits (adjusted risk ratio: 3.7; 95% CI [2.8, 4.8]). When CVD was comorbid with anxiety and depression, having 10 or more annual GP visits was more common (adjusted risk ratio: 1.8; 95% CI [1.2, 2.5]). Multimorbidity patterns involving CVD, especially for multimorbidity that includes CVD with comorbid anxiety and depression, should be considered in developing clinical trials to better inform medical decision-making and care for patients with CVD and comorbid conditions.

Intestinal failure-associated liver disease (IFALD) is a risk of parenteral nutrition (PN)-dependence. Intravenous soybean oil-based parenteral fat can exacerbate the risk of IFALD while intravenous fish oil can minimize its progression, yet the mechanisms by which soybean oil harms and fish oil protects the liver are uncertain. Properties that differentiate soybean and fish oils include α-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little α-tocopherol. Fish oil contains abundant α-tocopherol and little phytosterols. This study tested whether α-tocopherol confers hepatoprotective properties while phytosterols confer hepatotoxicity to intravenous fat emulsions. Utilizing emulsions formulated in the laboratory, a soybean oil emulsion (SO) failed to protect from hepatosteatosis in mice administered a PN solution enterally. An emulsion of soybean oil containing α-tocopherol (SO+AT) preserved normal hepatic architecture. A fish oil emulsion (FO) and an emulsion of fish oil containing phytosterols (FO+P) protected from steatosis in this model. Expression of hepatic acetyl CoA carboxylase (ACC) and peroxisome proliferator-activated receptor gamma (PPARγ), was increased in animals administered SO. ACC and PPARγ levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for α-tocopherol in liver injury induced by the enteral administration of a parenteral nutrition solution. Phytosterols do not appear to compromise the hepatoprotective effects of fish oil.

Objectives: To determine if body image emotions (body-related shame and guilt, weight-related stress), perceptions (self-perceived overweight), or cognitions (trying to change weight) differ between adolescents characterized by smoking and physical activity (PA) behavior. Methods: Data for this cross-sectional analysis were collected in 2010–11 and were available for 1017 participants (mean (SD) age = 16.8 (0.5) years). Participants were categorized according to smoking and PA status into four groups: inactive smokers, inactive non-smokers, active smokers and active non-smokers. Associations between body image emotions, perceptions and cognitions, and group membership were estimated in multinomial logistic regression. Results: Participants who reported body-related shame were less likely (OR (95% CI) = 0.52 (0.29–0.94)) to be in the active smoker group than the inactive smoker group; those who reported body-related guilt and those trying to gain weight were more likely (2.14 (1.32–3.48) and 2.49 (1.22–5.08), respectively) to be in the active smoker group than the inactive smoker group; those who were stressed about weight and those perceiving themselves as overweight were less likely to be in the active non-smoker group than the inactive smoker group (0.79 (0.64–0.97) and 0.41 (0.19–0.89), respectively). Conclusion: Body image emotions and cognitions differentiated the active smoker group from the other three groups.

Using a genetic risk score (GRS) to predict a phenotype in a target sample can be complicated by missing data on the single nucleotide polymorphisms (SNPs) that comprise the GRS. This is usually addressed by imputation, omission of the SNPs or by replacing the missing SNPs with proxy SNPs. To assess the impact of the omission and proxy approaches on effect size estimation and predictive ability of weighted and unweighted GRS with small numbers of SNPs, we simulated a dichotomous phenotype conditional on real genotype data. We considered scenarios in which the proportion of missing SNPs ranged from 20-70%. We assessed the impact of omitting or replacing missing SNPs on the association between the GRS and phenotype, the corresponding statistical power and the area under the receiver operating curve. Omission resulted in a larger bias towards the null value of the effect size, a smaller predictive ability and greater loss of statistical power than proxy approaches. The predictive ability of a weighted GRS that includes SNPs with large weights depends of the availability of these large-weight SNPs.

Despite its widespread clinical use, there is little data available from population-based studies on the determinants of serum sex hormone binding globulin (SHBG). We aimed to examine multifactorial determinants of circulating SHBG levels in community-dwelling men. Study participants comprised randomly selected 35-80 y.o. men (n = 2563) prospectively-followed for 5 years (n = 2038) in the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study. After excluding men with illness or medications known to affect SHBG (n = 172), data from 1786 men were available at baseline, and 1476 at follow-up. The relationship between baseline body composition (DXA), serum glucose, insulin, triglycerides, thyroxine (fT4), sex steroids (total testosterone (TT), oestradiol (E2)), and pro-inflammatory cytokines and serum SHBG level at both baseline & follow-up was determined by linear and penalized logistic regression models adjusting for age, lifestyle & demographic, body composition, metabolic, and hormonal factors. Restricted cubic spline analyses was also conducted to capture possible non-linear relationships. At baseline there were positive cross-sectional associations between age (β = 0.409, p

Objectives: To describe the relationship between screen time and dietary intake among children, and to examine this association in relation to body weight. Methods: A cross-sectional analysis of 630 Canadian children aged 8–10 years with at least one obese biological parent. Measurements included body mass index (BMI), screen time (television, video game, computer), physical activity (accelerometer over 7 days), and diet (three 24-hour recalls for the calculation of the Canadian Healthy Eating Index (HEI-C)). Multivariate linear regression models were used to describe the relationship between screen time (≥2 h/d vs.

Predators and prey co-evolve, each maximizing their own fitness, but the effects of predator–prey interactions on cellular and molecular machinery are poorly understood. Here, we study this process using the predator Caenorhabditis elegans and the bacterial prey Streptomyces, which have evolved a powerful defense: the production of nematicides. We demonstrate that upon exposure to Streptomyces at their head or tail, nematodes display an escape response that is mediated by bacterially produced cues. Avoidance requires a predicted G-protein-coupled receptor, SRB-6, which is expressed in five types of amphid and phasmid chemosensory neurons. We establish that species of Streptomyces secrete dodecanoic acid, which is sensed by SRB-6. This behavioral adaptation represents an important strategy for the nematode, which utilizes specialized sensory organs and a chemoreceptor that is tuned to recognize the bacteria. These findings provide a window into the molecules and organs used in the coevolutionary arms race between predator and potential prey.

Introduction: Ultrasound plays an integral role in pregnancy management in Australia. The role of a sonographer as the frontline practitioner is to scan the patient and identify any possible abnormalities, including foetal demise. This study sought the views, experiences and practices of Australian sonographers in communicating an adverse outcome to pregnant patients in different departmental settings in public and private sector practice. Method: Ten individual semi-structured interviews were conducted with 9 sonographers from metropolitan Sydney and 1 rural based sonographer. Results: The key themes emerging from the interview data were of ambiguity and inconsistency both in understanding the sonographer role and with practice protocols around communication when delivering “bad news” to pregnant patients. Most of the participants had not received any formal training in communication techniques. Conclusion: The sonographers wanted more autonomy, but with support and an agreed and consistent approach from their radiologists or sonologists. Practice sites that achieved the best results were those that had the greatest direct collaboration between the sonographer and the sonologist, which was demonstrated in the obstetrician-sonologist-run practices. Policy reform, improved clarity and standardised protocols are needed to improve practice guidelines for sonographers in communicating adverse outcomes to an expectant mother.

Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive network that drives cancer escape by disabling T cell adaptive immunity. The prevailing view is that MDSC-mediated immunosuppression is restricted to tissues where MDSC co-mingle with T cells. Here we show that splenic or, unexpectedly, blood-borne MDSC execute far-reaching immune suppression by reducing expression of the L-selectin lymph node (LN) homing receptor on naïve T and B cells. MDSC-induced L-selectin loss occurs through a contact-dependent, post-transcriptional mechanism that is independent of the major L-selectin sheddase, ADAM17, but results in significant elevation of circulating L-selectin in tumor-bearing mice. Even moderate deficits in L-selectin expression disrupt T cell trafficking to distant LN. Furthermore, T cells preconditioned by MDSC have diminished responses to subsequent antigen exposure, which in conjunction with reduced trafficking, severely restricts antigen-driven expansion in widely-dispersed LN. These results establish novel mechanisms for MDSC-mediated immunosuppression that have unanticipated implications for systemic cancer immunity.

In the fall of 2014, an international news agency reported that patients suffering from Ebola virus disease (EVD) in Liberia were treated successfully with lamivudine, an antiviral drug used to treat human immunodeficiency virus-1 and hepatitis B virus infections. According to the report, 13 out of 15 patients treated with lamivudine survived and were declared free from Ebola virus disease. In this study, the anti-Ebola virus (EBOV) activity of lamivudine and another antiretroviral, zidovudine, were evaluated in a diverse set of cell lines against two variants of wild-type EBOV. Variable assay parameters were assessed to include different multiplicities of infection, lengths of inoculation times, and durations of dosing. At a multiplicity of infection of 1, lamivudine and zidovudine had no effect on EBOV propagation in Vero E6, Hep G2, or HeLa cells, or in primary human monocyte-derived macrophages. At a multiplicity of infection of 0.1, zidovudine demonstrated limited anti-EBOV activity in Huh 7 cells. Under certain conditions, lamivudine had low anti-EBOV activity at the maximum concentration tested (320 μM). However, lamivudine never achieved greater than 30% viral inhibition, and the activity was not consistently reproducible. Combination of lamivudine and zidovudine showed no synergistic antiviral activity. Independently, a set of in vitro experiments testing lamivudine and zidovudine for antiviral activity against an Ebola-enhanced green fluorescent protein reporter virus was performed at the Centers for Disease Control and Prevention. No antiviral activity was observed for either compound. A study evaluating the efficacy of lamivudine in a guinea pig model of EVD found no survival benefit. This lack of benefit was observed despite plasma lamivudine concentrations in guinea pig of about 4 μg/ml obtained in a separately conducted pharmacokinetics study. These studies found no evidence to support the therapeutic use of lamivudine for the treatment of EVD.

Although iron- and sulfate-reducing bacteria in subsurface environments have crucial roles in biogeochemical cycling of C, Fe, and S, how specific electron donors impact the compositional structure and activity of native iron- and/or sulfate-reducing communities is largely unknown. To understand this better, we created bicarbonate-buffered batch systems in duplicate with three different electron donors (acetate, lactate, or glucose) paired with ferrihydrite and sulfate as the electron acceptors and inoculated them with subsurface sediment as the microbial inoculum. Sulfate and ferrihydrite reduction occurred simultaneously and were faster with lactate than with acetate. 16S rRNA-based sequence analysis of the communities over time revealed that Desulfotomaculum was the major driver for sulfate reduction coupled with propionate oxidation in lactate-amended incubations. The reduction of sulfate resulted in sulfide production and subsequent abiotic reduction of ferrihydrite. In contrast, glucose promoted faster reduction of ferrihydrite, but without reduction of sulfate. Interestingly, the glucose-amended incubations led to two different biogeochemical trajectories among replicate bottles that resulted in distinct coloration (white and brown). The two outcomes in geochemical evolution might be due to the stochastic evolution of the microbial communities or subtle differences in the initial composition of the fermenting microbial community and its development via the use of different glucose fermentation pathways available within the community. Synchrotron-based x-ray analysis indicated that siderite and amorphous Fe(II) were formed in the replicate bottles with glucose, while ferrous sulfide and vivianite were formed with lactate or acetate. These data sets reveal that use of different C utilization pathways projects significant changes in microbial community composition over time that uniquely impact both the geochemistry and mineralogy of subsurface environments.

4R-cembranoid (4R) is a natural cyclic diterpenoid found in tobacco leaves that displays neuroprotective activity. 4R protects against NMDA, paraoxon (POX), and diisopropylfluorophosphate (DFP) damage in rat hippocampal slices and against DFP in rats in vivo. The purpose of this study was to examine the metabolism and pharmacokinetics of 4R as part of its preclinical development as a neuroprotective drug. 10 µM 4R was found to be very stable in plasma for up to 1 hr incubation. 4R metabolism in human microsomes was faster than in the rat. Ten metabolites of 4R were detected in the microsomal samples; 6 dihydroxy and 4 monohydroxy forms of 4R. Male rats received a single dose of 4R at 6 mg/kg i.v., i.m., or s.c. The i.v. group had the highest plasma concentration of 1017 ng/mL. The t1/2 was 36 min and reached the brain within 10 min. The brain peak concentration was 6516 ng/g. The peak plasma concentration in the i.m. group was 163 ng/mL compared to 138 ng/mL in the s.c. group. The t1/2 of 4R after i.m. and s.c. administration was approximately 1.5 hr. The brain peak concentration was 329 ng/g in the i.m. group and 323 ng/g for the s.c. group. The brain to plasma ratio in the i.v. group was 6.4, reached 10 min after dose, whereas in the i.m. and s.c. groups was 2.49 and 2.48, respectively, at 90 min after dose. Our data show that 4R crosses the BBB and concentrates in the brain where it exerts its neuroprotective effect.

The relationship between lower urinary tract symptoms (LUTS) and common mental health disorders such as depression and anxiety in men remains unclear. Inflammation has recently been identified as an independent risk factor for LUTS and depression. This study aimed to assess the association between depression, anxiety and LUTS, and the moderating influence of systemic inflammation, in the presence of other biopsychosocial confounders.Participants were randomly-selected from urban, community-dwelling males aged 35-80 years at recruitment (n = 1195; sample response rate:67.8%). Of these, 730 men who attended baseline (2002-5) and follow-up clinic visits (2007-10), with complete outcome measures, and without prostate or bladder cancer and/or surgery, neurodegenerative conditions, or antipsychotic medications use, were selected for the present study. Unadjusted and multi-adjusted regression models of incident storage and voiding LUTS and incident depression and anxiety were combined with serum inflammatory markers (high-sensitive C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), myeloperoxidase (MPO), soluble e-selectin (e-Sel)) and socio-demographic, lifestyle, and health-related factors. Hierarchical multiple regression was used to assessed the moderating effect of inflammatory markers.The incidence of storage, voiding LUTS, depression and anxiety was 16.3% (n = 108), 12.1% (n = 88), 14.5% (n = 108), and 12.2% (n = 107). Regression models demonstrated that men with depression and anxiety at baseline were more likely to have incident storage, but not voiding LUTS (OR: 1.26, 99%CI: 1.01-4.02; and OR:1.74; 99%CI:1.05-2.21, respectively). Men with anxiety and storage LUTS at baseline were more likely to have incident depression (OR: 2.77, 99%CI: 1.65-7.89; and OR:1.45; 99%CI:1.05-2.36, respectively), while men with depression and voiding LUTS were more likely to have anxiety at follow-up (OR: 5.06, 99%CI: 2.81-9.11; and OR:2.40; 99%CI:1.16-4.98, respectively). CRP, TNF-α, and e-Sel were found to have significant moderating effects on the development of storage LUTS (1.06, 0.91-1.96, R2 change: 12.7%), depression (1.17, 1.01-1.54, R2 change: 9.8%), and anxiety (1.35, 1.03-1.76, R2 change: 10.6%), respectively.There is a bidirectional relationship between storage, but not voiding, LUTS and both depression and anxiety. We observed variable moderation effects for selected inflammatory markers on the development of depression, anxiety and storage LUTS.

Campylobacter jejuni is a leading bacterial cause of human gastroenteritis. The goal of this study was to analyze the C. jejuni F38011 strain, recovered from an individual with severe enteritis, at a genomic and proteomic level to gain insight into microbial processes. The C. jejuni F38011 genome is comprised of 1,691,939 bp, with a mol.% (G+C) content of 30.5%. PacBio sequencing coupled with REBASE analysis was used to predict C. jejuni F38011 genomic sites and enzymes that may be involved in DNA restriction-modification. A total of five putative methylation motifs were identified as well as the C. jejuni enzymes that could be responsible for the modifications. Peptides corresponding to the deduced amino acid sequence of the C. jejuni enzymes were identified using proteomics. This work sets the stage for studies to dissect the precise functions of the C. jejuni putative restriction-modification enzymes. Taken together, the data generated in this study contributes to our knowledge of the genomic content, methylation profile, and encoding capacity of C. jejuni.

While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.In a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator).The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value

Although reports in adults suggest that breaks in sedentary time are associated with reduced cardiometabolic risk, these findings have yet to be replicated in children.To investigate whether objectively measured sedentary behavior, sedentary bouts or breaks in sedentary time are independently associated with cardiometabolic risk in a cohort of Canadian children aged 8-11 years with a family history of obesity.Data from 286 boys and 236 girls living in Quebec, Canada, with at least one biological parent with obesity (QUALITY cohort) were collected from 2005-2008, and analyzed in 2013. Sedentary behavior, light and moderate-to-vigorous physical activity were measured over 7 days using accelerometry. Leisure time computer/video game use and TV viewing over the past 7 days were self-reported. Outcomes included waist circumference, body mass index Z-score, fasting insulin, fasting glucose, triglycerides, HDL-cholesterol, C-reactive protein and a continuous cardiometabolic risk score.After adjustment for confounders, breaks in sedentary time and the number of sedentary bouts lasting 1-4 minutes were associated with reduced cardiometabolic risk score and lower BMI Z-score in both sexes (all p

BackgroundThe relationship between menopausal hormone therapy (MHT) and cardiovascular risk remains controversial, with a number of studies advocating the use of MHT in reducing risk of cardiovascular diseases, while others have shown it to increase risk. The aim of this study was to determine the association between menopausal hormone therapy and high blood pressure.Methods and findingsA total of 43,405 postmenopausal women were included in the study. Baseline data for these women were sourced from the 45 and Up Study, Australia, a large scale study of healthy ageing. These women reported being postmenopausal, having an intact uterus, and had not been diagnosed with high blood pressure prior to menopause. Odds ratios for the association between MHT use and having high blood pressure were estimated using logistic regression, stratified by age (ConclusionsMenopausal hormone therapy use is associated with significantly higher odds of having high blood pressure, and the odds increase with increased duration of use. High blood pressure should be conveyed as a health risk for people considering MHT use.

Innate immune activation via Toll-like receptors (TLRs), although critical for host defense against infection, must be regulated to prevent sustained cell activation that can lead to cell death. Cells repeatedly stimulated with lipopolysaccharide (LPS) develop endotoxin tolerance making the cells hypo-responsive to additional TLR stimulation. We show here that DOK3 is a negative regulator of TLR signaling by limiting LPS-induced ERK activation and cytokine responses in macrophages. LPS induces ubiquitin-mediated degradation of DOK3 leading to SOS1 degradation and inhibition of ERK activation. DOK3 mice are hypersensitive to sublethal doses of LPS and have altered cytokine responses in vivo. During endotoxin tolerance, DOK3 expression remains stable, and it negatively regulates the expression of SHIP1, IRAK-M, SOCS1, and SOS1. As such, DOK3-deficient macrophages are more sensitive to LPS-induced tolerance becoming tolerant at lower levels of LPS than wild type cells. Taken together, the absence of DOK3 increases LPS signaling, contributing to LPS-induced tolerance. Thus, DOK3 plays a role in TLR signaling during both naïve and endotoxin-induced tolerant conditions.

BackgroundThe human innate immune system relies on the coordinated activity of macrophages and polymorphonuclear leukocytes (neutrophils or PMNs) for defense against bacterial pathogens. Yersinia spp. subvert the innate immune response to cause disease in humans. In particular, the Yersinia outer protein YopJ (Y. pestis and Y. pseudotuberculosis) and YopP (Y. enterocolitica) rapidly induce apoptosis in murine macrophages and dendritic cells. However, the effects of Yersinia Yop J/P on neutrophil fate are not clearly defined.Methodology/principal findingsIn this study, we utilized wild-type and mutant strains of Yersinia to test the contribution of YopJ and YopP on induction of apoptosis in human monocyte-derived macrophages (HMDM) and neutrophils. Whereas YopJ and YopP similarly induced apoptosis in HMDMs, interaction of human neutrophils with virulence plasmid-containing Yersinia did not result in PMN caspase activation, release of LDH, or loss of membrane integrity greater than PMN controls. In contrast, interaction of human PMNs with the virulence plasmid-deficient Y. pestis strain KIM6 resulted in increased surface exposure of phosphatidylserine (PS) and cell death. PMN reactive oxygen species (ROS) production was inhibited in a virulence plasmid-dependent but YopJ/YopP-independent manner. Following phagocytic interaction with Y. pestis strain KIM6, inhibition of PMN ROS production with diphenyleneiodonium chloride resulted in a reduction of PMN cell death similar to that induced by the virulence plasmid-containing strain Y. pestis KIM5.ConclusionsOur findings showed that Yersinia YopJ and/or YopP did not induce pronounced apoptosis in human neutrophils. Furthermore, robust PMN ROS production in response to virulence plasmid-deficient Yersinia was associated with increased PMN cell death, suggesting that Yersinia inhibition of PMN ROS production plays a role in evasion of the human innate immune response in part by limiting PMN apoptosis.

Abstract Background Prediction of the location of culprit lesions responsible for ST-segment elevation myocardial infarctions may allow for prevention of these events. A retrospective analysis of coronary artery motion (CAM) was performed on coronary angiograms of 20 patients who subsequently had ST-segment elevation myocardial infarction treated by primary or rescue angioplasty and an equal number of age and sex matched controls with normal angiograms. Findings There was no statistically significant difference between the frequency of CAM types of the ST-segment elevation acute myocardial infarction and control patients (p = 0.97). The compression type of CAM is more frequent in the proximal and mid segments of all three coronary arteries. No statistically significant difference was found when the frequency of the compression type of CAM was compared between the ST-segment elevation acute myocardial infarction and control patients for the individual coronary artery segments (p = 0.59). Conclusion The proportion of the compression type of coronary artery motion for individual artery segments is not different between patients who have subsequent ST-segment elevation myocardial infarctions and normal controls.

The origins of standards and guidelines in medicine are traced from work in the 1970s showing that treatment variations could not be accounted for by objective differences in the disease or other conditions of patients. Guidelines based on evidence can be effective in reducing such variation and in reducing costs. However, population disparities in disease and access, as well as dramatically rising insurance costs, pose challenges. Standards based entirely on efficacy of procedures will leave unanswered important questions about diagnosis and effective allocation of resources throughout population groups. [ABSTRACT FROM AUTHOR]