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Routinely collected health data (RCD) including electronic health records, disease registries, health administrative data and wearables data are not specifically collected for research purposes. Analysis of these data poses unique methodological challenges that must be addressed when conducting research, particularly as availability and use increase. This scoping review aimed to identify methodological challenges in research using RCD from existing literature (registered protocol: https://doi.org/10.17605/OSF.IO/EBM4D). We searched 6 electronic databases, including medical, health economics, nursing and psychology research databases, between Jan 2015 and Jan 2023, combining multiple “RCD” and “research” search terms (e.g., epidemiologic, informatics, pharmaceutical research). After screening abstracts and full-texts, we doubly extracted methodological themes, categorizing them into different study stages. We screened more than 23,000 records and included 430 papers. Bias and confounding were the most common methodological issues identified, discussed in relation to both study design and data analysis. Data quality, including data accuracy, validation, completeness, timeliness and cleaning, also posed substantial challenges, particularly during data processing stage. Record linkage and conducting analyses using distributed health networks also pose unique methodological challenges. Heterogeneity, incorporating social determinants of health and statistical models that address methodological challenges are also described in the literature. External validity and reporting are important considerations for RCD research. Our review identified several methodological challenges facing researchers using RCD. These issues should be addressed to ensure methodologically sound research. These findings will inform the development of a standardized protocol template and accompanying educational platform aimed at enhancing methodological quality and transparency when conducting research using RCD.

Background Hospitalizations are a resource-intensive form of healthcare use, particularly for persons with chronic conditions such as those with HIV. Interhospital transfers typically appear as separate records in Canadian databases; misclassifying transfers as independent hospitalizations can bias key metrics such as readmission rates. We examined approaches of combining sequential, related records into hospitalization episodes of care (HEoCs) among persons with and without HIV (PWH; PWoH) in British Columbia (BC), Canada. Methods BC hospitalization records (1992 to 2020) were sourced from the Comparative Outcomes and Service Utilization Trends (COAST) study, a data linkage that includes samples of PWH and PWoH. We constructed 8 HEoC definitions that varied by the: a) time gap between records, and b) transfer indication. Comparisons were informed by the proportion of multi-record HEoCs (mHEoCs; episodes with multiple hospitalization records) generated, and feasibility given data quality. Results We analyzed 98,553 hospitalization records from 13,498 PWH, and 1,874,507 hospitalization records from 385,011 PWoH. Across the definitions, the proportion of mHEoCs varied from 2.46% to 5.27% for PWH and 2.73% to 4.18% for PWoH. Definitions requiring no transfer indication yielded the highest proportion of mHEoCs, whereas those requiring two-way agreement of hospital identifiers yielded the lowest proportion of mHEoCs. Patterns were comparable among PWH and PWoH. A pragmatic approach to defining HEoCs can be a reasonable option for general purposes – requiring at least one populated hospital identifier field, and ≤ 1 day gap between hospitalizations. Conclusions Various approaches can be employed to combine sequential, related hospitalization records into HEoCs to help provide less biased estimates of hospitalization-related metrics.

Background: Medical school involves high expectations of medical students, which may increase their risk for burnout. Physical activity (PA) and sedentary behaviour (SB) are modifiable risk factors for burnout. However, medical students are insufficiently taught about PA and SB and may therefore be less likely to meet guideline-recommended levels of these two movement behaviours or promote them in practice. Few studies have examined the relationships between medical students’ PA intensity, SB, and burnout; such examination could help clarify educational needs for improving levels of movement behaviours and their promotion. Purpose: This study investigated (1) the relationships between light, moderate, vigorous, and total PA, SB, and burnout among medical students, and (2) moderate-to-vigorous PA as a moderator of the relationship between SB and burnout, to guide future curriculum renewal. Methods: Medical students (N = 129) at two Canadian institutions completed online validated questionnaires assessing light, moderate, vigorous, and total PA, SB, and burnout. Results: Regression analyses indicated that light PA (β = -.191, p = .039) and SB (β=-.230, p = .013) were negatively associated with burnout. Moderate-to-vigorous PA did not significantly moderate the relationship between SB and burnout. Conclusions: Engaging in lighter forms of PA and SB within guideline recommendations may help mitigate medical student burnout. Competencies to promote movement behaviours may dually target medical student burnout and curriculum gaps.

Phosphodiesterase 3A (PDE3A) gene mutations have recently been associated with hypertension and brachydactyly syndrome (HTNB). This report shows how the recent recognition of the role of the PDE3A gene in HTNB facilitated the diagnosis of HTNB in a 20-year-old female who could not be diagnosed at her initial presentation at 6 years of age.

Abstract Background Social support has previously been found to be associated with improved health outcomes of individuals managing chronic illnesses, including amongst people living with HIV (PLWH). For women and people who use injection drugs who continue to experience treatment disparities in comparison to other PLWH, social support may have potential in facilitating better treatment engagement and retention. In this analysis, we examined determinants of social support as measured by the Medical Outcomes Study – Social Support Survey (MOS-SSS) scale, and quantified the relationship between MOS-SSS and HIV treatment interruptions (TIs) among PLWH in British Columbia, Canada. Methods Between January 2016 and September 2018, we used purposive sampling to enroll PLWH, 19 years of age or older living in British Columbia into the STOP HIV/AIDS Program Evaluation study. Participants completed a baseline survey at enrolment which included the MOS-SSS scale, where higher MOS-SSS scores indicated greater social support. Multivariable linear regression modeled the association between key explanatory variables and MOS-SSS scores, whereas multivariable logistic regression modeled the association between MOS-SSS scores and experiencing TIs while controlling for confounders. Results Among 644 PLWH, we found that having a history of injection drug use more than 12 months ago but not within the last 12 months, self-identifying as Indigenous, and sexual activity in the last 12 months were positively associated with MOS-SSS, while being single, divorced, or dating (vs. married), experiences of lifetime violence, and diagnosis of a mental health disorder were inversely associated. In a separate multivariable model adjusted for gender, ethnicity, recent homelessness, sexual activity in the last 12 months, and recent injection drug use, we found that higher MOS-SSS scores, indicating more social support, were associated with a lower likelihood of HIV treatment interruptions (adjusted odds ratio: 0.90 per 10-unit increase, 95% confidence interval: 0.83, 0.99). Conclusions Social support may be an important protective factor in ensuring HIV treatment continuity among PLWH. Future research should examine effective means to build social support among communities that have potential to promote increased treatment engagement.

Cardiometabolic diseases remain the leading cause of death in the United States. Lifestyle factors contribute the majority of risk for these diseases. Although diet and exercise have been the primary focus of research on modifiable behaviors to target for interventions to prevent cardiometabolic disease, recent evidence suggests that sleep also plays an important role. Indeed, the updated American Heart Association campaign includes sleep as one of its “Essential Eight”. This review details the reciprocally reinforcing positive relationship between sleep and daytime physical activity behaviors and explores how this relationship differs based on age, gender and race. For example, interventions to improve moderate intensity physical activity may be particularly beneficial to women, older adults, and Black Americans, who are at increased risk for sleep disturbances. Communicating to Americans the importance of managing their time to meet current physical activity and sleep recommendations is a challenge given that there are so many competing behaviors consuming large amounts of time (e.g., social media, gaming), but is critical given the importance of these behaviors for cardiometabolic health.

Iron plays a crucial role in many physiological processes, including oxygen transport, bioenergetics, and immune function. Iron is assimilated from food and also recycled from senescent red blood cells. Iron exists in two dietary forms: heme (animal based) and non-heme (mostly plant based). The body uses iron for metabolic purposes, and stores the excess mainly in splenic and hepatic macrophages. Physiologically, iron excretion in humans is inefficient and not highly regulated, so regulation of intestinal absorption maintains iron homeostasis. Iron losses occur at a steady rate via turnover of the intestinal epithelium, blood loss, and exfoliation of dead skin cells, but overall iron homeostasis is tightly controlled at cellular and systemic levels. Aging can have a profound impact on iron homeostasis and induce a dyshomeostasis where iron deficiency or overload (sometimes both simultaneously) can occur, potentially leading to several disorders and pathologies. To maintain physiologically balanced iron levels, reduce risk of disease, and promote healthy aging, it is advisable for older adults to follow recommended daily intake guidelines and periodically assess iron levels. Clinicians can evaluate body iron status using different techniques but selecting an assessment method primarily depends on the condition being examined. This review provides a comprehensive overview of the forms, sources, and metabolism of dietary iron, associated disorders of iron dyshomeostasis, assessment of iron levels in older adults, and nutritional guidelines and strategies to maintain iron balance in older adults.

Abstract Background Verbal rating scales (VRS) are widely used in patient-reported outcome (PRO) measures. At our institution, patients complete an online instrument using VRSs with a five-point brief response scale to assess symptoms as part of routine follow-up after ambulatory cancer surgery. We received feedback from patients that the brief VRS descriptors such as “mild” or “somewhat” were vague. We added explicit descriptors to our VRSs, for instance, “Mild: I can generally ignore my pain” for pain severity or “Somewhat: I can do some things okay, but most of my daily activities are harder because of fatigue” for fatigue interference. We then compared responses before and after this change was made. Methods The symptoms investigated were pain, fatigue and nausea. Our hypothesis was that the explicit descriptors would reduce overall variance. We therefore compared the coefficient of variation of scores and tested the association between symptoms scores and known predictors thereof. We also compared time to completion between questionnaires with and without the additional descriptors. Results A total of 17,500 patients undergoing 21,497 operations were assigned questionnaires in the period before the descriptors were added; allowing for a short transition period, 1,417 patients having 1436 operations were assigned questionnaires with the additional descriptors. Symptom scores were about 10% lower with the additional descriptors but the coefficient of variation was slightly higher. Moreover, the only statistically significant difference between groups for association with a known predictor favored the item without the additional language for nausea severity (p = 0.004). Total completion time was longer when the instrument included the additional descriptors, particularly the first and second time that the questionnaire was completed. Conclusions Adding descriptors to a VRS of post-operative symptoms did not improve scale properties in patients undergoing ambulatory cancer surgery. We have removed the additional descriptors from our tool. We recommend further comparative psychometric research using data from PROs collected as part of routine clinical care.

Abstract Background Health care providers have reported low knowledge, skill, and confidence for discussing movement behaviours (i.e., physical activity, sedentary behaviour, and sleep), which may be improved with the use of tools to guide movement behaviour discussions in their practice. Past reviews have examined the psychometric properties, scoring, and behavioural outcomes of physical activity discussion tools. However, the features, perceptions, and effectiveness of discussion tools for physical activity, sedentary behaviour, and/or sleep have not yet been synthesized. The aim of this review was to report and appraise tools for movement behaviour discussions between health care providers and adults 18 + years in a primary care context within Canada or analogous countries. Methods An integrated knowledge translation approach guided this review, whereby a working group of experts in medicine, knowledge translation, communications, kinesiology, and health promotion was engaged from research question formation to interpretation of findings. Three search approaches were used (i.e., peer-reviewed, grey literature, and forward searches) to identify studies reporting on perceptions and/or effectiveness of tools for physical activity, sedentary behaviour, and/or sleep. The quality of included studies was assessed using the Mixed Methods Appraisal Tool. Results In total, 135 studies reporting on 61 tools (i.e., 51 on physical activity, one on sleep, and nine combining two movement behaviours) met inclusion criteria. Included tools served the purposes of assessment (n = 57), counselling (n = 50), prescription (n = 18), and/or referral (n = 12) of one or more movement behaviour. Most tools were used or intended for use by physicians, followed by nurses/nurse practitioners (n = 11), and adults accessing care (n = 10). Most tools were also used or intended to be used with adults without chronic conditions aged 18–64 years (n = 34), followed by adults with chronic conditions (n = 18). The quality of the 116 studies that evaluated tool effectiveness varied. Conclusions Many tools were positively perceived and were deemed effective at enhancing knowledge of, confidence for, ability in, and frequency of movement behaviour discussions. Future tools should guide discussions of all movement behaviours in an integrated manner in line with the 24-Hour Movement Guidelines. Practically, this review offers seven evidence-based recommendations that may guide future tool development and implementation.

Background: Prenatal fluoride exposure can have adverse effects on children’s development; however, associations with visual and cardiac autonomic nervous system functioning are unknown. We examined associations between prenatal fluoride exposure and visual acuity and heart rate variability (HRV) in 6-month-old infants. Methods: We used data from Canadian mother-infant pairs participating in the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort. We estimated prenatal fluoride exposure using: i) fluoride concentration in drinking water (mg/L), ii) maternal urinary fluoride adjusted for specific gravity (MUFSG; mg/L) and averaged across pregnancy, and iii) maternal fluoride intake (µg/kg/day) from consumption of water, tea, and coffee, adjusted for maternal body weight (kg). We used multivariable linear regression to examine associations between each measure of fluoride exposure and Teller Acuity Card visual acuity scores (n = 435) and assessed HRV (n = 400) using two measures: root mean square of successive differences (RMSSD) and the standard deviation of N-N intervals (SDNN) measured at 6-months of age. Results: Median (IQR) values for water fluoride, MUFSG, and daily fluoride intake were 0.20 (IQR: 0.13–0.56) mg/L; 0.44 (0.28–0.70) mg/L and 4.82 (2.58–10.83) µg/kg/day, respectively. After adjustment for confounding variables, water fluoride concentration was associated with poorer infant visual acuity (B = -1.51; 95 % CI: −2.14,-0.88) and HRV as indicated by lower RMSSD (B = -1.60; 95 % CI: −2.74,-0.46) but not SDNN. Maternal fluoride intake was also associated with poorer visual acuity (B = -0.82; 95 % CI: −1.35,-0.29) and lower RMSSD (B = -1.22; 95 % CI: −2.15,-0.30). No significant associations were observed between MUFSG and visual acuity or HRV. Conclusion: Fluoride in drinking water was associated with reduced visual acuity and alterations in cardiac autonomic function in infancy, adding to the growing body of evidence suggesting fluoride's developmental neurotoxicity.

By definition, aging is a natural, gradual and continuous process. On the other hand, frailty reflects the increase in vulnerability to stressors and shortens the time without disease (health span) while longevity refers to the length of life (lifespan). The average life expectancy has significantly increased during the last few decades. A longer lifespan has been accompanied by an increase in frailty and decreased independence in older adults, with major differences existing between men and women. For example, women tend to live longer than men but also experience higher rates of frailty and disability. Sex differences prevent optimization of lifestyle interventions and therapies to effectively prevent frailty. Sex differences in frailty and aging are rooted in a complex interplay between uncontrollable (genetic, epigenetic, physiological), and controllable factors (psychosocial and lifestyle factors). Thus, understanding the underlying causes of sex differences in frailty and aging is essential for developing personalized interventions to promote healthy aging and improve quality of life in older men and women. In this review, we have discussed the key contributors and knowledge gaps related to sex differences in aging and frailty.

Abstract Maternal stress during reproduction can influence how offspring respond to stress later in life. Greater lifetime exposure to glucocorticoid hormones released during stress is linked to greater risks of behavioral disorders, disease susceptibility, and mortality. The immense variation in individual’s stress responses is explained, in part, by prenatal glucocorticoid exposure. To explore the long-term effects of embryonic glucocorticoid exposure, we injected Japanese quail (Coturnix japonica) eggs with corticosterone. We characterized the endocrine stress response in offspring and measured experienced aggression at three different ages. We found that prenatal glucocorticoid exposure affected (1) the speed at which the stress response was terminated suggesting dysregulated negative feedback, (2) baseline corticosterone levels in a manner dependent on current environmental conditions with higher levels of experienced aggression associated with higher levels of baseline corticosterone, (3) the magnitude of an acute stress response based on baseline concentrations. We finish by proposing a framework that can be used to test these findings in future work. Overall, our findings suggest that the potential adaptive nature of prenatal glucocorticoid exposure is likely dependent on environmental context and may also be tempered by the negative effects of longer exposure to glucocorticoids each time an animal faces a stressor.

Abstract Background Canada’s 24-Hour Movement Guidelines for Adults have shifted the focus from considering movement behaviours (i.e., physical activity, sedentary behaviour, and sleep) separately to a 24-h paradigm, which considers how they are integrated. Accordingly, primary care providers (PCPs) have the opportunity to improve their practice to promote all movement behaviours cohesively. However, PCPs have faced barriers to discussing physical activity alone (e.g., time, competing priorities, inadequate training), leading to low frequency of physical activity discussions. Consequently, discussing three movement behaviours may seem challenging. Tools to facilitate primary care discussions about physical activity have been developed and used; however, few have undergone usability testing and none have integrated all movement behaviours. Following a synthesis of physical activity, sedentary behaviour, and sleep tools for PCPs, we developed the Whole Day Matters Tool and User Guide that incorporate all movement behaviours. The present study aimed to explore PCPs’ perceptions on the usability, acceptability, and future implementation of the Whole Day Matters Tool and User Guide to improve their relevancy among PCPs. Methods Twenty-six PCPs were observed and audio–video recorded while using the Tool and User Guide in a think-aloud procedure, then in a near-live encounter with a mock service-user. A debriefing interview using a guide informed by Normalization Process Theory followed. Recordings were transcribed verbatim and analysed using content analysis and a critical friend to enhance rigour. Results PCPs valued aspects of the Tool and User Guide including their structure, user-friendliness, visual appeal, and multi-behaviour focus and suggested modifications to improve usability and acceptability. Findings are further discussed in the context of Normalization Process Theory and previous literature. Conclusions The Tool and User Guide were revised, including adding plain language, reordering and renaming sections, reducing text, and clarifying instructions. Results also informed the addition of a Preamble and a Handout for adults accessing care (i.e., patients/clients/service-users) to explain the evidence underpinning the 24-Hour Movement Guidelines for Adults and support a person-centered approach. These four resources (i.e., Tool, User Guide, Preamble, Handout) have since undergone a consensus building process to arrive at their final versions before being disseminated into primary care practice.

BackgroundRace-based anxiety is a critical health issue within the Black community. Mindfulness interventions hold promise for treating race-based anxiety in Black Americans; however, there are many barriers that prevent Black Americans from using these treatments, such as low cultural relevance, significant time burdens, and excessive costs. ObjectiveThis study is a replication and extension of findings that “healing attempt”—a brief (

This study replicates and extends findings that “healing attempt”—a brief digital music-based mindfulness intervention—represents a feasible and potentially effective intervention for race-based anxiety in the Black community.

IntroductionChemotherapy-induced cognitive impairment colloquially referred to as chemobrain is a poorly understood phenomenon affecting a highly variable proportion of patients with breast cancer. Here we investigate the association between anxiety and despair-like behaviors in mice treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) along with host histological, proteomic, gene expression, and gut microbial responses.MethodsForced swim and sociability tests were used to evaluate depression and despair-like behaviors. The tandem mass tag (TMT) proteomics approach was used to assess changes in the neural protein network of the amygdala and hippocampus. The composition of gut microbiota was assessed through 16S rRNA gene sequencing. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate changes in intestinal gap junction markers.Results and discussionWe observed that CMF induced social and despair-like behavior in mice 96 hours following treatment. Proteomic analysis identified changes in various proteins related to progressive neurological disease, working memory deficit, primary anxiety disorder, and gene expression revealing increases in NMDA and AMPA receptors in both the hippocampus and the amygdala because of CMF treatment. These changes finally, we observed immediate changes in the microbial population after chemotherapy treatment, with a notable abundance of Muribaculaceae and Romboutsia which may contribute to changes seen in the gut.

Abstract Background Linked electronic medical records and administrative data have the potential to support a learning health system and data-driven quality improvement. However, data completeness and accuracy must first be assessed before their application. We evaluated the processes, feasibility, and limitations of linking electronic medical records and administrative data for the purpose of quality improvement within five specialist diabetes clinics in Edmonton, Alberta, a province known for its robust health data infrastructure. Methods We conducted a retrospective cross-sectional analysis using electronic medical record and administrative data for individuals ≥ 18 years attending the clinics between March 2017 and December 2018. Descriptive statistics were produced for demographics, service use, diabetes type, and standard diabetes benchmarks. The systematic and iterative process of obtaining results is described. Results The process of integrating electronic medical record with administrative data for quality improvement was found to be non-linear and iterative and involved four phases: project planning, information generating, limitations analysis, and action. After limitations analysis, questions were grouped into those that were answerable with confidence, answerable with limitations, and not answerable with available data. Factors contributing to data limitations included inaccurate data entry, coding, collation, migration and synthesis, changes in laboratory reporting, and information not captured in existing databases. Conclusion Electronic medical records and administrative databases can be powerful tools to establish clinical practice patterns, inform data-driven quality improvement at a regional level, and support a learning health system. However, there are substantial data limitations that must be addressed before these sources can be reliably leveraged.

BackgroundMarfan syndrome is a potentially fatal inherited autosomal dominant condition impacting the cardiovascular and the skeletal system with an estimated 25% cases caused by sporadic genetic variations. Given the genetic inheritance pattern, an autopsy of probands with Marfan syndrome–associated mortality is critical to establish the phenotypic expression and clinical implications of the particular genetic variant, especially for first-degree relatives. We present the findings of a Marfan syndrome proband decedent presenting with sudden onset abdominal pain and unexplained retroperitoneal abdominal hemorrhage.MethodsAn autopsy was performed to inform the blood relatives of the phenotypic expression and penetrance of the potentially heritable condition. A clinical laboratory improvement amendment (CLIA)-certified clinical grade genetic sequencing was performed to identify pathogenic variants in genes associated with aortopathy.ResultsThe autopsy showed intra-abdominal and retroperitoneal hemorrhage due to infarction of the right kidney caused by dissection of the right renal artery. Genetic testing identified a heterozygous pathogenic FBN1 gene variant. The specific variant is FBN1 NM_000138.4 c.2953G > A p.(Gly985Arg).ConclusionsWe report a case of a previously undiagnosed Marfan syndrome death due to a de novo FBN1 variant, c.2953G > A.

BackgroundThe Coronavirus Disease 2019 (COVID-19) pandemic has exacerbated mental health challenges among physicians and non-physicians. However, it is unclear if the worsening mental health among physicians is due to specific occupational stressors, reflective of general societal stressors during the pandemic, or a combination. We evaluated the difference in mental health and addictions health service use between physicians and non-physicians, before and during the COVID-19 pandemic.Methods and findingsWe conducted a population-based cohort study in Ontario, Canada between March 11, 2017 and August 11, 2021 using data collected from Ontario's universal health system. Physicians were identified using registrations with the College of Physicians and Surgeons of Ontario between 1990 and 2020. Participants included 41,814 physicians and 12,054,070 non-physicians. We compared the first 18 months of the COVID-19 pandemic (March 11, 2020 to August 11, 2021) to the period before COVID-19 pandemic (March 11, 2017 to February 11, 2020). The primary outcome was mental health and addiction outpatient visits overall and subdivided into virtual versus in-person, psychiatrists versus family medicine and general practice clinicians. We used generalized estimating equations for the analyses. Pre-pandemic, after adjustment for age and sex, physicians had higher rates of psychiatry visits (aIRR 3.91 95% CI 3.55 to 4.30) and lower rates of family medicine visits (aIRR 0.62 95% CI 0.58 to 0.66) compared to non-physicians. During the first 18 months of the COVID-19 pandemic, the rate of outpatient mental health and addiction (MHA) visits increased by 23.2% in physicians (888.4 pre versus 1,094.7 during per 1,000 person-years, aIRR 1.39 95% CI 1.28 to 1.51) and 9.8% in non-physicians (615.5 pre versus 675.9 during per 1,000 person-years, aIRR 1.12 95% CI 1.09 to 1.14). Outpatient MHA and virtual care visits increased more among physicians than non-physicians during the first 18 months of the pandemic. Limitations include residual confounding between physician and non-physicians and challenges differentiating whether observed increases in MHA visits during the pandemic are due to stressors or changes in health care access.ConclusionsThe first 18 months of the COVID-19 pandemic was associated with a larger increase in outpatient MHA visits in physicians than non-physicians. These findings suggest physicians may have had larger negative mental health during COVID-19 than the general population and highlight the need for increased access to mental health services and system level changes to promote physician wellness.

Early preimplantation mouse embryos are sensitive to increased osmolarity, which can block their development. To overcome this, they accumulate organic osmolytes to maintain cell volume. The main organic osmolyte used by early mouse embryos is glycine. Glycine is transported during the mature egg and 1-cell to 4-cell embryo stages by a transporter identified as GLYT1, encoded by the Slc6a9 gene. Here, we have produced an oocyte-specific knockout of Slc6a9 by crossing mice that have a segment of the gene flanked by LoxP elements with transgenic mice expressing iCre driven by the oocyte-specific Gdf9 promoter. Slc6a9 null oocytes failed to develop glycine transport activity during meiotic maturation. However, females with these oocytes were fertile. When enclosed in their cumulus-oocyte complex, Slc6a9 null oocytes could accumulate glycine via GLYT1 transport in their coupled cumulus cells, which may support female fertility in vivo. In vitro, embryos derived from Slc6a9 null oocytes displayed a clear phenotype. While glycine rescued complete preimplantation development of wild type embryos from increased osmolarity, embryos derived from null oocytes failed to develop past the 2-cell stage even with glycine. Thus, Slc6a9 is required for glycine transport and protection against increased osmolarity in mouse eggs and early embryos.

Abstract Background We described the impact of different lengths of lookback window (LW), a retrospective time period to observe diagnoses in administrative data, on the prevalence and incidence of eight chronic diseases. Methods Our study populations included people living with HIV (N = 5151) and 1:5 age-sex-matched HIV-negative individuals (N = 25,755) in British Columbia, Canada, with complete follow-up between 1996 and 2012. We measured period prevalence and incidence of diseases in 2012 using LWs ranging from 1 to 16 years. Cases were deemed prevalent if identified in 2012 or within a defined LW, and incident if newly identified in 2012 with no previous cases detected within a defined LW. Chronic disease cases were ascertained using published case-finding algorithms applied to population-based provincial administrative health datasets. Results Overall, using cases identified by the full 16-year LW as the reference, LWs ≥8 years and ≥ 4 years reduced the proportion of misclassified prevalent and incidence cases of most diseases to

IntroductionCase-finding algorithms can be applied to administrative healthcare records to identify people with diseases, including people with HIV (PWH). When supplementing an existing registry of a low prevalence disease, near-perfect specificity helps minimize impacts of adding in algorithm-identified false positive cases. We evaluated the performance of algorithms applied to healthcare records to supplement an HIV registry in British Columbia (BC), Canada.MethodsWe applied algorithms based on HIV-related diagnostic codes to healthcare practitioner and hospitalization records. We evaluated 28 algorithms in a validation sub-sample of 7,124 persons with positive HIV tests (2,817 with a prior negative test) from the STOP HIV/AIDS data linkage-a linkage of healthcare, clinical, and HIV test records for PWH in BC, resembling a disease registry (1996-2020). Algorithms were primarily assessed based on their specificity-derived from this validation sub-sample-and their impact on the estimate of the total number of PWH in BC as of 2020.ResultsIn the validation sub-sample, median age at positive HIV test was 37 years (Q1: 30, Q3: 46), 80.1% were men, and 48.9% resided in the Vancouver Coastal Health Authority. For all algorithms, specificity exceeded 97% and sensitivity ranged from 81% to 95%. To supplement the HIV registry, we selected an algorithm with 99.89% (95% CI: 99.76% - 100.00%) specificity and 82.21% (95% CI: 81.26% - 83.16%) sensitivity, requiring five HIV-related healthcare practitioner encounters or two HIV-related hospitalizations within a 12-month window, or one hospitalization with HIV as the most responsible diagnosis. Upon adding PWH identified by this highly-specific algorithm to the registry, 8,774 PWH were present in BC as of March 2020, of whom 333 (3.8%) were algorithm-identified.DiscussionIn the context of an existing low prevalence disease registry, the results of our validation study demonstrate the value of highly-specific case-finding algorithms applied to administrative healthcare records to enhance our ability to estimate the number of PWH living in BC.

Obesity is a complex medical condition that is linked to various health complications such as infertility, stroke, and osteoarthritis. Understanding the neurobiology of obesity is crucial for responding to the etiology of this disease. The hypothalamus coordinates many integral activities such as hormone regulation and feed intake and numerous studies have observed altered hypothalamic gene regulation in obesity models. Previously, it was reported that the promoter region of the satiety gene, Pomc, has increased DNA methylation in the hypothalamus following short-term exposure to a high fat diet, suggesting that epigenetic-mediated repression of hypothalamic Pomc might contribute to the development of obesity. However, due to technical limitations, this has never been directly tested. Here, we used the CRISPR-dCas9-TET1 and dCas9-DNMT3a systems to test the role of Pomc DNA methylation in the hypothalamus in abnormal weight gain following acute exposure to a high fat diet in male rats. We found that exposure to a high fat diet increases Pomc DNA methylation and reduces gene expression in the hypothalamus. Despite this, we found that CRISPR-dCas9-TET1-mediated demethylation of Pomc was not sufficient to prevent abnormal weight gain following exposure to a high fat diet. Furthermore, CRISPR-dCas9-DNMT3a-mediated methylation of Pomc did not alter weight gain following exposure to standard or high fat diets. Collectively, these results suggest that high fat diet induced changes in Pomc DNA methylation are a consequence of, but do not directly contribute to, abnormal weight gain during the development of obesity.

Space exploration has advanced substantially over recent decades and plans to increase the duration of deep space missions are in preparation. One of the primary health concerns is potential damage to the central nervous system (CNS), resulting in loss of cognitive abilities and function. The majority of ground-based research on space radiation-induced health risks has been conducted using single particle simulations, which do not effectively model real-world scenarios. Thus, to improve the safety of space missions, we must expand our understanding of the effects of simulated galactic cosmic rays (GCRs) on the CNS. To assess the effects of low-dose GCR, we subjected 6-month-old male BALB/c mice to 50 cGy 5-beam simplified GCR spectrum (1H, 28Si, 4He, 16O, and 56Fe) whole-body irradiation at the NASA Space Radiation Laboratory. Animals were tested for cognitive performance with Y-maze and Morris water maze tests 3 months after irradiation. Irradiated animals had impaired short-term memory and lacked spatial memory retention on day 5 of the probe trial. Glial cell analysis by flow cytometry showed no significant changes in oligodendrocytes, astrocytes, microglia or neural precursor cells (NPC’s) between the sham group and GCR group. Bone marrow cytogenetic data showed a significant increase in the frequency of chromosomal aberrations after GCR exposure. Finally, tandem mass tag proteomics identified 3,639 proteins, 113 of which were differentially expressed when comparing sham versus GCR exposure (fold change > 1.5; p < 0.05). Our data suggest exposure to low-dose GCR induces cognitive deficits by impairing short-term memory and spatial memory retention.

Bovine Respiratory Disease (BRD) represents a significant burden to the health of feedlot cattle and the profitability of the beef industry in the US. Mannheimia haemolytica is widely regarded as the primary bacterial pathogen driving acute BRD. While Mycoplasma bovis is most commonly implicated in chronic cases of BRD, this agent's potential role in acute stages of BRD is unclear. Therefore, this study aimed to evaluate potential associations between M. bovis and M. haemolytica during acute BRD in feedlot cattle. Nasal swabs (n = 1,044) were collected over time from feedlot cattle (n = 270) enrolled in an experiment assessing the effect of vaccination for Bovine Respiratory Syncytial Virus (BRSV). Swabs were analyzed for detection of M. bovis, M. haemolytica, Pasteurella multocida, Histophilus somni, and BRSV via multiplex qPCR assays. Data were analyzed using inverse conditional probability weighted (ICPW) logistic regression models to investigate potential effects of M. bovis presence on arrival (d0), day seven (d7) and day 14 (d14) post-arrival on M. haemolytica prevalence on day 28 (d28) post-arrival, adjusting for the previous history of P. multocida, H. somni, BRSV, BRD morbidity, and body weight. The potential association between time-to-BRD detection and M. bovis presence on d0, d7, and d14 post-arrival, was inferred via an ICPW time-to-event model. The presence of M. bovis in nasal swabs collected on d7 post-arrival was significantly associated with an increase in the prevalence of M. haemolytica on d28 (prevalence difference: 45%; 95% Confidence Interval: 31%, 60%; P-value < 0.001). Significant time-varying coefficients for M. bovis presence were detected at d0, d7, and d14 post-arrival in the ICPW time-to-event model (P-value < 0.001). The shortest median time-to-BRD detection was 29 days in cattle that were M. bovis positive on d0, d7, and d14 post-arrival and in those that were positive on d0 and d14 post-arrival. Under the conditions of this study, our findings suggest that M. bovis may be influencing the respiratory environment during the acute phase of BRD, increasing the abundance of M. haemolytica, which could have important impacts on the occurrence of BRD.

Abstract Serine proteases catalyze a multi-step covalent catalytic mechanism of peptide bond cleavage. It has long been assumed that serine proteases including thrombin carry-out catalysis without significant conformational rearrangement of their stable two-β-barrel structure. We present nuclear magnetic resonance (NMR) and hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments on the thrombin-thrombomodulin (TM) complex. Thrombin promotes procoagulative fibrinogen cleavage when fibrinogen engages both the anion binding exosite 1 (ABE1) and the active site. It is thought that TM promotes cleavage of protein C by engaging ABE1 in a similar manner as fibrinogen. Thus, the thrombin-TM complex may represent the catalytically active, ABE1-engaged thrombin. Compared to apo- and active site inhibited-thrombin, we show that thrombin-TM has reduced μs-ms dynamics in the substrate binding (S1) pocket consistent with its known acceleration of protein C binding. Thrombin-TM has increased μs-ms dynamics in a β-strand connecting the TM binding site to the catalytic aspartate. Finally, thrombin-TM had doublet peaks indicative of dynamics that are slow on the NMR timescale in residues along the interface between the two β-barrels. Such dynamics may be responsible for facilitating the N-terminal product release and water molecule entry that are required for hydrolysis of the acyl-enzyme intermediate.

Stoneflies (Plecoptera) are often associated with inhabiting cold perennial streams, but many species also inhabit intermittent streams that experience reduced or lack of flow during summer and autumn. In this study, the influence of stream permanence on stonefly assemblage composition and spatial distribution at Mammoth Cave National Park, Kentucky, USA, was addressed, based on a 14 month sampling regime from the fullest range of stream sizes and habitable flow regions available. Adult stoneflies were collected monthly from 43 sites at the Park plus an additional two sites at the near-adjacent Western Kentucky University Green River Preserve. Collections were done from December 2018–November 2019 using a standard timed protocol with beating sheets for adults and once in December 2019–January 2020 for larvae. Stream sites were assigned one of five category types: perennial spring runs, perennial spring seeps, upland perennial streams, perennial riverine and summer dry runs. In total, 34 species were collected. The most prominent difference in stonefly community structure was between spring runs, spring seeps and summer dry streams vs. upland perennial streams. Approximately 88% of species collected had univoltine-fast life cycles and 79% likely had an extended period of egg or larval diapause. Due to the predominance of small upland perennial and summer dry streams, species commonly typically found in larger lotic systems are fundamentally filtered out of the region due to the lack of available habitats. Species able to survive in intermittent habitats do so by life history adaptations including to survive desiccation as larvae or eggs.

Many age-associated changes in the human hematopoietic system have been reproduced in murine models; however, such changes have not been as robustly explored in rats despite the fact these larger rodents are more physiologically similar to humans. We examined peripheral blood of male F344 rats ranging from 3 to 27 months of age and found significant age-associated changes with distinct leukocyte population shifts. We report CD25+ CD4+ population frequency is a strong predictor of healthy aging, generate a model using blood parameters, and find rats with blood profiles that diverge from chronologic age indicate debility; thus, assessments of blood composition may be useful for non-lethal disease profiling or as a surrogate measure for efficacy of aging interventions. Importantly, blood parameters and DNA methylation alterations, defined distinct juncture points during aging, supporting a non-linear aging process. Our results suggest these inflection points are important considerations for aging interventions. Overall, we present rat blood aging metrics that can serve as a resource to evaluate health and the effects of interventions in a model system physiologically more reflective of humans.

Depression is the most common and prevalent mental disorder today, affecting an estimated 1 in 4 Canadians at some point in their lifetime. Physical activity is recommended as a primary treatment for mild to moderate depression and a secondary treatment for moderate to severe depression. Despite this, specific guidelines are still lacking on how to best promote physical activity in this population. Accordingly, this policy brief provides evidence-based recommendations for primary care providers and allied health professionals to promote lifelong physical activity in individuals with depression. Recommendations include asking for permission to discuss physical activity with the individual; framing physical activity as something that they have control over in order to feel better; clarifying that incorporating even a few more minutes of weekly physical activity is better than nothing and that mild forms are enough to achieve mental health benefits; and providing choices of activities to try and accompanying them on their first few sessions. Moreover, this article highlights the importance of promoting physical activity enjoyment for this population, which can be done by guiding the individual to slowly build up the frequency, duration and intensity of activity; encouraging them to be selfcompassionate toward physical activity; suggesting they engage in outdoor activity, listen to music, and/or participate with a buddy or group; and incorporate self-monitoring or journalling to solidify the link between physical activity and improved mood. Practitioners are encouraged to use these evidence-informed recommendations—especially maximizing choices, enhancing physical activity enjoyment and emphasizing personal preferences—to help individuals with depression move, recover and flourish. These recommendations may also be used to tailor future interventions and inform policy guidelines to reduce depression rates in Canada.

Résumé: La dépression est aujourd’hui le trouble mental le plus répandu, et on estime qu’un Canadien sur quatre en souffrira à un moment ou à un autre de sa vie. Même si l’activité physique est recommandée comme traitement principal de la dépression légère à modérée et comme traitement secondaire de la dépression modérée à grave, on ne dispose toujours pas de lignes directrices précises sur la meilleure façon de promouvoir l’activité physique auprès de la population atteinte de dépression. Cet exposé de politique vise donc à fournir des recommandations fondées sur des données probantes aux fournisseurs de soins primaires et aux professionnels paramédicaux afin de promouvoir l’activité physique à vie chez les personnes atteintes de dépression. Ces recommandations consistent notamment à demander la permission de parler d’activité physique avec les personnes concernées; à présenter l’activité physique comme un élément sur lequel elles ont un contrôle afin de se sentir mieux; à préciser qu’intégrer ne serait-ce que quelques minutes supplémentaires d’activité physique hebdomadaire vaut mieux que rien et que des exercices légers sont suffisants pour obtenir des bienfaits sur la santé mentale et enfin à proposer plusieurs choix d’activités et essayer d’accompagner les personnes lors de leurs premières séances. En outre, cet article souligne l’importance de promouvoir, auprès de cette population, le plaisir que procure l’activité physique, ce qui peut être fait en aidant la personne à augmenter progressivement la fréquence, la durée et l’intensité de l’activité; en l’encourageant à faire preuve de bienveillance envers elle­même à propos de l’activité physique; en lui suggérant de s’adonner à une activité de plein air, d’écouter de la musique, d’être accompagnée d’un(e) ami(e) ou de faire partie d’un groupe; en utilisant un système d’autosuivi ou un journal pour renforcer le lien entre activité physique et amélioration de l’humeur. Les praticiens sont encouragés à utiliser ces recommandations fondées sur des données probantes (en particulier l’offre d’un maximum de choix, l’insistance sur le plaisir procuré par l’activité physique et la mise en avant des préférences personnelles) afin d’aider les personnes atteintes de dépression à bouger, à se rétablir et à s’épanouir. Ces recommandations sont également utilisables pour concevoir les futures interventions et pour éclairer les lignes directrices visant à réduire les taux de dépression au Canada.

The incidence of chronic kidney disease (CKD) is increasing among people living with HIV (PLWH). Routine monitoring of indicators such as CD4:CD8 ratio might improve the early detection of CKD. Our objective was to identify clinically relevant CD4:CD8 ratio trajectories indicative of CKD risk. Participants were ≥ 18 years old, initiated antiretroviral therapy between 2000 and 2016, and were followed for ≥6 months until 31 March 2017 or last contact date. Outcome was incidence of CKD. Growth mixture models (GMMs) and decay models were used to compare CD4:CD8 ratio trajectories. Following GMM, 4547 (93.5%) participants were classified in Class 1 with 5.4% developing CKD, and 316 (6.5%) participants were classified in Class 2 with 20.9% developing CKD. The final model suggested that participants in Class 2 had 8.72 times the incidence rate of developing CKD than those in Class 1. Exponential decay models indicated a significant CD4:CD8 ratio decline among Class 2 participants who developed CKD. Among those who developed CKD in Class 2, starting at 5.5 years of follow-up, the slope of their ratio trajectory curve changed significantly, and the rate of decline increased dramatically. Routine monitored CD4:CD8 ratios can be an effective strategy to identify early CKD risk among PLWH.

There is substantial evidence showing that medical student wellness is a worsening problem in Canada. It is apparent that medical students’ wellness deteriorates throughout their training. Medical schools and their governing bodies are responding by integrating wellness into competency frameworks and accreditation standards through a combination of system- and individual-level approaches. System-level strategies that consider how policies, medical culture, and the “hidden curriculum” impact student wellness, are essential for reducing burnout prevalence and achieving optimal wellness outcomes. Individual-level initiatives such as wellness programming are widespread and more commonly used. These are often didactic, placing the onus on the student without addressing the learning environment. Despite significant progress, there is little programming consistency across schools or training levels. There is no wellness curriculum framework for Canadian undergraduate medical education that aligns with residency competencies. Creating such a framework would help align individual- and system-level initiatives and smooth the transition from medical school to residency. The framework would organize goals within relevant wellness domains, allow for local adaptability, consider basic learner needs, and be learner-informed. Physicians whose wellness has been supported throughout their training will positively contribute to the quality of patient care, work environments, and in sustaining a healthy Canadian population.

In animal studies, the combination of in utero fluoride exposure and low iodine has greater negative effects on offspring learning and memory than either alone, but this has not been studied in children. We evaluated whether the maternal urinary iodine concentration (MUIC) modifies the association between maternal urinary fluoride (MUF) and boys’ and girls’ intelligence. We used data from 366 mother–child dyads in the Maternal–Infant Research on Environmental Chemicals Study. We corrected trimester-specific MUF and MUIC for creatinine, and averaged them to yield our exposure variables (MUFCRE, mg/g; MUICCRE, µg/g). We assessed children’s full-scale intelligence (FSIQ) at 3 to 4 years. Using multiple linear regression, we estimated a three-way interaction between MUFCRE, MUICCRE, and child sex on FSIQ, controlling for covariates. The MUICCRE by MUFCRE interaction was significant for boys (p = 0.042), but not girls (p = 0.190). For boys whose mothers had low iodine, a 0.5 mg/g increase in MUFCRE was associated with a 4.65-point lower FSIQ score (95% CI: −7.67, −1.62). For boys whose mothers had adequate iodine, a 0.5 mg/g increase in MUFCRE was associated with a 2.95-point lower FSIQ score (95% CI: −4.77, −1.13). These results suggest adequate iodine intake during pregnancy may minimize fluoride’s neurotoxicity in boys.

Introduction People living with HIV (PLHIV) are increasingly at risk of age-related comorbidities such as diabetes mellitus (DM). While DM is associated with elevated mortality and morbidity, understanding of DM among PLHIV is limited. We assessed the incidence of DM among people living with and without HIV in British Columbia (BC), Canada, during 2001–2013.Methods We used longitudinal data from a population-based cohort study linking clinical data and administrative health data. We included PLHIV who were antiretroviral therapy (ART) naïve at baseline, and 1:5 age-sex-matched persons without HIV. All participants had ≥5 years of historic data pre-baseline and ≥1 year(s) of follow-up. DM was identified using the BC Ministry of Health’s definitions applied to hospitalisation, physician billing and drug dispensation datasets. Incident DM was identified using a 5-year run-in period. In addition to unadjusted incidence rates (IRs), we estimated adjusted incidence rate ratios (IRR) using Poisson regression and assessed annual trends in DM IRs per 1000 person years (PYs) between 2001 and 2013.Results A total of 129 PLHIV and 636 individuals without HIV developed DM over 17 529 PYs and 88,672 PYs, respectively. The unadjusted IRs of DM per 1000 PYs were 7.4 (95% CI 6.2 to 8.8) among PLHIV and 7.2 (95% CI 6.6 to 7.8) for individuals without HIV. After adjustment for confounding, HIV serostatus was not associated with DM incidence (adjusted IRR: 1.03, 95% CI 0.83 to 1.27). DM incidence did not increase over time among PLHIV (Kendall trend test: p=0.9369), but it increased among persons without HIV between 2001 and 2013 (p=0.0136).Conclusions After adjustment, HIV serostatus was not associated with incidence of DM, between 2001 and 2013. Future studies should investigate the impact of ART on mitigating the potential risk of DM among PLHIV.

IntroductionSeveral methods have been proposed to estimate the time of HIV seroconversion, including those based on CD4 cell depletion models. However, previous models have failed to consider the heterogeneity that exists in CD4 trajectories among different sub-populations. Our objective was to estimate the time from HIV seroconversion relative to the HIV diagnosis date in a population-based cohort of people living with HIV (PLWH) in the province of British Columbia, Canada.MethodsWe used linked administrative and clinical data from the British Columbia Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) cohort, which contains longitudinal individual-level data on all PLWH ever diagnosed in the province. Eligible participants were aged ≥18 years and diagnosed with HIV between 1989 and 2013. The outcome was pre-antiretroviral treatment CD4 cell count measurements assessed every six months. Models were stratified by age and stage of HIV infection at diagnosis. Several explanatory variables were considered including longitudinal viral load measurements. Longitudinal CD4, square root transformed, was modeled via a non-linear mixed effects model; time was modeled using an exponential decay function. We assumed a Gaussian distribution (identity link), an AR(1) correlation structure, and a random intercept and slope for the longitudinal viral load measurements. Due to the population variation in CD4 count among uninfected individuals, we assumed 500 to 1500 cells/mm3 as the normal range when estimating the time of HIV seroconversion.ResultsLongitudinal data on 1,253 individuals were analysed: 80% male, 33% White, and the median age at diagnosis was 38 years (25th-75th percentile [Q1-Q3], 31 to 45). CD4 decay differed by stage of infection at diagnosis and age, with those ≥50 years in Stages 1 and 2 experiencing a faster decline in CD4 over time. The median duration of infection from seroconversion until HIV diagnosis was 6.9 (Q1-Q3, 3.9 to 10.1) years.ConclusionsConsidering the heterogeneity that exists in individual CD4 cell trajectories in a population, we presented a methodology that only relies on routinely collected HIV-related data, which can be further extended to estimate other epidemic measures.

Objectives As people living with HIV (PLWH) live longer, morbidity and mortality from non-AIDS comorbidities have emerged as major concerns. Our objective was to compare prevalence trends and age at diagnosis of nine chronic age-associated comorbidities between individuals living with and without HIV.Design and setting This population-based cohort study used longitudinal cohort data from all diagnosed antiretroviral-treated PLWH and 1:4 age-sex-matched HIV-negative individuals in British Columbia, Canada.Participants The study included 8031 antiretroviral-treated PLWH and 32 124 HIV-negative controls (median age 40 years, 82% men). Eligible participants were ≥19 years old and followed for ≥1 year during 2000 to 2012.Primary and secondary outcome measures The presence of non-AIDS-defining cancers, diabetes, osteoarthritis, hypertension, Alzheimer’s and/or non-HIV-related dementia, cardiovascular, kidney, liver and lung diseases were identified from provincial administrative databases. Beta regression assessed annual age-sex-standardised prevalence trends and Kruskal-Wallis tests compared the age at diagnosis of comorbidities stratified by rate of healthcare encounters.Results Across study period, the prevalence of all chronic age-associated comorbidities, except hypertension, were higher among PLWH compared with their community-based HIV-negative counterparts; as much as 10 times higher for liver diseases (25.3% vs 2.1%, p value

The majority of pediatric visits occur in general emergency departments. Caring for critically ill neonates is a low-frequency but high-stakes event for emergency physicians, which requires specialized knowledge and hands-on training. We describe a novel clinical rotation for emergency medicine (EM) residents that specifically augments skills in neonatal resuscitation through direct participation as a member of the neonatal resuscitation team. The neonatal resuscitation rotation evaluation median score of 4 (interquartile range [IQR] 3,4) was higher compared to all other off-service senior resident rotations combined (median 3, IQR 3,4) for the academic year 2018–2019. Ninety-two percent of residents evaluated the curriculum change as beneficial (median 4, IQR 4,4). The neonatal resuscitation rotation was rated more favorably than the pediatric intensive care rotation (median 4 IQR 3,4 vs median 3, IQR 2, 3) at a tertiary care children’s hospital during the third year. Residency programs may want to consider implementing a directed neonatal resuscitation experience as part of a comprehensive pediatric curriculum for EM residents.

The space extending beyond Earth’s magnetosphere is subject to a complex field of high-energy charged nuclei, which are capable of traversing spacecraft shielding and human tissues, inducing dense ionization events. The central nervous system is a major area of concern for astronauts who will be exposed to the deep-space radiation environment on a mission to Mars, as charged-particle radiation has been shown to elicit changes to the dendritic arbor within the hippocampus of rodents, and related cognitive-behavioral deficits. We exposed 6-month-old male mice to whole-body 1H (0.5 Gy; 150 MeV/n; 18–19 cGy/minute) and an hour later to 16O (0.1Gy; 600 MeV/n; 18–33 Gy/min) at NASA’s Space Radiation Laboratory as a galactic cosmic ray-relevant model. Animals were housed with bedding which provides cognitive enrichment. Mice were tested for cognitive behavior 9 months after exposure to elucidate late radiation effects. Radiation induced significant deficits in novel object recognition and short-term spatial memory (Y-maze). Additionally, we observed opposing morphological differences between the mature granular and pyramidal neurons throughout the hippocampus, with increased dendritic length in the dorsal dentate gyrus and reduced length and complexity in the CA1 subregion of the hippocampus. Dendritic spine analyses revealed a severe reduction in mushroom spine density throughout the hippocampus of irradiated animals. Finally, we detected no general effect of radiation on single-nucleotide polymorphisms in immediate early genes, and genes involved in inflammation but found a higher variant allele frequency in the antioxidants thioredoxin reductase 2 and 3 loci.

Advances in the early diagnosis and treatment have led to increases in breast cancer survivorship. Survivors report cognitive impairment symptoms such as loss of concentration and learning and memory deficits which significantly reduce the patient’s quality of life. Additional therapies are needed to prevent these side effects and, the precise mechanisms of action responsible are not fully elucidated. However, increasing evidence points toward the use of neuroprotective compounds with antioxidants and anti-inflammatory properties as tools for conserving learning and memory. Here, we examine the ability of piperlongumine (PL), an alkaloid known to have anti-inflammatory and antioxidant effects, to play a neuroprotective role in 16-week-old female C57BL/6J mice treated with a common breast cancer regimen of doxorubicin, cyclophosphamide, and docetaxel (TAC). During social memory testing, TAC-treated mice exhibited impairment, while TAC/PL co-treated mice did not exhibit measurable social memory deficits. Proteomics analysis showed ERK1/2 signaling is involved in TAC and TAC/PL co-treatment. Reduced Nrf2 mRNA expression was also observed. mRNA levels of Gria2 were increased in TAC treated mice and reduced in TAC/PL co-treated mice. In this study, PL protects against social memory impairment when co-administered with TAC via multifactorial mechanisms involving oxidative stress and synaptic plasticity.

A small outbreak of the gypsy moth, Lymantria dispar (L.), was discovered in June 1995 in the South Woodford area of northeast London, near Epping Forest. The origin of this outbreak remains unknown, but the eggs may have been transported from continental Europe, where major outbreaks occurred in the early 1990s. A risk assessment concluded that severe defoliation by this forest pest was unlikely to occur in the UK under current climatic conditions, but if the gypsy moth did become established, then sporadic damage to amenity tree species could be expected. Therefore an eradication programme was undertaken, which involved determining the extent of the outbreak area via population monitoring, and chemical treatments of any larval infestations, to prevent further spread. A series of targeted publicity campaigns was carried out with the aim of raising public awareness of the pest in the wider outbreak area. Details of gypsy moth finds (egg masses and larvae) and pheromone trap catches (adult males) are given for the years 1995 - 2003. Pheromone traps were maintained at a relatively high density ( c. 188 per 1 km 2 ) in the immediate outbreak area--and similarly in an adjacent portion of the Epping Forest--and it remains a possibility that some mating disruption has occurred. Although Lymantria dispar persists at this site, the numbers of adult male moths trapped has declined markedly in comparison to the first 2 years (1995 - 1996). The outbreak is, however, continuing to persist at a very low level and may be becoming more widely dispersed, albeit very sparsely. It is also possible that observed population trends in terms of pheromone trap catches reflect a natural population cycle, and for these reasons work is continuing in an attempt to eradicate this damaging broadleaf tree pest from the UK. [ABSTRACT FROM AUTHOR]

Background Despite not being collected for research purposes, linked administrative health data are increasingly being used to conduct observational epidemiologic analyses. In the field of HIV research in British Columbia (BC), Canada, the Comparative Outcomes And Service Utilization Trends (COAST) Study is based on a linkage between HIV-related clinical data and several provincial administrative health datasets. Specifically, the BC Centre for Excellence in HIV/AIDS Drug Treatment Program, which manages antiretroviral therapy (ART) dispensation for all known people living with HIV (PLWH) in BC, is linked with several Population Data BC data holdings. Population Data BC is a repository that houses longitudinal administrative data for all BC residents. Rationale While the use of administrative data for research poses several challenges, bias due to confounding remains to be a key issue in this context. While randomized controlled trials of ART are common, an objective of COAST is to further examine the "real-world" impact of ART on health and clinical outcomes in a population-based sample of 13,907 PLWH in BC. Therefore, while longitudinal administrative data provide a unique opportunity to estimate the effect of ART on outcomes that are infrequently assessed in trials (e.g., chronic conditions), such data often lacks information on sociodemographic, socioeconomic, and behavioural confounders. Approach It has been shown that adjustment for large numbers of covariates, in the form of administrative codes (e.g., diagnostic ICD codes, procedure codes, drug identification numbers), allows for better control of confounding bias. Therefore, relying on an established methodology in pharmacoepidemiology, we will use the high-dimensional propensity score algorithm to select and prioritize covariates (codes) that collectively act as proxies for unmeasured confounders. The use of this causal inference methodology in COAST will enhance our ability to generate stronger evidence to inform strategies that may improve the health and wellbeing of PLWH in this setting.

Despite the evidence supporting the benefits of physical activity in the prevention and treatment of most medical conditions, physical activity remains under-prescribed by physicians. Medical students will form habits during training that they are likely to maintain as future physicians. The overall purpose of this study was to investigate the underlying mechanism(s) contributing to frequency in recommending physical activity, to provide insight into how we can increase physical activity recommendations in future practice as physicians. First to fourth year medical students at three Canadian universities responded to an online survey (N = 221; 12% response rate) between November 2017 and January 2018. Results revealed that engaging in strenuous physical activity was a strong predictor for frequency in recommending physical activity to patients (p

BACKGROUND:Resistant starch is a prebiotic metabolized by the gut bacteria. It has been shown to attenuate chronic kidney disease (CKD) progression in rats. Previous studies employed taxonomic analysis using 16S rRNA sequencing and untargeted metabolomics profiling. Here we expand these studies by metaproteomics, gaining new insight into the host-microbiome interaction. METHODS:Differences between cecum contents in CKD rats fed a diet containing resistant starch with those fed a diet containing digestible starch were examined by comparative metaproteomics analysis. Taxonomic information was obtained using unique protein sequences. Our methodology results in quantitative data covering both host and bacterial proteins. RESULTS:5,834 proteins were quantified, with 947 proteins originating from the host organism. Taxonomic information derived from metaproteomics data surpassed previous 16S RNA analysis, and reached species resolutions for moderately abundant taxonomic groups. In particular, the Ruminococcaceae family becomes well resolved-with butyrate producers and amylolytic species such as R. bromii clearly visible and significantly higher while fibrolytic species such as R. flavefaciens are significantly lower with resistant starch feeding. The observed changes in protein patterns are consistent with fiber-associated improvement in CKD phenotype. Several known host CKD-associated proteins and biomarkers of impaired kidney function were significantly reduced with resistant starch supplementation. Data are available via ProteomeXchange with identifier PXD008845. CONCLUSIONS:Metaproteomics analysis of cecum contents of CKD rats with and without resistant starch supplementation reveals changes within gut microbiota at unprecedented resolution, providing both functional and taxonomic information. Proteins and organisms differentially abundant with RS supplementation point toward a shift from mucin degraders to butyrate producers.

Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Furthermore, though recent evidence suggests that neuronal activity triggers DNA double-strand breaks (DSBs) in some early-response genes, it is currently unknown if DSBs contribute to the reconsolidation of a memory following retrieval. Here, using chromatin immunoprecipitation (ChIP) analyses, we report a significant overlap between DSBs and H3K4me3 in area CA1 of the hippocampus during the reconsolidation process. We found an increase in phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker of DSB, in the Npas4, but not c-fos, promoter region 5 min after retrieval, which correlated with increased H3K4me3 levels, suggesting that the two epigenetic marks may work in concert during the reconsolidation process. Consistent with this, in vivo siRNA-mediated knockdown of topoisomerase II β, the enzyme responsible for DSB, prior to retrieval, reduced Npas4 promoter-specific H2A.XpS139 and H3K4me3 levels and impaired long-term memory, indicating an indispensable role of DSBs in the memory reconsolidation process. Collectively, our data propose a novel mechanism for memory reconsolidation through increases in epigenetic-mediated transcriptional control via DNA double-strand breaks.

Artificial extracellular matrices (aECMs) are an extension of biomaterials that were developed as in-vitro model environments for tissue cells that mimic the native in vivo target tissues’ structure. This bibliometric analysis evaluated the research productivity regarding aECM based on tissue engineering technology. The Web of Science citation index was examined for articles published from 1990 through 2019 using three distinct aECM-related topic sets. Data were also visualized using network analyses (VOSviewer). Terms related to in-vitro, scaffolds, collagen, hydrogels, and differentiation were reoccurring in the aECM-related literature over time. Publications with terms related to a clinical direction (wound healing, stem cells, artificial skin, in-vivo, and bone regeneration) have steadily increased, as have the number of countries and institutions involved in the artificial extracellular matrix. As progress with 3D scaffolds continues to advance, it will become the most promising technology to provide a therapeutic option to repair or replace damaged tissue.