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Introduction: Early adolescents who are new to Canada experience dual challenges of navigating developmental changes and multiple cultures. This study examined how changes in early adolescents' emotional health from ages 9 to 12 differed by immigration background, and to what extent peer belonging and supportive school climate protected or promoted their emotional health., Methods: This study drew upon linked self-report and administrative data. Across 10 school districts in British Columbia, Canada, N = 4479 non-immigrant, immigrant, and refugee adolescents reported on their peer belonging, school climate, and emotional health (life satisfaction, optimism, self-esteem, sadness, worries) in Grades 4 and 7, using the Middle Years Development Instrument. Immigration background including immigration class (economic, family, refugee) and generation status (first, second) were obtained from linked Immigration, Refugees, and Citizenship Canada data. Multi-level modeling assessed the effect of time (grade level), immigration group, and changes in peer belonging and school climate on changes in self-reported emotional health. Analyses were adjusted for gender, English first language, and low family income., Results: Immigrant and refugee adolescents reported worse emotional health in Grade 4 compared to non-immigrants. Non-immigrant and immigrant adolescents reported declines in emotional health from Grades 4 to 7. In contrast, first-generation refugee adolescents reported significant improvements in life satisfaction, and first- and second-generation refugees reported improvements in worries over this period. Perceived improvements in peer belonging and school climate were associated with positive changes in emotional health for all adolescents., Conclusions: Changes in adolescents' emotional health from Grades 4 to 7 differed between immigrants, refugees, and non-immigrants. Immigrants and refugees who enter adolescence with lower emotional health than their non-immigrant peers may particularly benefit from culturally responsive school and community-based interventions., (© 2024 The Author(s). Journal of Adolescence published by John Wiley & Sons Ltd on behalf of Foundation for Professionals in Services to Adolescents.)

Background Aims: Despite promising results in pre-clinical studies, mesenchymal stromal cells (MSCs) face significant challenges in clinical translation. A scoping review by our group highlighted two key issues contributing to this gap: (i) lack of a clear and consensus definition for MSCs and (ii) under-reporting of critical parameters in MSC clinical studies. To address these issues, we conducted a modified Delphi study to establish and implement a consensus definition for MSCs and develop reporting guidelines for MSC clinical studies., Methods: A steering committee of 22 international experts, including stakeholders from different MSC research fields, participated in the three Delphi rounds. For the first round, to obtain a broad perspective, additional investigators recommended by the steering committee were invited to participate. The first two rounds consisted of online surveys, whereas the third round took the form of a virtual meeting. Participants were asked to rate a series of potential defining characteristics of MSCs and items for reporting guidelines. Consensus was defined as at least 80% of the participants rating the item in the same category of importance., Results: Eighty-seven international participants participated in the first round survey (spring 2023), 17 participants participated in the second online survey (fall 2023) and 15 participants participated in the final virtual consensus meeting (January 2024). For the MSC definition, 20 items were considered and nine reached consensus. Items included terminology (one item), cell marker expression (five items), tissue origin (one item), stemness (one item) and description of critical quality attributes (one item). For the reporting guidelines, with the 28 initial items and the additional items suggested during round 1, a total of 33 items to report were included. This included items on MSC intervention group and control (e.g., MSC product, dose and administration), MSC characteristics (e.g., MSC provenance, "fitness," viability and immune compatibility) and MSC culture conditions (e.g., oxygen environment, culture medium and use of serum)., Conclusions: By applying a Delphi method to establish a consensus definition for MSCs and reporting guidelines for MSC-based clinical trials, this work represents a significant advance in improving transparency and reproducibility in the conduct and reporting of MSC research., Competing Interests: Declaration of competing interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. All rights reserved.)

The causes of Alzheimer's disease (AD) are poorly understood, although many genes are known to be involved in this pathology. To gain insights into the underlying molecular mechanisms, it is essential to identify the relationships between individual AD genes. Previous work has shown that the splice variant E of KLC1 (KLC1_vE) promotes AD, and that the CELF1 gene, which encodes an RNA-binding protein involved in splicing regulation, is at a risk locus for AD. Here, we identified a functional link between CELF1 and KLC1 in AD pathogenesis. Transcriptomic data from human samples from different ethnic groups revealed that CELF1 mRNA levels are low in AD brains, and the splicing pattern of KLC1 is strongly correlated with CELF1 expression levels. Specifically, KLC1_vE is negatively correlated with CELF1. Depletion and overexpression experiments in cultured cells demonstrated that the CELF1 protein down-regulates KLC1_vE. In a cross-linking and immunoprecipitation sequencing (CLIP-seq) database, CELF1 directly binds to KLC1 RNA, following which it likely modulates terminal exon usage, hence KLC1_vE formation. These findings reveal a new pathogenic pathway where a risk allele of CELF1 is associated with reduced CELF1 expression, which up-regulates KLC1_vE to promote AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Introduction: This study examined profiles of social connectedness among early adolescents in grade 7 before the COVID-19 pandemic was declared (Winter 2020), and in grade 8 during the second Wave of the pandemic (Winter 2021)., Method: Linked data from 1753 early adolescents (49% female) from British Columbia, Canada who completed the Middle Years Development Instrument survey in grades 7 and 8 were used. Participants reported on life satisfaction, depressive symptoms, and connectedness with peers and adults at home, school and in the community. We used Latent Profile Analysis to identify connectedness profiles at both time points, and Latent Transition Analysis to examine transitions in connectedness profiles over time. Multiple regression analyses examined the associations between profile membership in grade 7 and mental well-being in grade 8, and the associations between transitions in profile membership (i.e., increase vs. decrease in connectedness over time) and mental well-being., Results: Connectedness in multiple domains in grade 7 was related to significantly higher levels of mental well-being in grade 8, controlling for demographics, well-being in grade 7, and COVID-related mental health worries. Well-being was highest when students felt highly connected in all domains and lowest when they felt lower levels of connection. Increases in connectedness were associated with improvements in mental well-being and decreases with a decline in well-being over time., Conclusions: Experiencing connectedness with peers and adults is critical for the mental well-being in early adolescence. Providing opportunities to connect is important in the context of major societal challenges such as the COVID-19 pandemic., (© 2023 The Authors. Journal of Adolescence published by Wiley Periodicals LLC on behalf of Foundation for Professionals in Services to Adolescents.)

Objective: To examine the risk of hospitalization within 14 days of COVID-19 diagnosis among people living with HIV (PLWH) and HIV-negative individuals who had laboratory-confirmed SARS-CoV-2 infection., Methods: We used Cox proportional hazard models to compare the relative risk of hospitalization in PLWH and HIV-negative individuals. Then, we used propensity score weighting to examine the influence of sociodemographic factors and comorbid conditions on risk of hospitalization. These models were further stratified by vaccination status and pandemic period (pre-Omicron: December 15, 2020, to November 21, 2021; Omicron: November 22, 2021, to October 31, 2022)., Results: The crude hazard ratio (HR) for risk of hospitalization in PLWH was 2.44 (95% confidence interval [CI]: 2.04-2.94). In propensity score-weighted models that included all covariates, the relative risk of hospitalization was substantially attenuated in the overall analyses (adjusted HR [aHR]: 1.03; 95% CI: 0.85-1.25), in vaccinated (aHR 1.00; 95% CI: 0.69-1.45), inadequately vaccinated (aHR: 1.04; 95% CI: 0.76-1.41) and unvaccinated individuals (aHR: 1.15; 95% CI: 0.84-1.56)., Conclusion: PLWH had about two times the risk of COVID-19 hospitalization than HIV-negative individuals in crude analyses which attenuated in propensity score-weighted models. This suggests that the risk differential can be explained by sociodemographic factors and history of comorbidity, underscoring the need to address social and comorbid vulnerabilities (e.g., injecting drugs) that were more prominent among PLWH., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Since the emergence of the SARS-CoV-2 Omicron variant, multiple observational studies have reported negative vaccine effectiveness (VE) against infection, symptomatic infection, and even severity (hospitalization), potentially leading to an interpretation that vaccines were facilitating infection and disease. However, current observations of negative VE likely stem from the presence of various biases (e.g., exposure differences, testing differences). Although negative VE is more likely to arise when true biological efficacy is generally low and biases are large, positive VE measurements can also be subject to the same mechanisms of bias. In this perspective, we first outline the different mechanisms of bias that could lead to false-negative VE measurements and then discuss their ability to potentially influence other protection measurements. We conclude by discussing the use of suspected false-negative VE measurements as a signal to interrogate the estimates (quantitative bias analysis) and to discuss potential biases when communicating real-world immunity research., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: We estimated the effectiveness of COVID-19 vaccines against laboratory-confirmed SARS-CoV-2 infection among people living with HIV (PLWH) and compared the estimates with a matched HIV-negative cohort., Methods: We used the British Columbia COVID-19 Cohort, a population-based data platform, which integrates COVID-19 data on SARS-CoV-2 tests, laboratory-confirmed cases, and immunizations with provincial health services data. The vaccine effectiveness (VE) was estimated with a test-negative design using the multivariable logistic regression., Results: The adjusted VE against SARS-CoV-2 infection was 71.1% (39.7, 86.1%) 7-59 days after two doses, rising to 89.3% (72.2, 95.9%) between 60 and 89 days. VE was preserved 4-6 months after the receipt of two doses, after which noticeable waning was observed (51.3% [4.8, 75.0%]). In the matched HIV-negative cohort (n = 375,043), VE peaked at 91.4% (90.9, 91.8%) 7-59 days after two doses and was sustained for up to 4 months, after which evidence of waning was observed, dropping to 84.2% (83.4, 85.0%) between 4 and 6 months., Conclusion: The receipt of two COVID-19 vaccine doses was effective against SARS-CoV-2 infection among PLWH pre-Omicron. VE estimates appeared to peak later in PLWH than in the matched HIV-negative cohort and the degree of waning was relatively quicker in PLWH; however, peak estimates were comparable in both populations., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Alcohol consumption is more prevalent among sexual minorities than among heterosexuals; however, differences between minority sexual orientation groups are understudied. This systematic review and meta-analysis aimed to summarize existing evidence on the prevalence of alcohol use among bisexual people compared to their lesbian/gay and heterosexual counterparts., Methods: A systematic review of literature from 1995 to May 2020 was performed using Medline, PsycInfo, and Embase (OVID), Scopus, CINHAL and LGBT Life (EBSCO), combining keywords for bisexuality and alcohol use. Peer-reviewed publications that reported quantitative data on alcohol use among bisexual people were included. A random-effects model was used to pool the prevalence of two outcomes: any alcohol use and heavy episodic drinking (HED). Subgroup analysis and random-effects meta-regression were used to explore heterogeneity., Results: Of 105 studies eligible for data extraction, the overall prevalence of alcohol use was higher among bisexuals compared to lesbian/gay and heterosexual people. For example, the prevalence of past-month HED was 30.0% (28.2, 31.8) among bisexual people versus 25.5% (23.8, 27.2) among lesbian/gay and 21.3% (19.6, 23.0) among heterosexual individuals. Pooled odds ratio estimates showed that bisexual people were more likely to report alcohol use and HED compared to their counterparts. Gender was a significant effect modifier in meta-regression analysis, with greater disparities among women than among men., Conclusions: These results highlight the need for additional research to understand factors underlying bisexual people's greater risk, and particularly bisexual women, as well as alcohol use interventions that are targeted towards the specific needs of bisexual people., (Copyright © 2022 Elsevier B.V. All rights reserved.)

While Indigenous food systems remain critical for community well-being, traditionally harvested foods are a potential source of toxic exposures. The Tsleil-Waututh Nation (TWN) is seeking to restore shellfish harvesting in Burrard Inlet (British Columbia [BC], Canada), where the cumulative effects of industrial activity have nearly eliminated safe harvesting. The Trans Mountain Expansion project would triple the capacity to transport oil through the inlet, threatening TWN's progress to restore shellfish harvesting. To inform ongoing efforts we assessed contamination by heavy metals (arsenic, cadmium, lead, and mercury) and 48 polycyclic aromatic hydrocarbons (PAHs) congeners in different shellfish species (Softshell clams, Varnish clams, and Dungeness crab) in three areas. We compared our results against local screening values (SVs) established by the TWN and BC Ministry of Environment and Climate Change Strategy, as well as provincial and national benchmarks. In total, we analyzed 18 composite samples of Softshell clams and Varnish clams (5 individuals per sample), as well as 17 individual crabs. We found chemical contamination in all species at all sites. PAHs were most frequently detected in Softshell clams, highest in the site closest to the pipeline terminus. Clams presented higher levels of contamination than crabs for PAHs, but not for heavy metals. For Softshell and Varnish clams, all heavy metals across study sites exceeded at least one of the population-specific SVs. Of the 14 PAHs detected, benzo(a)pyrene presented a median concentration in Softshell clams of 3.25 μ/kg, exceeding local SV for subsistence fisher. Our results call for further assessment of human health impacts related to food harvesting within Burrard Inlet and establishing a long-term coordinated program co-led by the TWN to monitor contamination and inform future harvesting programs. The study draws attention to the need to consider locally-relevant toxicity benchmarks, and include potential health impacts of food contamination in appraising development project proposals., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A mounting body of evidence suggests that polysubstance use (PSU) is common among people who use opioids (PWUO). Measuring PSU, however, is statistically and methodologically challenging. Person-centered analytical approaches (e.g., latent class analysis) provide a holistic understanding of individuals' substance use patterns and help understand PSU heterogeneities among PWUO and their specific needs in an inductive manner. We reviewed person-centered studies that characterized latent patterns of PSU among PWUO., Methods: We searched MEDLINE, Embase, CINAHL, PsycINFO, Web of Science, and Google Scholar from inception, through to June 15, 2020, for empirical peer-reviewed studies or gray literature that reported on latent classes of PSU among PWUO. Two independent reviewers completed the title, abstract, full-text screening, and data extraction. The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale, and quality of reporting was evaluated using the Guidelines for Reporting on Latent Trajectory Studies checklist. Studies' findings were summarized and presented in a narrative fashion., Results: Out of the 3372 initial unique studies identified, 30 were included. PSU operationalization varied substantially among the studies. We identified five distinct PSU latent classes frequently observed across the studies: Infrequent/low PSU, PSU primarily involving heroin use, PSU primarily involving heroin and stimulant use, PSU primarily involving stimulant use, and frequent PSU. Belonging to higher frequency or severity PSU classes were associated with frequent injection drug use, sharing needles and paraphernalia, high-risk sexual behaviours, as well as experiences of adversities, such as homelessness, incarceration, and poor mental health., Conclusion: PSU patterns vary significantly across different subgroups of PWUO. The substantial heterogeneities among PWUO need to be acknowledged in substance use clinical practices and policy developments. Findings call for comprehensive interventions that recognize these within-group diversities and address the varying needs of PWUO., Competing Interests: Declarations of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Over the past century, evidence has emerged that endocrine disrupting chemicals (EDCs) have an impact on reproductive health. An increased frequency of reproductive disorders has been observed worldwide in both wildlife and humans that is correlated with accidental exposures to EDCs and their increased production. Epidemiological and experimental studies have highlighted the consequences of early exposures and the existence of key windows of sensitivity during development. Such early in life exposures can have an immediate impact on gonadal and reproductive tract development, as well as on long-term reproductive health in both males and females. Traditionally, EDCs were thought to exert their effects by modifying the endocrine pathways controlling reproduction. Advances in knowledge of the mechanisms regulating sex determination, differentiation and gonadal development in fish and rodents have led to a better understanding of the molecular mechanisms underlying the effects of early exposure to EDCs on reproduction. In this manuscript, we review the key developmental stages sensitive to EDCs and the state of knowledge on the mechanisms by which model EDCs affect these processes, based on the roadmap of gonad development specific to fish and mammals., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To enumerate pregnancy outcomes for a representative sample of women in Australia surveyed in 2012-2013 (primary aim) and compare these with women surveyed in 2001-2002 (secondary aim)., Methods: Computer-assisted telephone interviews with over 10,000 women aged 16-69 years (participation rate 68.4%). Results are weighted for chance of selection and to reflect the population as a whole., Results: Of women with experience of vaginal intercourse, 75.1% had ever been pregnant, 18.4% reported difficulties getting pregnant and 10.0% had had fertility treatment. Of those who had been pregnant, 91.3% had ever had a live birth, 34.3% a miscarriage, 22.8% an abortion and 2.3% a stillbirth; 0.9% had relinquished a child for adoption. The proportion first pregnant in their 30s was 11% among women aged 60-69 and 26% among those aged 40-49. Fewer older women reported difficulties getting pregnant. Of the 21,882 pregnancies reported, 70% led to live births and 10% were terminated. Compared with our 2001-2002 survey, fewer women reported ever having been pregnant. Giving up newborns for adoption has become very rare., Conclusions: Falling fertility since the 1960s reflects greater access to contraception and abortion and higher opportunity costs of childbearing. Implications for public health: These findings on women's lifetime reproductive experiences complement routine annual data collections., (© 2021 The Authors.)

Background: A remarkable reduction in AIDS-related mortality has been achieved through the widespread use of triple combination antiretroviral therapy, considerably increasing the life expectancy of people living with HIV (PLWH). However, these survival gains are now at risk in North America due to an unprecedented public health emergency: the deadly drug overdose epidemic. Drug overdoses are now the leading cause of unintentional death in British Columbia (BC), Canada and the United States due to synthetic opioids (e.g., fentanyl) in illegal markets. This manuscript aimed to estimate the effect of overdose mortality on life expectancy and identify covariates associated with the hazard for overdose mortality in the presence of competing risk among PLWH in BC., Methods: Those eligible were aged ≥20 years, initiated antiretroviral therapy from 1-Apr-1996 to 30-Dec-2017, and were followed until 31-Dec-2017, last contact or death date. We estimated the potential gains in life expectancy from abridged life tables. We modelled the association between covariates and the cause-specific hazard for overdose mortality, accounting for mortality of other causes as a competing risk., Results: Among the 10,362 PLWH, 3% experienced overdose mortality. The life expectancy at age 20 increased by 8.7 years from 2002-2007 to 2008-2013 compared to only 3.0 years from 2008-2013 to 2014-2017. The potential gain in life expectancy was 3.3 years at age 20 during the ongoing overdose epidemic (2014-2017). There were gender differences in life expectancies throughout the study period. People who have ever injected drugs, women and viral load monitoring non-compliance were key covariates associated with an increased hazard of overdose mortality., Conclusion: Survival gains among PLWH have been considerably reduced due to the ongoing overdose epidemic., Competing Interests: Declarations of Interest JSGM has received institutional grants from Gilead Sciences, J&J, Merck, ViiV Healthcare, and a Knowledge Translation Award from the Canadian Institutes of Health Research. JSGM also served as an advisor to the Government of Canada and the Government of British Columbia in the last year. All other authors declare no competing interests., (Copyright © 2021. Published by Elsevier B.V.)

Vascular smooth muscle cells are unusual in that differentiated, contractile cells possess the capacity to "de-differentiate" into a synthetic phenotype that is characterized by being replicative, secretory, and migratory. One aspect of this phenotypic modulation is a shift from voltage-gated Ca 2+ signalling in electrically coupled, differentiated cells to increased dependence on store-operated Ca 2+ entry and sarcoplasmic reticulum Ca 2+ release in synthetic cells. Conversely, an increased voltage-gated Ca 2+ entry is seen when proliferating A7r5 smooth muscle cells quiesce. We asked whether this change in Ca 2+ signalling was linked to changes in the expression of the phenotype-regulating transcriptional co-activator myocardin or α-smooth muscle actin, using correlative epifluorescence Ca 2+ imaging and immunocytochemistry. Cells were cultured in growth media (DMEM, 10% serum, 25 mM glucose) or differentiation media (DMEM, 1% serum, 5 mM glucose). Coinciding with growth arrest, A7r5 cells became electrically coupled, and spontaneous Ca 2+ signalling showed increasing dependence on L-type voltage-gated Ca 2+ channels that were blocked with nifedipine (5 μM). These synchronized oscillations were modulated by ryanodine receptors, based on their sensitivity to dantrolene (5 μM). Actively growing cultures had spontaneous Ca 2+ transients that were insensitive to nifedipine and dantrolene but were blocked by inhibition of the sarco-endoplasmic reticulum ATPase with cyclopiazonic acid (10 μM). In cells treated with differentiation media, myocardin and αSMA immunoreactivity increased prior to changes in the Ca 2+ signalling phenotype, while chronic inhibition of voltage-gated Ca 2+ entry modestly increased immunoreactivity of myocardin. Stepwise regression analyses suggested that changes in myocardin expression had a weak relationship with Ca 2+ signalling synchronicity, but not frequency or amplitude. In conclusion, we report a 96-well assay and analytical pipeline to study the link between Ca 2+ signalling and smooth muscle differentiation. This assay showed that changes in the expression of two molecular differentiation markers (myocardin and αSMA) tended to precede changes in the Ca 2+ signalling phenotype., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Speaking involves both retrieving the sounds of a word (phonological planning) and realizing these selected sounds in fluid speech (articulation). Recent phonetic research on speech errors has argued that multiple candidate sounds in phonological planning can influence articulation because the pronunciation of mis-selected error sounds is slightly skewed towards unselected target sounds. Yet research to date has only examined these phonetic distortions in experimentally-elicited errors, leaving doubt as to whether they reflect tendencies in spontaneous speech. Here, we analyzed the pronunciation of speech errors of English-speaking adults in natural conversations relative to matched correct words by the same speakers, and found the conjectured phonetic distortions. Comparison of these data with a larger set of experimentally-elicited errors failed to reveal significant differences between the two types of errors. These findings provide ecologically-valid data supporting models that allow for information about multiple planning representations to simultaneously influence speech articulation., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Dementia of Alzheimer's type (DAT) is associated with devastating and irreversible cognitive decline. Predicting which patients with mild cognitive impairment (MCI) will progress to DAT is an ongoing challenge in the field. We developed a deep learning model to predict conversion from MCI to DAT. Structural magnetic resonance imaging scans were used as input to a 3-dimensional convolutional neural network. The 3-dimensional convolutional neural network was trained using transfer learning; in the source task, normal control and DAT scans were used to pretrain the model. This pretrained model was then retrained on the target task of classifying which MCI patients converted to DAT. Our model resulted in 82.4% classification accuracy at the target task, outperforming current models in the field. Next, we visualized brain regions that significantly contribute to the prediction of MCI conversion using an occlusion map approach. Contributory regions included the pons, amygdala, and hippocampus. Finally, we showed that the model's prediction value is significantly correlated with rates of change in clinical assessment scores, indicating that the model is able to predict an individual patient's future cognitive decline. This information, in conjunction with the identified anatomical features, will aid in building a personalized therapeutic strategy for individuals with MCI., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background Aims: Studies examining crowdfunding campaigns for stem cell interventions have typically focused on campaigns seeking funds to send individuals to businesses marketing unlicensed and unproven stem cell products. However, some crowdfunding campaigns identify academic medical centers as destinations for individuals seeking access to stem cell products provided either in clinical studies or on an expanded access basis. This study examines crowdfunding campaigns seeking funds to enable children diagnosed with autism spectrum disorder access to stem cell interventions., Methods: This study compares and contrasts crowdfunding campaigns, identifying an international stem cell clinic marketing a purported umbilical cord blood-derived stem cell treatment for autism spectrum disorder, with campaigns soliciting donations intended to help children with autism spectrum disorder either participate in clinical studies or obtain expanded access to stem cell products provided at an academic medical center in the US., Results: Campaigns connected to both sites contained inaccurate claims. However, campaigns identifying the international clinic as the intended destination site made stronger claims about efficacy and were more reliant upon testimonials than campaigns listing the US-based academic medical center as the planned clinical site. Acknowledging these important distinctions, clinical studies and press releases associated with the academic medical center played an important role in lending the perception of credibility to the putative stem cell treatments marketed by the international clinic., Conclusions: The study's findings emphasize how important it is for researchers at academic medical centers and comparable research facilities to avoid engaging in stem cell hyperbole; highlight the preliminary nature of early clinical studies; ensure that any claims about safety and efficacy are based upon robust and reliable evidence; and promote responsible science communication by exercising restraint when crafting press releases, conducting media interviews and otherwise publicizing clinical research findings., (Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: Cross-country comparisons of coronavirus disease (COVID-19) have largely been applied to mortality analyses. The goal of this analysis is to explore predictors of COVID-19 testing through cross-country comparisons, to better inform international health policies., Methods: Testing and case-based data were amassed from Our World in Data, and information regarding predictors was gathered from the World Bank. We investigate Human Development Index (HDI), health expenditure, universal health coverage (UHC), urban population, service industry workers (%), and air pollution as predictors. We explored testing data through July 31, 2020, or most recently available, using case-indexing methods, which involve synchronizing countries by date of first reported COVID-19 case as an index date and normalizing to the cumulative tests 25 days post-index date. Three multivariable linear regression models were built in a stepwise fashion to explore the association between the indexed number of COVID-19 tests and HDI scores., Results: A total of 86 countries were included in the final analytical sample, excluding countries with missing data. HDI and urban population were found to be significantly associated with testing levels., Conclusions: Results suggest that social conditions and government capacity remain consistently salient in the consideration of testing rates. International efforts to assist low-HDI countries are needed to support the global COVID-19 response., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

IL-33 induces airway inflammation and hyper-responsiveness in respiratory diseases. Although defined as a therapeutic target, there are limited studies that have comprehensively investigated IL-33-mediated responses in the lungs in vivo. In this study, we characterized immunological and physiological responses induced by intranasal IL-33 challenge, in a mouse model. We identified specific cytokines, IL-4, IL-5, IL-6, IL-10, IP-10 and MIP1-α, that are increased in bronchoalveolar lavage and lung tissues by IL-33. Using transcriptomics (RNA-Seq) we demonstrated that 2279 transcripts were up-regulated and 1378 downregulated (≥ 2-fold, p < 0.01) in lung tissues, in response to IL-33. Bioinformatic interrogation of the RNA-Seq data was used to predict biological pathways and upstream regulators involved in IL-33-mediated responses. We showed that the mRNA and protein of STAT4, a predicted upstream regulator of IL-33-induced transcripts, was significantly enhanced in the lungs following IL-33 challenge. Overall, this study provides specific IL-33-induced molecular targets and endpoints that can be used as a resource for in vivo studies, e.g. in preclinical murine models examining novel interventions to target downstream effects of IL-33., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: It is unclear whether cadmium (Cd) exposure during fetal brain development is associated with child neurobehavior., Objective: To examine the potential associations between Cd exposure during pregnancy and neurobehavior among children., Methods: We used data from 276 children in the Health Outcomes and Measures of the Environment (HOME) Study, a well-established prospective pregnancy and birth cohort. We measured maternal urinary Cd concentrations at 26 weeks of gestation. For cognitive function, we assessed Mental Development Index (MDI) and Full-Scale Intelligence Quotient (FSIQ) using the Bayley Scales of Infant Development-II, the Wechsler Preschool and Primary Scales of Intelligence-III, or the Wechsler Intelligence Scales for Children-IV at ages 1, 2, 3, 5, and 8 years. We assessed child behaviors using the Behavior Assessment System for Children-2 at ages 2, 3, 4, 5, and 8 years, yielding four composite measures: Externalizing Problems, Internalizing Problems, Behavioral Symptoms Index, and Adaptive Skills. We used linear mixed models with covariate adjustment to estimate the associations between maternal urinary Cd concentrations and child neurobehavior., Results: We categorized study participants into three groups based on maternal urinary Cd concentrations (Group 1: < limit of detection (LOD), Group 2: 0.06-0.22 μg/g creatinine, Group 3: ＞0.22 μg/g creatinine). In linear mixed models adjusting for maternal and child characteristics, maternal urinary Cd levels were not significantly associated with cognitive function at ages 1, 2, 3, 5, and 8 years or with behavioral composite measures at 2, 3, 4, 5, and 8 years., Conclusions: No significant associations were observed between maternal urinary Cd and cognitive or behavioral measures in children at 1-8 years of age in this study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Male and female condoms are the only available Multipurpose Prevention Technologies (MPTs) that can prevent unintended pregnancy and sexually transmitted infections including HIV. If used correctly and consistently, condoms can provide levels of pregnancy protection similar to many hormonal methods. Condoms remain one of the most common methods used at first sexual intercourse and are relied on as a current use of contraception by adolescents in many regions of the world. Male and female condoms are safe and require no prescription; in particular male condoms are generally easy to access at low cost. Female condoms are more expensive than male condoms and less accessible; however, they have the advantage of being a female-initiated method. Condom users may experience some common challenges; however, recent advances in condom technology have led to new designs and modifications of existing products to improve quality and make them more attractive, acceptable and pleasurable for consumers and increase its use., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction: Youth who use drugs (YWUD) are vulnerable to experience or encounter drug related overdose deaths. Fentanyl has increased the risks, calling greater attention to overdose. In response, there have been increases in harm reduction services and policies such as the Good Samaritan Drug Overdose Act (GSDOA) which exempts people who witness an overdose and call 9-1-1 from being charged for possession of drugs. However, fear of police continues to be a barrier to calling 9-1-1. This paper focuses on the experiences of youth with police in overdose situations and their knowledge of GSDOA., Methods: Youth, aged 16-30, who had used drugs at least weekly, and had encountered police in the past year were recruited between May 2017 and June 2018 in three non-metropolitan cities in British Columbia, Canada. 38 participants completed qualitative interviews asking them about their experiences with police, overdose, decisions to call 9-1-1, and their understanding of the GSDOA. Their responses were coded in NVIVO and analyzed using interpretive description., Results: For many YWUD in this study, overdoses are an ever-present part of their lives and fear of fentanyl has left them concerned for themselves and others. Negative experiences occurred when police used their power without benefit to youth or were rough or disrespectful, without care for the person overdosing. Youth saw police in a positive light if they were compassionate, stepping aside for paramedics or reviving someone experiencing an overdose. Youth had very mixed knowledge of the GSDOA and were concerned about criminalization if they called 9-1-1., Conclusions: Collaboration with police and local stakeholders is required to address the concerns of YWUD and to increase awareness and penetration of policies such as the GSDOA. Changes to policing cultures that prioritize health rather than criminalize YWUD may increase youth's trust of police and increase calls to 9-1-1., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The zebrafish has proven to be an excellent organism for manipulation of its genome from a long history of transcript down-regulation using morpholino oligimers to more recent genome editing tools such as CRISPR-Cas9. Early forward and reverse genetic screens significantly benefited from the transparency of zebrafish embryos, allowing cardiac development as a function of genetics to be directly observed. However, gradual loss of transparency with subsequent maturation limited many of these approaches to the first several days post-fertilization. As many genes are developmentally regulated, the immature phenotype is not entirely indicative of that of the mature zebrafish. For accurate phenotyping, subsequent developmental stages including full maturation must also be considered. In adult zebrafish, cardiac function can now be studied in great detail due both to the size of the hearts as well as recent technological improvements. Because of their small size, zebrafish are particularly amenable to high frequency echocardiography for detailed functional recordings. Although relatively small, the hearts are easily excised and contractile parameters can be measured from whole hearts, heart slices, individual cardiomyocytes and even single myofibrils. Similarly, electrical activity can also be measured using a variety of techniques, including in vivo and ex vivo electrocardiograms, optical mapping and traditional microelectrode techniques. In this report, the major advantages and technical considerations of these physiological tools are discussed., (Copyright © 2019. Published by Elsevier B.V.)

Despite the proliferation of fentanyl and fentanyl-adulterated opioids in North America, the impacts of this drug market change on injection initiation processes have not been examined. With the aim of informing structural interventions to address injection initiation and related harms, we explore how people who inject drugs (PWID) in Vancouver, Canada understand and navigate social norms of initiating others into injecting within the context of an overdose crisis. In-depth qualitative interviews were conducted with 19 PWID who reported helping someone inject for the first time. Participants were recruited from two cohort studies of PWID. Participants articulated moral dilemmas about assisting others with injecting. While participants described a 'moral code' prohibiting assisting injection-naïve individuals, this code was not the sole consideration shaping social action around injection initiation. Rather, PWID exercised agency about whether and how to assist novice injectors within the context of constraining and enabling social norms around practicing interpersonal responsibility. Changes to the drug market heightened feelings of moral culpability and criminal liability among PWID who assisted others into injection, given that injecting heightened initiates' risk of overdose. These concerns operated in tension with the aim of protecting novice injectors from harms associated with an increasingly potent and unpredictable drug supply by providing them with injection assistance, education and supervision. Our analysis of how PWID practice interpersonal responsibility helps conceptualise how 'moral codes' prohibiting initiation assistance are managed and negotiated amidst structural vulnerability. Structural interventions reducing the vulnerability of novice injectors should be prioritized, including the implementation of supervised injection sites allowing for assisted injection, Good Samaritan laws, and policy changes conducive to a safer drug supply., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is associated with disrupted circadian rhythms and sleep, which are thought to reflect an impairment of internal circadian timekeeping that contribute to clinical symptoms and disease progression. To evaluate these hypotheses, a suitable preclinical model of AD is needed. We performed a comprehensive assessment of circadian rhythms and sleep in the APP swe /PS1 dE9 (APP/PS1) mouse model using long-term in vivo electroencephalogram (EEG) monitoring and behavioral assays from 5 to 22 months of age. APP/PS1 mice were crossed with a PERIOD2::LUCIFERASE (PER2::LUC) mouse model to evaluate synchrony among peripheral circadian oscillators. The APP/PS1 mice exhibited a mild but persistent phase delay of nocturnal activity onset in 12:12h light:dark conditions, as well as a shift toward higher frequencies in the EEG power spectra compared to littermate controls. Our results suggest that APP/PS1 mice may not be the optimal preclinical model for studying the specific circadian changes associated with AD but that quantitative EEG may offer a sensitive measure of AD-associated changes in sleep quality that can be modeled in APP/PS1 mice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Breast cancer rates vary internationally and between immigrant and non-immigrant populations. We describe breast cancer incidence by birth region and country in British Columbia, Canada., Methods: We linked population-based health and immigration databases for a population with >1.29 million immigrants to assess breast cancer incidence among immigrant and non-immigrant women. We report age-standardized incidence ratios (SIRs) by birth region and country using non-immigrant women as the standard., Results: SIRs varied widely by both birth country and region. Low rates were found for South (SIR = 0.52, 95% CI: 0.47,0.59) and East Asian (SIR = 0.75, 95% CI: 0.72,0.79) women and a higher rate for Western Europeans (SIR = 1.15, 95% CI: 1.01,1.30)., Conclusion: There is considerable variation in SIRs across some of British Columbia's largest immigrant populations and several demonstrate significantly different risk profiles compared to non-immigrants. These findings provide unique data to support breast cancer prevention and control., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Bisphenol A (BPA) is a high production volume chemical and because of its use in many consumer products, exposure is ubiquitous. Gestational BPA exposure has been associated with excess adiposity in rodent studies, but not consistently in human studies. We investigated the relation between gestational BPA exposure and early childhood adiposity in a prospective cohort study of 719 mother-child pairs., Methods: We used data from the MIREC Study, a prospective Pan-Canadian pregnancy and birth cohort study. We measured BPA in urine samples collected at an average of 12.1 weeks (range: 6.3-15 weeks) gestation and measured children's weight, height, waist/hip circumference, and subscapular/triceps skinfold thickness at an average age of 3.5 years (range: 1.9-6.2). We estimated covariate-adjusted associations of log 2 -transformed BPA concentrations with child adiposity measures and examined whether these associations differed in boys and girls., Results: Median BPA concentrations were 0.8 ng/mL (IQR: 0.5-1.4). Among both boys and girls, each 2-fold increase in BPA concentrations was associated with higher waist-to-hip ratio (β: 0.003; 95% CI: 0.001, 0.005). The association of BPA with waist circumference and subscapular skinfold thickness was modified by sex (sex x BPA interaction p-values<0.2). In girls, each 2-fold increase in BPA concentrations was associated with a 0.2 cm (95% CI: 0.0, 0.5) and 0.15 mm (95% CI: 0.01, 0.30) increase in waist circumference and subscapular skinfolds, respectively. Associations were generally null or slightly inverse in boys., Conclusions: In this cohort, gestational urinary BPA concentrations were associated with subtle increases in girl's central adiposity during early childhood., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Opioid agonist treatment (OAT) is an effective biomedical intervention to manage opioid use disorder among persons who inject drugs (PWID). Preliminary evidence suggests that OAT may also disrupt the social communicability of injection drug use (IDU) practices by established PWID. We therefore aim to investigate the association between OAT enrollment and initiating others into IDU among PWID in Vancouver, Canada., Methods: Preventing Injecting by Modifying Existing Responses (PRIMER; NIDA DP2-DA040256-01) is a prospective multi-cohort study seeking to identify structural interventions that reduce the risk that PWID initiate others into IDU. The present analysis was conducted using data from a participating cohort of PWID in Vancouver, Canada, between December 2014 and May 2017. Multivariable logistic regression models were built to assess the association between reporting active (i.e., within the past six months) OAT enrollment and assisting others in injection initiation. A final model was determined using a manual stepwise approach whereby covariates were excluded if their removal altered the coefficient of interest by <5%., Results: Participants (n = 1740) were predominantly male (62.3%); 35.1% reported daily injecting (n = 611); 860 (49.4%) reported active OAT enrollment, and 80 (4.6%) reported recently providing injection initiation assistance. In a multivariable model, participants who reported active OAT enrollment had significantly lower odds of recently providing injection initiation assistance (Adjusted Odds Ratio = 0.52, 95% Confidence Interval: 0.31-0.87, P = 0.01)., Conclusion: Results suggest a protective association between OAT and the expansion of IDU practices among vulnerable populations, suggesting its potential use as 'addiction treatment as prevention.', (Copyright © 2019. Published by Elsevier B.V.)

Objective: In humans, loss-of-function mutations in the gene encoding pregnancy-associated pregnancy protein-A2 cause short stature and slightly reduced bone density. The goal of this study was to determine the effects of Pappa2 deletion on bone in mice., Design: Pappa2 deletion mice and littermate controls were culled at 10, 19 or 30 weeks of age and femurs were analysed by micro-computed tomography. Serum markers of bone turnover and insulin-like growth factor binding protein 5 (IGFBP-5), a proteolytic target of PAPP-A2, were measured by ELISA., Results: At 10 and 19 weeks of age, Pappa2 deletion mice had slightly reduced trabecular parameters, but by 19 weeks of age, female deletion mice had increased cortical tissue mineral density, and this trait was increased by a small amount in deletion mice of both sexes at 30 weeks. Cortical area fraction was increased in Pappa2 deletion mice at all ages. Deletion of Pappa2 increased circulating IGFBP-5 levels and reduced markers of bone turnover (PINP and TRACP 5b)., Conclusions: PAPP-A2 contributes to the regulation of bone structure and mass in mice, likely through control of IGFBP-5 levels. The net effect of changes in bone formation and resorption depend on sex and age, and differ between trabecular and cortical bone., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Accelerated placental maturation is considered a sign of maternal vascular malperfusion, and is often interpreted as an adaptive, compensatory response by the placenta. We tested this interpretation by comparing outcomes in pregnancies with and without accelerated maturation., Methods: Using data from the National Collaborative Perinatal Project, we categorized preterm placentas (24-34 weeks, inclusive; 2525 births) by whether they showed placental villous hypermaturation (PVH), i.e., had the appearance of a placenta of 37 weeks or over upon microscopic examination. We assessed whether PVH was associated with maternal race, maternal BMI, fetal sex, type of preterm birth, preeclampsia, signs of infection or inflammation or placental abruption. We also assessed whether placentas showing PVH were associated with improved outcomes in terms of survival, Apgar score, or oxygen use., Results: PVH was more common in preeclamptic pregnancies and less common in pregnancies complicated by placental abruption or showing signs of placental infection or inflammation. Adjusting for potentially confounding factors, PVH was associated with reduced odds of fetal death, death between birth and 120 days of age, low Apgar scores and oxygen use. PVH was also associated with higher birthweights for gestational age. When correcting for the effect of birthweight, the association between PVH and reduced fetal and neonatal death remained significant., Discussion: Accelerated placental maturation, as manifested by PVH, is associated with improved outcomes. Our work therefore supports the hypothesis that accelerated maturation is a compensatory response by the placenta to improve its transport capacity in specific pregnancy complications., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Walkability indices are used to characterize the relationship between health and place. Indices make assumptions that affect analysis of the built environment and resulting walkability scores. This study compares three walkability indices created by health researchers focusing on the methods, variables, and walkability scores resulting from differences in definitions and methods. This paper deconstructs the walkability algorithms utilized by each index and rebuilds them in Vancouver, Canada. We find that neighbourhoods in the northern core closer to the downtown area have similar walkability scores across all three indices, while the outer peripheral neighbourhoods with moderate to low walkability have more variation in walkability scores across indices. Most walkability variables - residential density, street connectivity, and land-use - lack a rationale for inclusion, often assumed by researchers. Walkability indices used in health research prove to be incongruent with each other and misrepresentative of actual human behavior. We explore the impact of variable selection and methodologies on indices in the interest of more rigorous health research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Informal recycling refers to the street-based collection of discarded materials for reuse, resale, or return to a recycling facility for money. While qualitative research has explored experiences and perceptions of informal recycling, little is known about the scope and exposures associated with informal recycling among people who use drugs (PWUD)., Methods: Using data from two prospective longitudinal cohorts of PWUD, we examined the prevalence of informal recycling and its association with social, structural and health risks, including criminal justice system involvement., Results: Between June 2010 and May 2015, of 1664 participants, 557 (33.5%) reported engaging in informal recycling during the study period. In multivariable generalised estimating equations (GEE) analyses, informal recycling was positively associated with injection drug use (Adjusted Odds Ratio (AOR) = 1.43, 95% Confidence Interval (CI) 1.21-1.68), public injection (AOR = 1.27, 95% CI 1.09-1.49), methamphetamine use (AOR = 1.35, 95% CI 1.05-1.72), difficulty finding harm reduction equipment (AOR = 1.16, 95% CI 1.02-1.32), and police interactions (AOR = 1.35, 95% CI 1.18-1.55). Sub-analyses revealed PWUD engaged in informal recycling were more likely to be told to move on, ticketed, stopped for jaywalking, and directed to services by police., Conclusions: These findings suggest informal recycling as a situated practice for PWUD, with potential indications for higher-risk drug use, experiencing greater surveillance, and difficulty accessing health and addiction treatment services. This research highlights the significance of the broader risk environment and the need for health-promoting policies for socioeconomically marginalised PWUD engaged in informal recycling., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

While combination antiretroviral therapy (cART) has successfully converted HIV to a chronic but manageable infection in many parts of the world, HIV continues to persist within latent cellular reservoirs, which can become reactivated at any time to produce infectious virus. New therapies are therefore needed not only for HIV suppression but also for containing or eliminating HIV reservoirs. Compounds derived from plant, marine, and other natural products have been found to combat HIV infection and/or target HIV reservoirs, and these discoveries have substantially guided current HIV therapy-based studies. Here we summarize the role of natural product-derived compounds in current HIV suppression, remission, and cure strategies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: We sought to examine the association between childhood asthma and self-reported maternal smoking during pregnancy (MSDP) after adjusting for a range of exposure misclassification scenarios using a Bayesian approach that incorporated exposure misclassification probability estimates from the literature., Methods: Self-reported MSDP and asthma data were extracted from National Health and Nutrition Examination Survey 2011-2012. The association between self-reported MSDP and asthma was adjusted for exposure misclassification using a Bayesian bias model approach., Results: We included 3074 subjects who were 1-15 years of age, including 492 asthma cases. The mean (SD) of age of the participants was 8.5 (4.1) and 7.1 (4.2) years and the number (percentage) of female was 205 (42%) and 1314 (51%) among asthmatic and nonasthmatic groups, respectively. The odds ratio (OR) for the association between self-reported MSDP and asthma in logistic regression adjusted for confounders was 1.28 (95% confidence interval: 0.92, 1.77). In a Bayesian analysis that adjusted for exposure misclassification using external data, we found different ORs between MSDP and asthma by applying different priors (posterior ORs 0.90 [95% credible interval {CRI}: 0.47, 1.60] to 3.05 [95% CRI: 1.73, 5.53] in differential and 1.22 [CRI 95%: 0.62, 2.25] to 1.60 CRI: 1.18, 2.19) in nondifferential misclassification settings., Conclusions: Given the assumptions and the accuracy of the bias model, the estimated effect of MSDP on asthma after adjusting for misclassification was strengthened in many scenarios., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: The ratio of birthweight to placental weight (BW:PW) is often used as a measure of placental efficiency in humans and animals. However, ratios have properties that are known to lead to spurious results. An alternative approach is the use of residuals from regression, which reflect whether birthweight is higher or lower than expected for a given placental weight, given the population pattern. We hypothesized that biologically meaningful measures of placental efficiency would differ between placentas with and without pathology, and between adverse and normal perinatal and postnatal outcomes., Methods: We examined associations between measures of placental efficiency (BW:PW ratio or residuals) and placental pathology, Apgar scores and infant death using National Collaborative Perinatal Project data (4645 preterm births and 28497 term births)., Results: BW:PW ratios and residuals were significantly lower in placentas showing pathologies including signs of large infarcts or hemorrhage, although many of these differences were small. Low BW:PW ratios and residuals were also associated with low Apgar scores and increased risk of postnatal death. Whereas residuals were lower in term placentas that appeared immature by microscopic examination, the opposite was true for BW:PW ratios., Conclusion: The BW:PW ratio produced an artefact whereby histologically less mature placentas at term appeared to be more "efficient" than mature placentas, illustrating a known problem with the use of ratios. For other traits, residuals generally showed differences between placentas with and without pathology that were as great as those seen with BW:PW ratios, and often showed stronger associations with adverse outcomes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Exposure to poly- and perfluoroalkyl substances (PFAS), ubiquitous and persistent environmental contaminants, could be associated with adverse health outcomes, but there are limited longitudinal data assessing patterns and predictors of exposure during childhood. We quantified concentrations of eight different PFAS in sera collected from women during pregnancy and children at delivery and ages 3 and 8 years in 367 mother-child pairs enrolled in a prospective cohort from 2003 to 2006. In general, median childhood PFAS concentrations increased from birth to age 3 and then decreased by age 8. Maternal serum PFAS concentrations during pregnancy were strongly correlated with cord serum concentrations (0.76 < r < 0.94), but were weakly correlated with childhood concentrations (0.12 < r < 0.30). Several sociodemographic factors were associated with maternal PFAS concentrations, including income, race, and parity. In children, serum PFAS concentrations were associated with maternal age at delivery, race, parity, and child age. Breastfeeding duration was positively associated with childhood PFAS concentrations at ages 3 and 8 years. In addition, stain repellant use was associated with higher perfluorooctanoic acid and perfluorohexane sulfonic acid concentrations at age 8 years. Serum PFAS concentrations are higher during early childhood, a potentially sensitive period of development, and were highest among breastfed children., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Treatment as Prevention (TasP) leading to increased HIV treatment optimism among men who have sex with men (MSM) has been previously associated with behavioural risk compensation, though not yet via crystal methamphetamine (CM) use. Among HIV-negative MSM in a TasP environment, this study aimed to investigate the prevalence of recent CM use over time, examine the association between HIV treatment optimism and CM use and initiation, and identify correlates of recent CM use and predictors of CM initiation., Methods: Using data from a prospective behavioural cohort study of sexually active MSM in the Vancouver area, we used multi-level generalized mixed effect models to evaluate temporal trends in CM use, univariable and multivariable logistic regression to identify covariates of recent CM use, and univariable and multivariable survival analysis to identify predictors of CM initiation., Results: Of 497 HIV-negative cohort participants, 10.3% reported any recent CM use at enrollment. From 2012-2016, there were no statistically significant temporal trends in overall CM use or with routes of administration. In multivariable logistic regression analyses, HIV treatment optimism was not associated with recent CM use (not retained in final model) or CM initiation (aHR = 1.06, 95% CI:0.98-1.15). Significant correlates of CM use include recent gamma-hydroxybutyrate (GHB) and ecstasy use, and having received/given drugs for sex., Conclusions: Among HIV-negative MSM in Vancouver, HIV treatment optimism does not appear to be independently associated with CM use or initiation of use, though use of CM was both prevalent and stable over time., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Perfluorooctanoic acid (PFOA), a perfluoroalkyl substance, is commonly detected in the serum of pregnant women and may impact fetal development via epigenetic re-programming. In a pilot study, we explored associations between serum PFOA concentrations during pregnancy and offspring peripheral leukocyte DNA methylation at delivery in women with high (n = 22, range: 12-26ng/mL) and low (n = 22, range: 1.1-3.1ng/mL) PFOA concentrations. After adjusting for cell type, child sex, and income, we did not find differences in CpG methylation in the two exposure groups that reached epigenome-wide significance. Among the 20 CpGs with the lowest p-values we found that seven CpG sites in three genes differed by exposure status. In a confirmatory cluster analysis, these 20 CpGs clustered into two groups that perfectly identified exposure status. Future studies with larger sample sizes should confirm these findings and determine if PFOA-associated changes in DNA methylation underlie potential health effects of PFOA., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Direct acting antivirals (DAA) raise the possibility of eliminating Hepatitis C virus (HCV) among people who inject drugs (PWID). However, concerns regarding treatment retention and reinfection challenge implementation efforts. Opioid agonist treatment (OAT) provides an opportunity to engage HCV-positive PWID into DAA-based treatment. Our objective was to identify when OAT adherence sufficiently improved to inform DAA initiation in OAT settings, assuming continuous OAT retention for at least twelve weeks is necessary to complete the DAA treatment course., Methods: This was a retrospective cohort study of HCV/HIV co-infected PWID from a population-level linked administrative database of people diagnosed and living with HIV in British Columbia, Canada between 01/1996 and 12/2013. We used monthly follow-up data after initial OAT entry and considered the effects of demographics, disease severity, and HIV and OAT treatment characteristics over time on the probability of subsequent OAT retention of ≥12 weeks, and ≥8 weeks for sensitivity analysis. We fit a generalized linear mixed model to the overall study population, and on stratified samples of those continuously engaged on combination antiretroviral therapy (≥95% ART adherence). A set of monthly indicator variables (months 1, …, 7, >7) were included to fulfil the study objective., Results: Our study included 1427 HCV/HIV co-infected PWID (39.0% female, 68.8% OAT-naïve). The odds of subsequent twelve-week retention in OAT were statistically significantly greater in month 3 versus month 1 (adjusted odds ratio: 1.18; 95% confidence interval: 1.02, 1.37); and the odds of subsequent 8-week retention in OAT were statistically significantly greater in month 2 versus month 1 (1.15, 95% CI: 1.02, 1.31). Among continuously ART-adherent individuals, the odds of subsequent twelve-week retention were not statistically significantly greater than in month 1 (month 2: 1.12 (0.82, 1.51); month 3: 1.08 (0.79, 1.47); month 4: 1.24 (0.91, 1.71))., Conclusion: We provide evidence that among HCV/HIV co-infected PWID, those retained in OAT for three or more months had higher odds of completing an additional twelve weeks of OAT, compared to no difference in those already receiving ART. These data may have implications for adherence to DAA therapy and further studies are needed to understand the optimal timing of DAA therapy in PWID receiving and not receiving OAT., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Prenatal exposure to organophosphate insecticides may be associated with autism spectrum disorders and related behaviors. This association may be modified by single nucleotide polymorphisms in the paraoxonase (PON1) enzyme., Objective: We examined the relationship of prenatal organophosphate insecticide biomarkers with reciprocal social, repetitive, and stereotypic behaviors in 8-year old children, and modification of this relationship by child PON1 polymorphisms., Methods: Among 224 pregnant women, we quantified concentrations of six nonspecific dialkyl phosphate (DAP) metabolites of organophosphate insecticides in two urine samples collected at ~16 and ~26 weeks gestation. When children were eight years old, we administered the Social Responsiveness Scale (SRS), a continuous measure of various dimensions of interpersonal behavior, communication, and repetitive/stereotypic behaviors. We estimated the association between a 10-fold increase in the sum of six DAP concentrations (ΣDAP) and SRS scores. We examined whether child PON1 192 and PON1 -108 genotypes modified this association., Results: After covariate adjustment, ΣDAP concentrations were not associated with SRS scores [β=-1.2; 95% confidence interval (CI): -4.0, 1.6]. Among children with the PON1 -108TT genotype, ΣDAP concentrations were associated with 2.5-point higher (95% CI: -4.9, 9.8) SRS scores; however, the association was not different from the 1.8-point decrease (95% CI: -5.8, 2.2) among children with PON1 -108CT/CC genotypes (ΣDAP × PON1 -108 p-value =0.54). The association between ΣDAP concentrations and SRS scores was not modified by PON1 192 (ΣDAP × PON1 192 p-value =0.89)., Conclusions: In this cohort, prenatal urinary DAP concentrations were not associated with children's social behaviors; these associations were not modified by child PON1 genotype., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Primary cilia are microtubule-based organelles found on most mammalian cell surfaces. They possess a soluble matrix and membrane contiguous with the cell body cytosol and plasma membrane, and yet, have distinct compositions that can be modulated to enable dynamic signal transduction. Here, we discuss how specialized ciliary compartments are established using a coordinated network of gating, trafficking and targeting activities. Cilium homeostasis is maintained by a size-selective molecular mesh that limits soluble protein entry, and by a membrane diffusion barrier localized at the transition zone. Bidirectional protein shuttling between the cell body and cilium uses IntraFlagellar Transport (IFT), and prenylated ciliary protein delivery is achieved through Lipidated protein IntraFlagellar Targeting (LIFT). Elucidating how these gates and transport systems function will help reveal the roles that cilia play in ciliary signaling and the growing spectrum of disorders termed ciliopathies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Accurate subtyping of ovarian carcinomas is an increasingly critical and often challenging diagnostic process. This work focuses on the development of an automatic classification model for ovarian carcinoma subtyping. Specifically, we present a novel clinically inspired contextual model for histopathology image subtyping of ovarian carcinomas. A whole slide image is modelled using a collection of tissue patches extracted at multiple magnifications. An efficient and effective feature learning strategy is used for feature representation of a tissue patch. The locations of salient, discriminative tissue regions are treated as latent variables allowing the model to explicitly ignore portions of the large tissue section that are unimportant for classification. These latent variables are considered in a structured formulation to model the contextual information represented from the multi-magnification analysis of tissues. A novel, structured latent support vector machine formulation is defined and used to combine information from multiple magnifications while simultaneously operating within the latent variable framework. The structural and contextual nature of our method addresses the challenges of intra-class variation and pathologists' workload, which are prevalent in histopathology image classification. Extensive experiments on a dataset of 133 patients demonstrate the efficacy and accuracy of the proposed method against state-of-the-art approaches for histopathology image classification. We achieve an average multi-class classification accuracy of 90%, outperforming existing works while obtaining substantial agreement with six clinicians tested on the same dataset., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In 2012, the Supreme Court of Canada (SCC) ruled that people living with HIV (PLWH) could face criminal charges if they did not disclose their serostatus before sex posing a "realistic possibility" of HIV transmission. Condom-protected vaginal sex with a low (i.e., <1500copies/mL) HIV viral load (VL) incurs no duty to disclose. Awareness and understanding of this ruling remain uncharacterized, particularly among marginalized PLWH., Methods: We used data from ACCESS, a community-recruited cohort of PLWH who use illicit drugs in Vancouver. The primary outcome was self-reported awareness of the 2012 SCC ruling, drawn from cross-sectional survey data. Participants aware of the ruling were asked how similar their understanding was to a provided definition. Sources of information from which participants learned about the ruling were determined. Multivariable logistic regression identified factors independently associated with ruling awareness., Results: Among 249 participants (39% female), median age was 50 (IQR: 44-55) and 80% had a suppressed HIV VL (<50copies/mL). A minority (112, 45%) of participants reported ruling awareness, and 44 (18%) had a complete understanding of the legal obligation to disclose. Among those aware (n=112), newspapers/media (46%) was the most frequent source from which participants learned about the ruling, with 51% of participants reporting that no healthcare providers had talked to them about the ruling. Ruling awareness was negatively associated with VL suppression (AOR:0.51, 95% CI:0.27,0.97) and positively associated with recent condomless sex vs. no sex (AOR:2.00, 95% CI:1.03,3.92)., Conclusion: Most participants were not aware of the 2012 SCC ruling, which may place them at risk of prosecution. Discussions about disclosure and the law were lacking in healthcare settings. Advancing education about HIV disclosure and the law is a key priority. The role of healthcare providers in delivering information and support to PLWH in this legal climate should be further explored., (Copyright © 2017. Published by Elsevier B.V.)

Background: Phthalate exposure is widespread. Prior research suggests that prenatal phthalate exposure may influence birth size and gestational duration, but published results have been inconsistent., Objective: We quantified the relationship between maternal urinary phthalate concentrations and infant birth weight z-scores, length, head circumference, and gestational duration., Methods: In a cohort of 368 women from the HOME Study, based in Cincinnati, OH, we measured nine phthalate metabolites representing exposure to six parent phthalate diesters in urine collected at approximately 16 and 26 weeks gestation. Infant birth size and gestational duration were abstracted from medical records. We used multivariable linear regression to estimate covariate adjusted associations between urinary phthalate metabolite concentrations and infant outcomes., Results: In unadjusted models, we observed a negative association between monoethyl phthalate (MEP) and birth weight z-scores, while mono-3-carboxypropyl phthalate (MCPP) was positively associated with gestational duration. After covariate adjustment, phthalate metabolite concentrations were no longer associated with birth size or gestational duration., Conclusions: In this cohort, urinary phthalate metabolite concentrations during pregnancy were not associated with infant birth size or gestational duration. Additional research is needed to determine if exposures during earlier periods of fetal development are associated with infant health., Competing Interests: The authors have no competing financial interests., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Neck pain (NP) is disabling and costly., Objectives: To assess the effectiveness of exercise on pain, disability, function, patient satisfaction, quality of life (QoL) and global perceived effect (GPE) in adults with NP., Methods: We searched computerised databases up to May 2014 for randomized controlled trials (RCTs) comparing exercise to a control in adults with NP with/without cervicogenic headache (CGH) or radiculopathy. Two reviewers independently conducted selection, data abstraction and assessed risk of bias. Meta-analyses were performed to establish pooled standardised mean differences (SMDp). The Grade of Recommendation, Assessment, Development and Evaluation (GRADE) was used to summarise the body of evidence., Main Results: The following exercises (27 trials) were supported by 'Moderate GRADE' evidence: For chronic NP, 1) cervico-scapulothoracic and upper extremity (UE) strengthening for moderate to large pain reduction immediately post treatment (IP) and at short-term (ST) follow-up; 2) scapulothoracic and UE endurance training for a small pain reduction (IP/ST); 3) cervical, shoulder and scapulothoracic strengthening and stretching exercise for a small to large pain reduction in the long-term (LT) (SMDp -0.45 [95%CI: -0.72 to -0.18]) and function improvement; 4) cervico-scapulothoracic strengthening/stabilisation exercises for pain and function at intermediate-term (IT) (SMDp -14.90 [95%CI: -22.40 to -7.39]). 5) mindfulness exercises (Qigong) for minor improved function but not GPE (ST). For chronic CGH, cervico-scapulothoracic strengthening and endurance exercises including pressure biofeedback for small/moderate improvement of pain, function and GPE (IP/LT)., Authors' Conclusions: Specific strengthening exercises of the neck, scapulothoracic and shoulder for chronic NP and chronic CGH are beneficial. Future research should explore optimal dosage., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Acute brain injury is a common cause of death and critical illness in children and young adults. Fundamental management focuses on early characterization of the extent of injury and optimizing recovery by preventing secondary damage during the days following the primary injury. Currently, bedside technology for measuring neurological function is mainly limited to using electroencephalography (EEG) for detection of seizures and encephalopathic features, and evoked potentials. We present a proof of concept study in patients with acute brain injury in the intensive care setting, featuring a bedside functional imaging set-up designed to map cortical brain activation patterns by combining high density EEG recordings, multi-modal sensory stimulation (auditory, visual, and somatosensory), and EEG source modeling. Use of source-modeling allows for examination of spatiotemporal activation patterns at the cortical region level as opposed to the traditional scalp potential maps. The application of this system in both healthy and brain-injured participants is demonstrated with modality-specific source-reconstructed cortical activation patterns. By combining stimulation obtained with different modalities, most of the cortical surface can be monitored for changes in functional activation without having to physically transport the subject to an imaging suite. The results in patients in an intensive care setting with anatomically well-defined brain lesions suggest a topographic association between their injuries and activation patterns. Moreover, we report the reproducible application of a protocol examining a higher-level cortical processing with an auditory oddball paradigm involving presentation of the patient's own name. This study reports the first successful application of a bedside functional brain mapping tool in the intensive care setting. This application has the potential to provide clinicians with an additional dimension of information to manage critically-ill children and adults, and potentially patients not suited for magnetic resonance imaging technologies.