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[This corrects the article DOI: 10.1371/journal.pone.0054014.].

In response to the current challenge in genetic studies to make new associations, we advocate for a shift toward leveraging population fine-scale structure. Our exploration brings to light distinct fine-structure within populations having undergone a founder effect such as the Ashkenazi Jews and the population of the Quebec' province. We leverage the fine-scale population structure to explore its impact on the frequency of rare variants. Notably, we observed an 8-fold increase in frequency for a variant associated with the Usher syndrome in one Quebec subpopulation. Our study underscores that smaller cohorts with greater genetic similarity demonstrate an important increase in rare variant frequencies, offering a promising avenue for new genetic variants' discovery.

BackgroundPatients can experience persistent cognitive complaints and deficits in long-COVID. Inflammation and capillary damage may contribute to symptoms by interfering with tissue oxygenation.MethodsThis was an exploratory pilot crossover study designed to describe the effects of supplemental oxygen (portable oxygen concentrator, POC) on cognitive performance and peripheral and cerebral oxygen saturation at rest and exercise. Participants with long-COVID (n = 21) were randomized 1:1 to: 1) POC (3h/day) for 2 weeks followed by standard of care (Control) for 2 weeks or 2) Control for 2 weeks then POC (3h/day) for 2 weeks, with a 1-week washout. Cognitive assessment (global cognition [Montreal Cognitive Assessment, MoCA], episodic memory [Hopkins], working memory [Digit Span], executive function [Verbal fluency]) was performed at baseline and after each treatment period. Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder-7 were completed. Peripheral and cerebral oxygen saturation were measured at rest and exercise (treadmill) at baseline and after each treatment period. Statistical analyses were descriptive without formal testing.ResultsMoCA scores were similar under POC (26.45±2.31) and Control (26.37±2.85); overall POC-Control difference was -0.090 (95% CI [-1.031, 0.850]). Because of a learning effect, post-hoc analyses were performed for Period 1, where the MoCA score difference was 1.705 [0.140, 3.271]. MoCA subscores suggested better performance with POC for Visuospatial/executive (0.618 [-0.106, 1.342]) and Attention (0.975 [0.207, 1.743]). POC trended to have better scores on Digit Span backward (difference: 0.822 [-0.067, 1.711]) and self-reported depressive symptoms (difference: -1.335 [-3.166, 0.495]). For specific PHQ-9 items, POC tended to have lower (better) scores for Q1 (Little interest/pleasure) and Q7 (Trouble concentrating). Cerebral oxygen saturations at end of exercise showed no difference between POC and Control. Peripheral saturations during exercise were similar under POC and Control (difference: 0.519% [-1.675, 2.714]).ConclusionAn advantage of POC over Control was observed for global cognition, attention, visuospatial/executive performance and depressive symptoms. Results need to be validated in a larger study.

Early life environments can have long-lasting effects on adult reproductive performance, but disentangling the influence of early and adult life environments on fitness is challenging, especially for long-lived species. Using a detailed dataset spanning over two centuries, we studied how both early and adult life environments impacted reproductive performance in preindustrial women. Due to a wide geographic range, agricultural production was lower in northern compared to southern parishes, and health conditions were worse in urban than rural parishes. We tested whether reproductive traits and offspring survival varied between early and adult life environments by comparing women who moved between different environments during their lifetime with those who moved parishes but remained in the same environment. Our findings reveal that urban-born women had an earlier age at first reproduction and less offspring surviving to adulthood than rural-born women. Moreover, switching from urban to rural led to increased offspring survival, while switching from rural to urban had the opposite effect. Finally, women who switched from rural to urban and from South to North had their first child at an older age compared to those who stayed in the same environment type. Our study underscores the complex and interactive effects of early and adult life environments on reproductive traits, highlighting the need to consider both when studying environmental effects on reproductive outcomes.

In Quebec (Canada), the roll-out of the vaccination started slowly in December 2020 due to limited vaccine supply. While the first and second doses were well-accepted among adults and vaccine uptake was above 90%, in late 2021 and 2022, vaccine acceptance decreased for children vaccination and receipt of a 3rd or a 4th dose. In the autumn of 2022, four focus groups were conducted with vaccine-hesitant parents of children aged 0-4 and adults who expressed little intention to receive a booster dose. The objective of this study was to gather participants' perspectives on vaccination in general, on the COVID-19 vaccination campaign and the information available, and to gain insights into the underlying reasons for their low intention of either having their child(ren) vaccinated, or receiving an additional dose of vaccine. A total of 35 participants took part in the focus groups. While participants expressed a certain level of trust and confidence in public health and government authorities regarding pandemic management and the vaccination campaign, they were also concerned that transparent information was lacking to support an informed decision on booster doses and children's vaccination. Many participants felt adequately protected against the infection during the focus groups, citing a lack of perceived benefits as the primary reason for refusing a booster dose. Parents who refused to administer the COVID-19 vaccine to their young children felt that the vaccine was not useful for children and were concerned about potential side effects. The majority reported that their opinions regarding other recommended vaccines had not changed since the beginning of the pandemic. While these results are reassuring, our findings highlight the importance of transparency in public health communications about vaccines to increase confidence and to develop strategies to address vaccine fatigue and complacency toward COVID-19 vaccines.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

ObjectiveAttention-deficit/hyperactivity disorder (ADHD) is a common condition that often persists into adulthood, although data suggest that the current diagnostic criteria may not represent how the condition presents in adults. We aimed to use qualitative methods to better understand ADHD symptomatology in young adults, especially regarding attentional and emotional dysregulation.MethodsNine focus groups involving young adults (aged 18-35 years; N = 43; 84% female; 86% US and Canada) with diagnoses of ADHD were conducted. Participants were asked about their perceptions of the current diagnostic criteria and how their symptoms have presented and changed over time. Data were analyzed using an interpretive phenomenological analysis framework.ResultsMost participants reported that the diagnostic criteria did not accurately capture their experiences with ADHD. They reported struggling with attention dysregulation, including hyperfocusing, and emotional dysregulation, including rejection-sensitive dysphoria. Many participants believed that their changing environments and behavioral adaptations influenced how their symptoms presented into adulthood.ConclusionCurrent diagnostic criteria for ADHD may not capture the range of symptoms present in young adults. More research is needed to characterize attentional and emotional dysregulation in this population.

Objectives1) To compare the average cost of an emergency department (ED) visit for various minor musculoskeletal disorders between two models of care (physiotherapist and ED physician or ED physician alone); 2) To evaluate the incremental cost-effectiveness ratio (ICER) of these two models of care over a 3-month period post-initial visit; and 3) To estimate the ICER of three ED models of care (physiotherapist and ED physician, ED physician alone, physiotherapist alone) over a two-year period.MethodsObj.1: The costs incurred by participants in the two groups during their ED visit will be calculated using the Time-Driven Activity-Based Costing (TDABC) method. These costs will be compared using generalized linear models. Obj. 2: The ICER of the two models will be evaluated over three months via a cost-utility analysis that will combine costs and effectiveness data (quality-adjusted life years) using both Health system and Societal perspectives (patient + health system costs). Obj. 3: The 2-year ICER of the three above-mentioned models will be estimated using a mathematical model including a decision tree (0-3 months post-visit) and a Markov model (3-24 months post-visit), also using both Health system and Societal perspectives. Data to answer the three objectives will come from data collected during a randomized clinical trial (n = 78, CHU de Québec)which will be supplemented with data obtained via some of the CHU de Québec administrative databases (nominative data; SIURGE (ED management software), Cristal-Net (patient electronic record), and the ED's pharmacy transactions directory; administrative data: drug costs repository), the literature, and public cost repositories.ConclusionThis study will help to determine which model of care is most efficient for the management of individuals who come to the ED with minor musculoskeletal disorders. The increased involvement of various health professionals in the management of patients in the ED paves the way for the development of new avenues of practice and more efficient organization of services.

While most individuals who have experienced sex trafficking will seek medical attention during their exploitation, very few will be identified by healthcare professionals (HCP). It constitutes a lost opportunity to provide appropriate support, resources, and services. In this study, we examined the experiences of accessing care of sex trafficking survivors in the Greater Montreal area and their interactions with HCPs to inform trafficking education programs for HCPs and allied health professionals regarding the needs of this patient population. We conducted seven semi-structured in-depth interviews with purposively selected sex trafficking survivors participating in "Les Survivantes," a program of the SPVM (Service de Police de la Ville de Montréal), designed to support trafficked individuals' exit journey. We used interpretive description to understand the lived experiences of trafficked individuals with direct applications to clinical education and care. Our results revealed that trafficked individuals accessing care present with a fragile trust in HCPs and how HCPs have many opportunities to conduct comprehensive examinations and query trafficking. Trafficked individuals' initial trust in HCPs can be strengthened by non-judgemental approaches or damaged by stigmatizing conduct, serving to isolate further and alienate this patient population. Health professionals' attitudes combined with healthcare settings' cultures of care (i.e., community vs emergency) and exposure to marginalized groups were key influencers of survivors' perception of healthcare interactions. The findings also emphasized the importance of routinely querying trafficking through sensitive psychosocial questioning based on observation of trafficking cues. Survivors reported a list of trafficking cues to recognize and emphasized the importance of trust as a condition of disclosure. Finally, survivors identified the need for exit planning to be centered around trafficked individuals' agency and holistic needs, and for streamlined community-based multidisciplinary collaboration to better serve this population. Our results highlight that most challenges experienced by trafficking survivors in accessing care and resources are modifiable through HCP education and training. Our study also provides new insights and concrete advice to improve care and support throughout the exiting process. We argue that healthcare services for this population be modeled harm reduction approaches that focus on victims' agency and needs, independent of their desire to exit trafficking. We emphasize the urgent need for proper case management and intersectoral and multidisciplinary care coordination in community-based settings as well as facilitated access to mental health support.

Migrating cells can extend their leading edge by forming myosin-driven blebs and F-actin-driven pseudopods. When coerced to migrate in resistive environments, Dictyostelium cells switch from using predominately pseudopods to blebs. Bleb formation has been shown to be chemotactic and can be influenced by the direction of the chemotactic gradient. In this study, we determine the blebbing responses of developed cells of Dictyostelium discoideum to cAMP gradients of varying steepness produced in microfluidic channels with different confining heights, ranging between 1.7 μm and 3.8 μm. We show that microfluidic confinement height, gradient steepness, buffer osmolarity and Myosin II activity are important factors in determining whether cells migrate with blebs or with pseudopods. Dictyostelium cells were observed migrating within the confines of microfluidic gradient channels. When the cAMP gradient steepness is increased from 0.7 nM/μm to 20 nM/μm, cells switch from moving with a mixture of blebs and pseudopods to moving only using blebs when chemotaxing in channels with confinement heights less than 2.4 μm. Furthermore, the size of the blebs increases with gradient steepness and correlates with increases in myosin-II localization at the cell cortex. Reduction of intracellular pressure by high osmolarity buffer or inhibition of myosin-II by blebbistatin leads to a decrease in bleb formation and bleb size. Together, our data reveal that the protrusion type formed by migrating cells can be influenced by the channel height and the steepness of the cAMP gradient, and suggests that a combination of confinement-induced myosin-II localization and cAMP-regulated cortical contraction leads to increased intracellular fluid pressure and bleb formation.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is characterized by balance impairment and mobility limitations, which both increase the risk of falling. The objective of this study was to explore the effects of a rehabilitation program aimed at increasing trunk and lower limb motor control on balance and walking abilities, and accomplishment of activities of daily living. In this exploratory study, a group-supervised rehabilitation program was performed three times a week for 8 weeks (two sessions at a rehabilitation gym and one pool session). Outcome measures included the Ottawa Sitting Scale, Berg Balance Scale, modified Activities-specific Balance Confidence Scale, 30-Second Chair Stand Test, 10-Meter Walk Test, Barthel Index, and Scale for the Assessment and Rating of Ataxia. Significant improvements in balance, trunk control, maximal and self-selected walking speed difference, ataxia severity and accomplishment of specific activities of daily living were noted for the whole group at the end of the program. At the individual level, all participants improved beyond the standard error of measurement in at least two outcome measures. Also, most participants reported many perceived improvements related to balance, posture and functional mobility. This study provides encouraging results on the effects of a rehabilitation program for ambulatory people with ARSACS. Group intervention could have a positive impact on their daily lives and improve the health care service offered to this population. Future studies with larger sample sizes including control groups and other forms of ataxia are necessary to validate our results to generalize them.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

Increasing evidence associates apathy with worsening in cognitive performance and greater risk of dementia, in both clinical and healthy older populations. In older adults with neurocognitive disorders, apathy has also been related to specific fronto-subcortical structural abnormalities, thus differentiating apathy and major depressive disorder. Yet, the neural mechanisms associated with apathy in healthy older adults are still unclear. In the present study, we investigated the frontal cortical response during a dual-task walking paradigm in forty-one healthy older adults with and without apathy symptoms, controlling for depressive symptoms. The dual-task walking paradigm included a single cognitive task (2-back), a single motor task (walking), and a dual-task condition (2-back whilst walking). The cortical response was measured by means of functional Near-Infrared Spectroscopy (fNIRS). The results revealed that participants with apathy symptoms showed greater activation of subregions of the prefrontal cortex and of the premotor cortex compared to healthy controls during the single cognitive component of the dual-task paradigm, whilst cognitive performance was equivalent between groups. Moreover, increased cortical response during the cognitive task was associated with higher odds of exhibiting apathy symptoms, independently of depressive symptoms. These findings suggest that apathy may be related to differential brain activation patterns in healthy older individuals and are in line with previous evidence of the distinctiveness between apathy and depression. Future research may explore the long-term effects of apathy on the cortical response in healthy older adults.

Background Collaborative care is an evidence-based approach to improving outcomes for common mental disorders in primary care. Efforts are underway to broadly implement the collaborative care model, yet the extent to which this model promotes person-centered mental health care has been little studied. The aim of this study was to describe practices related to two patient and family engagement strategies–personalized care planning and shared decision making–within collaborative care programs for depression and anxiety disorders in primary care. Methods We conducted an update of a 2012 Cochrane review, which involved searches in Cochrane CCDAN and CINAHL databases, complemented by additional database, trial registry, and cluster searches. We included programs evaluated in a clinical trials targeting adults or youth diagnosed with depressive or anxiety disorders, as well as sibling reports related to these trials. Pairs of reviewers working independently selected the studies and data extraction for engagement strategies was guided by a codebook. We used narrative synthesis to report on findings. Results In total, 150 collaborative care programs were analyzed. The synthesis showed that personalized care planning or shared decision making were practiced in fewer than half of programs. Practices related to personalized care planning, and to a lesser extent shared decision making, involved multiple members of the collaborative care team, with care managers playing a pivotal role in supporting patient and family engagement. Opportunities for quality improvement were identified, including fostering greater patient involvement in collaborative goal setting and integrating training and decision aids to promote shared decision making. Conclusion This review suggests that personalized care planning and shared decision making could be more fully integrated within collaborative care programs for depression and anxiety disorders. Their absence in some programs is a missed opportunity to spread person-centered mental health practices in primary care.

BackgroundWe hypothesized that heterogeneity exists within the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 spirometric category and that different subgroups could be identified within this GOLD category.MethodsPre-randomization study participants from two clinical trials were symptomatic/asymptomatic GOLD 1 chronic obstructive pulmonary disease (COPD) patients and healthy controls. A hierarchical cluster analysis used pre-randomization demographics, symptom scores, lung function, peak exercise response and daily physical activity levels to derive population subgroups.ResultsConsiderable heterogeneity existed for clinical variables among patients with GOLD 1 COPD. All parameters, except forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC), had considerable overlap between GOLD 1 COPD and controls. Three-clusters were identified: cluster I (18 [15%] COPD patients; 105 [85%] controls); cluster II (45 [80%] COPD patients; 11 [20%] controls); and cluster III (22 [92%] COPD patients; 2 [8%] controls). Apart from reduced diffusion capacity and lower baseline dyspnea index versus controls, cluster I COPD patients had otherwise preserved lung volumes, exercise capacity and physical activity levels. Cluster II COPD patients had a higher smoking history and greater hyperinflation versus cluster I COPD patients. Cluster III COPD patients had reduced physical activity versus controls and clusters I and II COPD patients, and lower FEV1/FVC versus clusters I and II COPD patients.ConclusionsThe results emphasize heterogeneity within GOLD 1 COPD, supporting an individualized therapeutic approach to patients.Trial registrationwww.clinicaltrials.gov. NCT01360788 and NCT01072396.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

BackgroundThe risk factors associated with the stages of Coronavirus Disease-2019 (COVID-19) disease progression are not well known. We aim to identify risk factors specific to each state of COVID-19 progression from SARS-CoV-2 infection through death.Methods and resultsWe included 648,202 participants from the Veteran Affairs Million Veteran Program (2011-). We identified characteristics and 1,809 ICD code-based phenotypes from the electronic health record. We used logistic regression to examine the association of age, sex, body mass index (BMI), race, and prevalent phenotypes to the stages of COVID-19 disease progression: infection, hospitalization, intensive care unit (ICU) admission, and 30-day mortality (separate models for each). Models were adjusted for age, sex, race, ethnicity, number of visit months and ICD codes, state infection rate and controlled for multiple testing using false discovery rate (≤0.1). As of August 10, 2020, 5,929 individuals were SARS-CoV-2 positive and among those, 1,463 (25%) were hospitalized, 579 (10%) were in ICU, and 398 (7%) died. We observed a lower risk in women vs. men for ICU and mortality (Odds Ratio (95% CI): 0.48 (0.30-0.76) and 0.59 (0.31-1.15), respectively) and a higher risk in Black vs. Other race patients for hospitalization and ICU (OR (95%CI): 1.53 (1.32-1.77) and 1.63 (1.32-2.02), respectively). We observed an increased risk of all COVID-19 disease states with older age and BMI ≥35 vs. 20-24 kg/m2. Renal failure, respiratory failure, morbid obesity, acid-base balance disorder, white blood cell diseases, hydronephrosis and bacterial infections were associated with an increased risk of ICU admissions; sepsis, chronic skin ulcers, acid-base balance disorder and acidosis were associated with mortality.ConclusionsOlder age, higher BMI, males and patients with a history of respiratory, kidney, bacterial or metabolic comorbidities experienced greater COVID-19 severity. Future studies to investigate the underlying mechanisms associated with these phenotype clusters and COVID-19 are warranted.

Urbanisation alters landscapes, introduces wildlife to novel stressors, and fragments habitats into remnant ‘islands’. Within these islands, isolated wildlife populations can experience genetic drift and subsequently suffer from inbreeding depression and reduced adaptive potential. The Western tiger snake (Notechis scutatus occidentalis) is a predator of wetlands in the Swan Coastal Plain, a unique bioregion that has suffered substantial degradation through the development of the city of Perth, Western Australia. Within the urban matrix, tiger snakes now only persist in a handful of wetlands where they are known to bioaccumulate a suite of contaminants, and have recently been suggested as a relevant bioindicator of ecosystem health. Here, we used genome-wide single nucleotide polymorphism (SNP) data to explore the contemporary population genomics of seven tiger snake populations across the urban matrix. Specifically, we used population genomic structure and diversity, effective population sizes (Ne), and heterozygosity-fitness correlations to assess fitness of each population with respect to urbanisation. We found that population genomic structure was strongest across the northern and southern sides of a major river system, with the northern cluster of populations exhibiting lower heterozygosities than the southern cluster, likely due to a lack of historical gene flow. We also observed an increasing signal of inbreeding and genetic drift with increasing geographic isolation due to urbanisation. Effective population sizes (Ne) at most sites were small (< 100), with Ne appearing to reflect the area of available habitat rather than the degree of adjacent urbanisation. This suggests that ecosystem management and restoration may be the best method to buffer the further loss of genetic diversity in urban wetlands. If tiger snake populations continue to decline in urban areas, our results provide a baseline measure of genomic diversity, as well as highlighting which ‘islands’ of habitat are most in need of management and protection.

Common scab is a potato disease characterized by the formation of scab-like lesions on the surface of potato tubers. The actinobacterium Streptomyces scabiei is the main causal agent of common scab. During infection, this bacterium synthesizes the phytotoxin thaxtomin A which is essential for the production of disease symptoms. While thaxtomin A can activate an atypical programmed cell death in plant cell suspensions, it is possible to gradually habituate plant cells to thaxtomin A to provide resistance to lethal phytotoxin concentrations. Potato 'Russet Burbank' calli were habituated to thaxtomin A to regenerate the somaclone RB9 that produced tubers more resistant to common scab than those obtained from the original cultivar. Compared to the Russet Burbank cultivar, somaclone RB9 generated up to 22% more marketable tubers with an infected tuber area below the 5% threshold. Enhanced resistance was maintained over at least two years of cultivation in the field. However, average size of tubers was significantly reduced in somaclone RB9 compared to the parent cultivar. Small RB9 tubers had a thicker phellem than Russet Burbank tubers, which may contribute to improving resistance to common scab. These results show that thaxtomin A-habituation in potato is efficient to produce somaclones with increased and durable resistance to common scab.

BackgroundFragile X syndrome (FXS) is the leading inherited cause of intellectual disability and is caused by the loss of expression of the Fragile X mental retardation protein (FMRP). In animal model of FXS, the absence of FMRP leads to an aberrant rate of neuronal protein synthesis, which in turn is believed to be at the origin of defects regarding spine morphology and synaptic plasticity. Normalisation of protein synthesis in these models has been associated with a rescue of FXS behavioral and biochemicals phenotype, thus establishing the rate of protein synthesis as one of the most promising monitoring biomarker for FXS. However, rate of protein synthesis alteration in fragile X individuals is not well characterized.MethodWe applied a robust radiolabeled assay to measure rate of protein synthesis in freshly extracted peripheral blood mononuclear cells (PBMCs) and blood platelets. We ultimately settle on PBMCs to measure and compare rate of protein synthesis in 13 males with fragile X and 14 matched controls individuals.ResultsUsing this method, we measured a 26.9% decrease (p = 0,0193) in the rate of protein synthesis in fragile X individuals PBMCs. Furthermore, the rate of protein synthesis measurements obtained were highly reproducible, highlighting the robustness of the method.ConclusionOur work presents the first evidence of a diminution of the rate of protein synthesis in a human peripheral model of fragile X. Our results also support the finding of previous studies using brain PET imaging in Fragile X individuals. Since our assay only requires a simple venous puncture, it could be used in other cases of intellectual disability in order to determine if an aberrant rate of protein synthesis is a common general mechanism leading to impairment in synaptic plasticity and to intellectual disability.

BackgroundConflicts of interest in biomedical research can influence research results and drive research agendas away from public health priorities. Previous agenda-setting studies share two shortfalls: they only account for direct connections between academic institutions and firms, as well as potential bias based on researchers' personal beliefs. This paper's goal is to determine the key actors and contents of the prevailing health and biomedical sciences (HBMS) research agenda, overcoming these shortfalls.MethodsWe performed a bibliometric and lexical analysis of 95,415 scientific articles published between 1999 and 2018 in the highest impact factor journals within HBMS, using the Web of Science database and the CorText platform. HBMS's prevailing knowledge network of institutions was proxied with network maps where nodes represent affiliations and edges the most frequent co-authorships. The content of the prevailing HBMS research agenda was depicted through network maps of prevalent multi-terms found in titles, keywords, and abstracts.ResultsThe HBMS research agendas of large private firms and leading academic institutions are intertwined. The prevailing HBMS agenda is mostly based on molecular biology (40% of the most frequent multi-terms), with an inclination towards cancer and cardiovascular research (15 and 8% of the most frequent multi-terms, respectively). Studies on pathogens and biological vectors related to recent epidemics are marginal (1% of the most frequent multi-terms). Content of the prevailing HBMS research agenda prioritizes research on pharmacological intervention over research on socio-environmental factors influencing disease onset or progression and overlooks, among others, the study of infectious diseases.ConclusionsPharmaceutical corporations contribute to set HBMS's prevailing research agenda, which is mainly focused on a few diseases and research topics. A more balanced research agenda, together with epistemological approaches that consider socio-environmental factors associated with disease spreading, could contribute to being better prepared to prevent and treat more diverse pathologies and to improve overall health outcomes.

Nanoparticles made of the coat protein of papaya mosaic virus (PapMV) and a single-strand RNA were previously shown to be an efficient antigen presentation system for the trigger of cellular immunity. Engineering of PapMV nano with a cytotoxic T lymphocyte epitope was previously shown activating specific T lymphocytes through a proteasome-independent major histocompatibility complex class I (MHC-I) cross-presentation. In this study, we provide new insights into the mechanism of the MHC-I cross-presentation mediated by PapMV nanoparticles. We demonstrate that PapMV nanoparticles do not require the transporter associated with antigen presentation (TAP), but rather depend on lysosome acidification and cathepsin S protease activity for presentation of the T cell epitope. We have also linked the induction of autophagy with this vacuolar MHC-I cross-presentation process. Interestingly, autophagy is induced in antigen-presenting cells after PapMV nanoparticles exposure and inhibition of autophagy reduce MHC-I cross-presentation. This study demonstrates that autophagy is associated with TAP- and proteasome-independent MHC-I cross-presentation. A deeper understanding of the autophagy-dependent MHC-I cross-presentation will be useful in designing vaccination platforms that aim to trigger an efficient cytotoxic T lymphocyte response.

The worldwide spread of a novel influenza A (H1N1) virus in 2009 showed that influenza remains a significant health threat, even for individuals in the prime of life. This paper focuses on the unusually high young adult mortality observed during the Spanish flu pandemic of 1918. Using historical records from Canada and the U.S., we report a peak of mortality at the exact age of 28 during the pandemic and argue that this increased mortality resulted from an early life exposure to influenza during the previous Russian flu pandemic of 1889-90. We posit that in specific instances, development of immunological memory to an influenza virus strain in early life may lead to a dysregulated immune response to antigenically novel strains encountered in later life, thereby increasing the risk of death. Exposure during critical periods of development could also create holes in the T cell repertoire and impair fetal maturation in general, thereby increasing mortality from infectious diseases later in life. Knowledge of the age-pattern of susceptibility to mortality from influenza could improve crisis management during future influenza pandemics.

Agricultural soil pests, including wireworms (Coleoptera: Elateridae), are managed primarily with pesticides applied directly to seeds before sowing. Seeds coated with neonicotinoids have been used widely in Quebec (Canada) for several years. To assess the agronomic and economic value of neonicotinoid seed treatments in soybeans and corn in Quebec, trials were conducted from 2012 to 2016 in 84 fields across seven regions in Quebec. We evaluated the effect of neonicotinoid seed treatments on soil pest densities, crop damage and yield. The results showed that 92.6% of corn fields and 69.0% of soybean fields had less than 1 wireworm per bait trap. However, no significant differences in plant stand or yield were observed between treated and untreated corn or soybeans during the study. This study shows that neonicotinoid seed treatments in field crops in Quebec are useful in less than 5% of cases, given the very low level of pest-associated pressure and damage, and that they should not be used prophylactically. Integrated pest management (IPM) strategies need to be developed for soil insect pests to offer effective alternative solutions to producers.

The Arctic Tern (Sterna paradisaea; takatakiaq in Inuttitut) breeds in the circumpolar Arctic and undertakes the longest known annual migration. In recent decades, Arctic Tern populations have been declining in some parts of their range, and this has been a cause of concern for both wildlife managers and Indigenous harvesters. However, limited scientific information is available on Arctic Tern abundance and distribution, especially within its breeding range in remote areas of the circumpolar Arctic. Knowledge held by Inuit harvesters engaged in Arctic Tern egg picking can shed light on the ecology, regional abundance and distribution of this marine bird. We conducted individual interviews and a workshop involving 12 Inuit harvesters and elders from Kuujjuaraapik, Nunavik (northern Québec), Canada, to gather their knowledge of Arctic Tern cultural importance, ecology, and stewardship. Interview contributors reported a regional decline in Arctic Tern numbers which appeared in the early 2000s on nesting islands near Kuujjuaraapik. Six possible factors were identified: (1) local harvest through egg picking; (2) nest disturbance and predation; (3) abandonment of tern nesting areas (i.e., islands that have become connected to the mainland due to isostatic rebound); (4) climate change; (5) natural abundance cycles within the Arctic Tern population; and (6) decline of the capelin (Mallotus villosus) in the region. Recommendations from Inuit contributors related to Arctic Tern stewardship and protection included: (1) conduct more research; (2) let nature take its course; (3) conduct an awareness campaign; (4) implement an egg picking ban; (5) coordinate local egg harvest; (6) start 'tern farming'; (7) protect Arctic Terns across their migration route; and (8) harvest foxes predating on terns. Our study highlighted complementarities between Inuit knowledge and ecological science, and showed that Inuit harvesters can make substantial contributions to ongoing and future Arctic tern research and management initiatives.

BackgroundAvailable COVID-19 mortality indices are limited to acute inpatient data. Using nationwide medical administrative data available prior to SARS-CoV-2 infection from the US Veterans Health Administration (VA), we developed the VA COVID-19 (VACO) 30-day mortality index and validated the index in two independent, prospective samples.Methods and findingsWe reviewed SARS-CoV-2 testing results within the VA between February 8 and August 18, 2020. The sample was split into a development cohort (test positive between March 2 and April 15, 2020), an early validation cohort (test positive between April 16 and May 18, 2020), and a late validation cohort (test positive between May 19 and July 19, 2020). Our logistic regression model in the development cohort considered demographics (age, sex, race/ethnicity), and pre-existing medical conditions and the Charlson Comorbidity Index (CCI) derived from ICD-10 diagnosis codes. Weights were fixed to create the VACO Index that was then validated by comparing area under receiver operating characteristic curves (AUC) in the early and late validation cohorts and among important validation cohort subgroups defined by sex, race/ethnicity, and geographic region. We also evaluated calibration curves and the range of predictions generated within age categories. 13,323 individuals tested positive for SARS-CoV-2 (median age: 63 years; 91% male; 42% non-Hispanic Black). We observed 480/3,681 (13%) deaths in development, 253/2,151 (12%) deaths in the early validation cohort, and 403/7,491 (5%) deaths in the late validation cohort. Age, multimorbidity described with CCI, and a history of myocardial infarction or peripheral vascular disease were independently associated with mortality-no other individual comorbid diagnosis provided additional information. The VACO Index discriminated mortality in development (AUC = 0.79, 95% CI: 0.77-0.81), and in early (AUC = 0.81 95% CI: 0.78-0.83) and late (AUC = 0.84, 95% CI: 0.78-0.86) validation. The VACO Index allows personalized estimates of 30-day mortality after COVID-19 infection. For example, among those aged 60-64 years, overall mortality was estimated at 9% (95% CI: 6-11%). The Index further discriminated risk in this age stratum from 4% (95% CI: 3-7%) to 21% (95% CI: 12-31%), depending on sex and comorbid disease.ConclusionPrior to infection, demographics and comorbid conditions can discriminate COVID-19 mortality risk overall and within age strata. The VACO Index reproducibly identified individuals at substantial risk of COVID-19 mortality who might consider continuing social distancing, despite relaxed state and local guidelines.

BIN1 is the most important risk locus for Late Onset Alzheimer's Disease (LOAD), after ApoE. BIN1 AD-associated SNPs correlate with Tau deposition as well as with brain atrophy. Furthermore, the level of neuronal-specific BIN1 isoform 1 protein is decreased in sporadic AD cases in parallel with neuronal loss, despite an overall increase in BIN1 total mRNA. To address the relationship between reduction of BIN1 and neuronal cell loss in the context of Tau pathology, we knocked-down endogenous murine Bin1 via stereotaxic injection of AAV-Bin1 shRNA in the hippocampus of mice expressing Tau P301S (PS19). We observed a statistically significant reduction in the number of neurons in the hippocampus of mice injected with AAV-Bin1 shRNA in comparison with mice injected with AAV control. To investigate whether neuronal loss is due to deletion of Bin1 selectively in neurons in presence Tau P301S, we bred Bin1flox/flox with Thy1-Cre and subsequently with PS19 mice. Mice lacking neuronal Bin1 and expressing Tau P301S showed increased mortality, without increased neuropathology, when compared to neuronal Bin1 and Tau P301S-expressing mice. The loss of Bin1 isoform 1 resulted in reduced excitability in primary neurons in vitro, reduced neuronal c-fos expression as well as in altered microglia transcriptome in vivo. Taken together, our data suggest that the contribution of genetic variation in BIN1 locus to AD risk could result from a cell-autonomous reduction of neuronal excitability due to Bin1 decrease, exacerbated by the presence of aggregated Tau, coupled with a non-cell autonomous microglia activation.

Health management information system (HMIS) data are important for guiding the attainment of health targets in low- and middle-income countries. However, the quality of HMIS data is often poor. High-quality information is especially important for populations experiencing high burdens of disease and mortality, such as pregnant women, newborns, and children. The purpose of this study was to assess the quality of maternal and child health (MCH) data collected through the Ethiopian Ministry of Health's HMIS in three districts of Jimma Zone, Oromiya Region, Ethiopia over a 12-month period from July 2014 to June 2015. Considering data quality constructs from the World Health Organization's data quality report card, we appraised the completeness, timeliness, and internal consistency of eight key MCH indicators collected for all the primary health care units (PHCUs) located within three districts of Jimma Zone (Gomma, Kersa and Seka Chekorsa). We further evaluated the agreement between MCH service coverage estimates from the HMIS and estimates obtained from a population-based cross-sectional survey conducted with 3,784 women who were pregnant in the year preceding the survey, using Pearson correlation coefficients, intraclass correlation coefficients (ICC), and Bland-Altman plots. We found that the completeness and timeliness of facility reporting were highest in Gomma (75% and 70%, respectively) and lowest in Kersa (34% and 32%, respectively), and observed very few zero/missing values and moderate/extreme outliers for each MCH indicator. We found that the reporting of MCH indicators improved over time for all PHCUs, however the internal consistency between MCH indicators was low for several PHCUs. We found poor agreement between MCH estimates obtained from the HMIS and the survey, indicating that the HMIS may over-report the coverage of key MCH services, namely, antenatal care, skilled birth attendance and postnatal care. The quality of MCH data within the HMIS at the zonal level in Jimma, Ethiopia, could be improved to inform MCH research and programmatic efforts.

Aims/hypothesisEarly recognition of those at high risk for diabetes as well as diabetes itself can permit preventive management, but many Americans with diabetes are undiagnosed. We sought to determine whether routinely available outpatient random plasma glucose (RPG) would be useful to facilitate the diagnosis of diabetes.MethodsRetrospective cohort study of 942,446 U.S. Veterans without diagnosed diabetes, ≥3 RPG in a baseline year, and ≥1 primary care visit/year during 5-year follow-up. The primary outcome was incident diabetes (defined by diagnostic codes and outpatient prescription of a diabetes drug).ResultsOver 5 years, 94,599 were diagnosed with diabetes [DIAB] while 847,847 were not [NONDIAB]. Baseline demographics of DIAB and NONDIAB were clinically similar, except DIAB had higher BMI (32 vs. 28 kg/m2) and RPG (150 vs. 107 mg/dl), and were more likely to have Black race (18% vs. 15%), all pConclusionsRPG levels below the diabetes "diagnostic" range (≥200 mg/dl) provide good discrimination for follow-up diagnosis. Use of such levels-obtained opportunistically, during outpatient visits-could signal the need for further testing, allow preventive intervention in high risk individuals before onset of disease, and lead to earlier identification of diabetes.

The US Institute of Medicine defined serum 25-hydroxyvitamin D (25OHD) cut point values of 30 nmol/L and 40 nmol/L were used to assess the vitamin D status of South Asian and European Canadians of self-identified ancestry living in the National Capital Region of Canada. Serum 25OHD values were measured in the spring and fall of 2012 to represent status during the winter and summer months, respectively. A total of 1238 measurements were obtained from 669 participants (49% South Asian ancestry): some participants were measured only once (spring or fall). Median 25OHD values were significantly higher in participants of European ancestry: 70.8 nmol/L (68.1, 73.5; 95% CI) versus South Asian ancestry: 42.7 nmol/L (40.5, 45.0; P

The Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a polycationic, amphiphilic and helical neuropeptide, is well known for its neuroprotective actions and cell penetrating properties. In the present study, we evaluated the potent antibacterial property of PACAP38 and related analogs against various bacterial strains. Interestingly, PACAP38 and related analogs can inhibit the growth of various bacteria including Escherichia coli (JM109), Bacillus subtilis (PY79), and the pathogenic Burkholderia cenocepacia (J2315). Investigation of the mechanism of action suggested that a PACAP metabolite, identified as PACAP(9-38), might indeed be responsible for the observed PACAP38 antibacterial action. Surprisingly, PACAP(9-38), which does not induce haemolysis, exhibits an increased specificity toward Burkholderia cenocepacia J2315 compared to other tested bacteria. Finally, the predisposition of PACAP(9-38) to adopt a π-helix conformation rather than an α-helical conformation like PACAP38 could explain this gain in specificity. Overall, this study has revealed a new function for PACAP38 and related derivatives that can be added to its pleiotropic biological activities. This innovative study could therefore pave the way toward the development of new therapeutic agents against multiresistant bacteria, and more specifically the Burkholderia cenocepacia complex.

Adverse event (AE)-related costs represent an important component of economic models for cancer care. However, since previous studies mostly focused on specific AEs, treatments, or cancer types, limited information is currently available. Therefore, this study assessed the incremental healthcare costs associated with a large number of AEs among patients diagnosed with some of the most prevalent types of cancer. Data were obtained from a large US claims database. Adult patients were included if diagnosed with and treated for one of the following cancer types: breast, digestive organs and peritoneum, genitourinary organs (including bladder and ovary and other uterine adnexa), lung, lymphatic and hematopoietic tissue, and skin. Treatment episodes were defined as the period from initiation of the first antineoplastic pharmacologic therapy to discontinuation (i.e., gap of ≥ 45 days), or change in treatment regimen, or end of data availability. A total of 36 AEs were selected from the product inserts of 104 treatments recommended by practice guidelines. A retrospective matched cohort design was used, matching a treatment episode with a certain AE with a treatment episode without that AE. A total of 412,005 patients were selected, for a total of 794,243 treatment episodes, resulting in 1,617,368 matched treatment episodes across all 36 AEs. Incremental healthcare costs associated with AEs of any severity ranged from $546 for cough/upper respiratory infections to $24,633 for gastrointestinal perforation. The three most costly AEs when considering any severity were gastrointestinal perforation ($24,633), central nervous system hemorrhage ($24,322), and sepsis/septicemia ($23,510). Incremental healthcare costs associated with severe AEs ranged from $15,709 for dermatitis and rash to $48,538 for gastrointestinal fistula. The three most costly severe AEs were gastrointestinal fistula ($48,538), gastrointestinal perforation ($41,281), and central nervous system hemorrhage ($38,428). In conclusion, AEs during treatment episodes for cancer were frequent and associated with a substantial economic burden.

BackgroundUnderstanding suicidality has proven challenging given the complex aetiology in early childhood. Being able to accurately predict groups at increased risk of developing suicidal thoughts may aid in the development of targeted prevention programs that mitigate increased vulnerability. Further, the predictors of suicidal thoughts may be shared with other outcomes in adolescence. Previous research has linked many factors to suicidality, so the objective of this study was to consider how these factors may act together to increase risk of suicidal thoughts and other non-mental health outcomes.MethodsTwo longitudinal datasets were used in this analysis: the National Longitudinal Survey of Children and Youth (NLSCY) and the Avon Longitudinal Survey of Parents and Children (ALSPAC). A Classification and Regression Tree model comprised of 75 factors describing early childhood was constructed to identify subgroups of adolescents at high risk of suicidal thoughts in the NLSCY and was validated in ALSPAC. These subgroups were investigated to see if they also had elevated rates of antisocial behaviour, substance misuse, poor physical health, poor mental health, risky health behaviours, and/or poor academic performance.ResultsThe sensitivity was calculated to be 22·7%, specificity was 89·2%, positive predictive value 17·8%, and negative predictive value 91·8% and had similar accuracy in the validation dataset. The models were better at predicting other adverse outcomes compared to suicidal thoughts.ConclusionThere are groups of risk factors present in early life that can predict higher risk of suicidality in adolescence. Notably, these factors were also predictive of a range of adverse outcomes in adolescence.

BACKGROUND:Thrombin activatable fibrinolysis inhibitor (TAFI), encoded by the Carboxypeptidase B2 gene (CPB2), is an inhibitor of fibrinolysis and plays a role in the pathogenesis of venous thrombosis. Experimental findings support a functional role of genetic variants in CPB2, while epidemiological studies have been unable to confirm associations with risk of venous thrombosis. Sex-specific effects could underlie the observed inconsistent associations between CPB2 genetic variants and venous thrombosis. METHODS:A comprehensive literature search was conducted for associations between Ala147Thr and Thr325Ile variants with venous thrombosis. Authors were contacted to provide sex-specific genotype counts from their studies. Combined and sex-specific random effects meta-analyses were used to estimate a pooled effect estimate for primary and secondary genetic models. RESULTS:A total of 17 studies met the inclusion criteria. A sex-specific meta-analysis applying a dominant model supported a protective effect of Ala147Thr on venous thrombosis in females (OR = 0.81, 95%CI: 0.68,0.97; p = 0.018), but not in males (OR = 1.06, 95%CI:0.96-1.16; p = 0.263). The Thr325Ile did not show a sex-specific effect but showed variation in allele frequencies by geographic region. A subgroup analysis of studies in European countries showed decreased risk, with a recessive model (OR = 0.83, 95%CI:0.71-0.97, p = 0.021) for venous thrombosis. CONCLUSIONS:A comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results. Sex-specific analyses explained apparent discrepancies across genetic studies of Ala147Thr and venous thrombosis. While, careful selection of genetic models based on population genetics, evolutionary and biological knowledge can increase power by decreasing the need to adjust for testing multiple models.

BACKGROUND:DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS:Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS:Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS:Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.

The purpose of the study was to examine the effects of exercise on total leukocyte count and subsets, as well as hormone and cytokine responses in a thermoneutral and cold environment, with and without an individualized pre-cooling protocol inducing low-intensity shivering. Nine healthy young men participated in six experimental trials wearing shorts and t-shirts. Participants exercised for 60 min on a treadmill at low (LOW: 50% of peak VO2) and moderate (MOD: 70% VO2peak) exercise intensities in a climatic chamber set at 22°C (NT), and in 0°C (COLD) with and without a pre-exercise low-intensity shivering protocol (SHIV). Core and skin temperature, heart rate and oxygen consumption were collected continuously. Blood samples were collected before and at the end of exercise to assess endocrine and immunological changes. Core temperature in NT was greater than COLD and SHIV by 0.4±0.2°C whereas skin temperature in NT was also greater than COLD and SHIV by 8.5±1.4°C and 9.3±2.5°C respectively in MOD. Total testosterone, adenocorticotropin and cortisol were greater in NT vs. COLD and SHIV in MOD. Norepinephrine was greater in NT vs. other conditions across intensities. Interleukin-2, IL-5, IL-7, IL-10, IL-17, IFN-γ, Rantes, Eotaxin, IP-10, MIP-1β, MCP-1, VEGF, PDGF, and G-CSF were elevated in NT vs. COLD and/or SHIV. Furthermore, IFN-γ, MIP-1β, MCP-1, IL-10, VEGF, and PDGF demonstrate greater concentrations in SHIV vs. COLD, mainly in the MOD condition. This study demonstrated that exercising in the cold can diminish the exercise-induced systemic inflammatory response seen in a thermoneutral environment. Nonetheless, prolonged cooling inducing shivering thermogenesis prior to exercise, may induce an immuno-stimulatory response following moderate intensity exercise. Performing exercise in cold environments can be a useful strategy in partially inhibiting the acute systemic inflammatory response from exercise but oppositely, additional body cooling may reverse this benefit.

"Vaccine hesitancy" is a concept now frequently used in vaccination discourse. The increased popularity of this concept in both academic and public health circles is challenging previously held perspectives that individual vaccination attitudes and behaviours are a simple dichotomy of accept or reject. A consultation study was designed to assess the opinions of experts and health professionals concerning the definition, scope, and causes of vaccine hesitancy in Canada. We sent online surveys to two panels (1- vaccination experts and 2- front-line vaccine providers). Two questionnaires were completed by each panel, with data from the first questionnaire informing the development of questions for the second. Our participants defined vaccine hesitancy as an attitude (doubts, concerns) as well as a behaviour (refusing some / many vaccines, delaying vaccination). Our findings also indicate that both vaccine experts and front-line vaccine providers have the perception that vaccine rates have been declining and consider vaccine hesitancy an important issue to address in Canada. Diffusion of negative information online and lack of knowledge about vaccines were identified as the key causes of vaccine hesitancy by the participants. A common understanding of vaccine hesitancy among researchers, public health experts, policymakers and health care providers will better guide interventions that can more effectively address vaccine hesitancy within Canada.

Migrating cells can extend their leading edge by forming myosin-driven blebs and F-actin-driven pseudopods. When coerced to migrate in resistive environments, Dictyostelium cells switch from using predominately pseudopods to blebs. Bleb formation has been shown to be chemotactic and can be influenced by the direction of the chemotactic gradient. In this study, we determine the blebbing responses of developed cells of Dictyostelium discoideum to cAMP gradients of varying steepness produced in microfluidic channels with different confining heights, ranging between 1.7 μm and 3.8 μm. We show that microfluidic confinement height, gradient steepness, buffer osmolarity and Myosin II activity are important factors in determining whether cells migrate with blebs or with pseudopods. Dictyostelium cells were observed migrating within the confines of microfluidic gradient channels. When the cAMP gradient steepness is increased from 0.7 nM/μm to 20 nM/μm, cells switch from moving with a mixture of blebs and pseudopods to moving only using blebs when chemotaxing in channels with confinement heights less than 2.4 μm. Furthermore, the size of the blebs increases with gradient steepness and correlates with increases in myosin-II localization at the cell cortex. Reduction of intracellular pressure by high osmolarity buffer or inhibition of myosin-II by blebbistatin leads to a decrease in bleb formation and bleb size. Together, our data reveal that the protrusion type formed by migrating cells can be influenced by the channel height and the steepness of the cAMP gradient, and suggests that a combination of confinement-induced myosin-II localization and cAMP-regulated cortical contraction leads to increased intracellular fluid pressure and bleb formation.

Port Phillip Bay, Australia, is a large semi-closed bay with over four million people living in its catchment basin. The Bay receives waters from the Yarra River which drains the city of Melbourne, as well as receiving the discharges of sewage treatment plants and petrochemical and agricultural chemicals. A 1999 study demonstrated that fish inhabiting Port Phillip Bay showed signs of effects related to pollutant exposure despite pollution management practices having been implemented for over a decade. To assess the current health status of the fish inhabiting the Bay, a follow up survey was conducted in 2015. A suite of biomarkers of exposure and effects were measured to determine the health status of Port Phillip Bay sand flathead (Platycephalus bassensis), namely ethoxyresorufin-O-deethylase (EROD) activity, polycyclic aromatic hydrocarbons (PAH) biliary metabolites, carboxylesterase activity (CbE) and DNA damage (8-oxo-dG). The reduction in EROD activity in the present study suggests a decline in the presence of EROD activity-inducing chemicals within the Bay since the 1990s. Fish collected in the most industrialised/urbanised sites did not display higher PAH metabolite levels than those in less developed areas of the Bay. Ratios of PAH biliary metabolite types were used to indicate PAH contaminant origin. Ratios indicated fish collected at Corio Bay and Hobsons Bay were subjected to increased low molecular weight hydrocarbons of petrogenic origin, likely attributed to the close proximity of these sites to oil refineries, compared to PAH biliary metabolites in fish from Geelong Arm and Mordialloc. Quantification of DNA damage indicated a localised effect of exposure to pollutants, with a 10-fold higher DNA damage level in fish sampled from the industrial site of Corio Bay relative to the less developed site of Sorrento. Overall, integration of biomarkers by multivariate analysis indicated that the health of fish collected in industrialised areas was compromised, with biologically significant biomarkers of effects (LSI, CF and DNA damage) discriminating between individuals collected in industrialised areas from observations made in fish collected in less developed areas of the Bay.

The porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important swine pathogens and often serves as an entry door for other viral or bacterial pathogens, of which Streptococcus suis is one of the most common. Pre-infection with PRRSV leads to exacerbated disease caused by S. suis infection. Very few studies have assessed the immunological mechanisms underlying this higher susceptibility. Since antigen presenting cells play a major role in the initiation of the immune response, the in vitro transcriptional response of bone marrow-derived dendritic cells (BMDCs) and monocytes in the context of PRRSV and S. suis co-infection was investigated. BMDCs were found to be more permissive than monocytes to PRRSV infection; S. suis phagocytosis by PRRSV-infected BMDCs was found to be impaired, whereas no effect was found on bacterial intracellular survival. Transcription profile analysis, with a major focus on inflammatory genes, following S. suis infection, with and without pre-infection with PRRSV, was then performed. While PRRSV pre-infection had little effect on monocytes response to S. suis infection, a significant expression of several pro-inflammatory molecules was observed in BMDCs pre-infected with PRRSV after a subsequent infection with S. suis. While an additive effect could be observed for CCL4, CCL14, CCL20, and IL-15, a distinct synergistic up-regulatory effect was observed for IL-6, CCL5 and TNF-α after co-infection. This increased pro-inflammatory response by DCs could participate in the exacerbation of the disease observed during PRRSV and S. suis co-infection.

OBJECTIVES:This study compared cardio-metabolic disease risk factors and their associations with serum vitamin D and omega-3 status in South Asian (SAC) and White Canadians (WC) living in Canada's capital region. METHODS:Fasting blood samples were taken from 235 SAC and 279 WC aged 20 to 79 years in Ottawa, and 22 risk factors were measured. RESULTS:SAC men and women had significantly higher fasting glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-IR), apolipoprotein B (ApoB), ratios of total (TC) to HDL cholesterol (HDLC) and ApoB to ApoA1, leptin, E-selectin, P-selectin, ICAM-1 and omega-3 (p < 0.05), but lower HDLC, ApoA1, vitamin D levels than WC (p < 0.05). SAC women had higher CRP and VEGF than WC women. Adequate (50-74.9 nmol/L) or optimal (≥ 75 nmol/L) levels of 25(OH)D were associated with lower BMI, glucose, insulin, HOMA-IR, TG, TC, low density lipoprotein cholesterol (LDLC), ApoB/ApoA1 ratio, CRP, leptin, and higher HDLC, ApoA1, omega-3 index, L-selectin levels in WC, but not in SAC. Intermediate (>4%-

In eastern Canada, the destruction of kelp beds by dense aggregations (fronts) of the omnivorous green sea urchin, Strongylocentrotus droebachiensis, is a key determinant of the structure and dynamics of shallow reef communities. Recent studies suggest that hydrodynamic forces, but not sea temperature, determine the strength of urchin-kelp interactions, which deviates from the tenets of the metabolic theory of ecology (MTE). We tested the hypothesis that water temperature can predict short-term kelp bed destruction by S. droebachiensis in calm hydrodynamic environments. Specifically, we experimentally determined relationships among water temperature, body size, and individual feeding in the absence of waves, as well as among wave velocity, season, and aggregative feeding. We quantified variation in kelp-bed boundary dynamics, sea temperature, and wave height over three months at one subtidal site in Newfoundland to test the validity of thermal tipping ranges and regression equations derived from laboratory results. Consistent with the MTE, individual feeding during early summer (June-July) obeyed a non-linear, size- and temperature-dependent relationship: feeding in large urchins was consistently highest and positively correlated with temperature

BackgroundWe hypothesized that heterogeneity exists within the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 spirometric category and that different subgroups could be identified within this GOLD category.MethodsPre-randomization study participants from two clinical trials were symptomatic/asymptomatic GOLD 1 chronic obstructive pulmonary disease (COPD) patients and healthy controls. A hierarchical cluster analysis used pre-randomization demographics, symptom scores, lung function, peak exercise response and daily physical activity levels to derive population subgroups.ResultsConsiderable heterogeneity existed for clinical variables among patients with GOLD 1 COPD. All parameters, except forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC), had considerable overlap between GOLD 1 COPD and controls. Three-clusters were identified: cluster I (18 [15%] COPD patients; 105 [85%] controls); cluster II (45 [80%] COPD patients; 11 [20%] controls); and cluster III (22 [92%] COPD patients; 2 [8%] controls). Apart from reduced diffusion capacity and lower baseline dyspnea index versus controls, cluster I COPD patients had otherwise preserved lung volumes, exercise capacity and physical activity levels. Cluster II COPD patients had a higher smoking history and greater hyperinflation versus cluster I COPD patients. Cluster III COPD patients had reduced physical activity versus controls and clusters I and II COPD patients, and lower FEV1/FVC versus clusters I and II COPD patients.ConclusionsThe results emphasize heterogeneity within GOLD 1 COPD, supporting an individualized therapeutic approach to patients.Trial registrationwww.clinicaltrials.gov. NCT01360788 and NCT01072396.

Ganglioside GD2 is a plasma membrane glycosphinogolipid. In healthy adults it is expressed at low levels, but it is over-expressed in many cancers. For cancer therapy, GD2 is targeted with anti-GD2 monoclonal antibodies (mAbs), and one adverse side effect is severe visceral pain. Pain is not neuropathic, cannot be blocked with morphine, and stops on discontinuation of mAb therapy. Here, we provide evidence that ligand binding to cell surface GD2 induces rapid and transient activation of Src-family kinases, followed by Src-dependent phosphorylation of NMDA-receptor NR2B subunits selectively, activation of Ca++ fluxes, production of cAMP, and changes in cellular morphology. These GD2-ligand activated signals differ in kinetics and in pharmacology from activation of the same signals in the same cells by BDNF, the growth factor agonist of the TrkB receptor, suggesting biological specificity. Hence, cell surface GD2 regulates pathways that can be associated with neoplasia and with morphine-intractable pain; and this can explain why expression of GD2 correlates with these two pathologies.

Cuttlefish are cephalopods capable of rapid camouflage responses to visual stimuli. However, it is not always clear to what these animals are responding. Previous studies have found cuttlefish to be more responsive to lateral stimuli rather than substrate. However, in previous works, the cuttlefish were allowed to settle next to the lateral stimuli. In this study, we examine whether juvenile cuttlefish (Sepia officinalis) respond more strongly to visual stimuli seen on the sides versus the bottom of an experimental aquarium, specifically when the animals are not allowed to be adjacent to the tank walls. We used the Sub Sea Holodeck, a novel aquarium that employs plasma display screens to create a variety of artificial visual environments without disturbing the animals. Once the cuttlefish were acclimated, we compared the variability of camouflage patterns that were elicited from displaying various stimuli on the bottom versus the sides of the Holodeck. To characterize the camouflage patterns, we classified them in terms of uniform, disruptive, and mottled patterning. The elicited camouflage patterns from different bottom stimuli were more variable than those elicited by different side stimuli, suggesting that S. officinalis responds more strongly to the patterns displayed on the bottom than the sides of the tank. We argue that the cuttlefish pay more attention to the bottom of the Holodeck because it is closer and thus more relevant for camouflage.

In cases of myeloma cast nephropathy in need of haemodialysis (HD), reduction of free light chains using HD with High-Cut-Off filters (HCO-HD), in combination with chemotherapy, may be associated with better renal recovery. The aim of the present study is to evaluate the effectiveness of haemodiafiltration (HDF) in reducing free light chain levels using a less expensive heat sterilized high-flux polyphenylene HF dialyzer (HF-HDF).In a single-centre prospective cohort study, 327 dialysis sessions were performed using a 2.2 m2 heat sterilized high-flux polyphenylene HF dialyzer (Phylther HF22SD), a small (1.1m2) or large (2.1 m2) high-cut-off (HCO) dialyzer (HCOS and HCOL) in a cohort of 16 patients presenting with dialysis-dependent acute cast nephropathy and elevated free light chains (10 kappa, 6 lambda). The outcomes of the study were the mean reduction ratio (RR) of kappa and lambda, the proportion of treatments with an RR of at least 0.65, albumin loss and the description of patient outcomes. Statistical analysis was performed using linear and logistic regression through generalized estimating equation analysis so as to take into account repeated observation within subjects and adjust for session duration.There were no significant differences in the estimated marginal mean of kappa RR, which were respectively 0.67, 0.69 and 0.70 with HCOL-HD, HCOS-HDF and HF-HDF (P = 0.950). The estimated marginal mean of the proportions of treatments with a kappa RR ≥0.65 were 68%, 63% and 71% with HCOL-HD, HCOS-HDF and HF-HDF, respectively (P = 0.913). The estimated marginal mean of lambda RR were higher with HCOL-HDF (0.78), compared to HCOL-HD and HF-HDF (0.62, and 0.61 respectively). The estimated marginal mean proportion of treatments with a lambda RR ≥0.65 were higher with HCOL-HDF (81%), compared to 57% in HF-HDF (P = 0.042). The median albumin loss were 7, 21 and 63 g/session with HF-HDF, HCOL-HD and HCOL-HDF respectively (P = 0.044). Among survivors, 9 out of 10 episodes of acute kidney injuries became dialysis-independent following a median time of renal replacement therapy of 40 days (range 7-181).Therefore, in patients with acute dialysis-dependent myeloma cast nephropathy, in addition to chemotherapy, HDF with a heat sterilized high-flux polyphenylene HF dialyzer could offer an alternative to HCO dialysis for extracorporeal kappa reduction with lower albumin loss.

Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to 10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co-exposure to ethanol.

Elevated major ions (or salinity) are recognised as being a key contributor to the toxicity of many mine waste waters but the complex interactions between the major ions and large inter-species variability in response to salinity, make it difficult to relate toxicity to causal factors. This study aimed to determine if the toxicity of a typical saline seepage water was solely due to its major ion constituents; and determine which major ions were the leading contributors to the toxicity. Standardised toxicity tests using two tropical freshwater species Chlorella sp. (alga) and Moinodaphnia macleayi (cladoceran) were used to compare the toxicity of 1) mine and synthetic seepage water; 2) key major ions (e.g. Na, Cl, SO4 and HCO3); 3) synthetic seepage water that were modified by excluding key major ions. For Chlorella sp., the toxicity of the seepage water was not solely due to its major ion concentrations because there were differences in effects caused by the mine seepage and synthetic seepage. However, for M. macleayi this hypothesis was supported because similar effects caused by mine seepage and synthetic seepage. Sulfate was identified as a major ion that could predict the toxicity of the synthetic waters, which might be expected as it was the dominant major ion in the seepage water. However, sulfate was not the primary cause of toxicity in the seepage water and electrical conductivity was a better predictor of effects. Ultimately, the results show that specific major ions do not clearly drive the toxicity of saline seepage waters and the effects are probably due to the electrical conductivity of the mine waste waters.