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Because international students encounter unique stressors in addition to those experienced by all higher education students they are often assumed to be at heightened risk for experiencing mental health difficulties. However, empirical studies have consistently found that international students report comparable or lower rates of depression and anxiety than their domestic counterparts. The present study investigates one possible explanation for these unexpected results: are international students relatively resilient? More particularly, we investigate self-compassion (SC) -- an emotion-regulation strategy known to buffer the impact of stressors on mental health. While SC has been associated with positive psycho-social outcomes in the higher education context, existing studies have not disaggregated international and domestic students. The present study addresses that gap by comparing the levels and estimating the effects of SC among international and domestic students. Analyses found that international students on average reported significantly higher SC than their domestic counterparts. Without the protection afforded by those higher levels of SC, we estimated that international students would report higher psychological distress and lower psychological wellbeing than domestic students. Implications for fostering and supporting the mental health and wellbeing of all higher education students are discussed.

Emerging data suggest that air pollution is a persistent source of neuroinflammation, reactive oxygen species (ROS), and neuropathology that contributes to central nervous system (CNS) disorders. Previous research using animal models has shown that exposure to diesel exhaust causes considerable disruption of the blood-brain barrier (BBB), leading to marked neuroinflammation. However, the effects of biodiesel exhaust on cerebrovascular integrity and neuroinflammation have not been explored previously. Therefore, in this study, 8-week-old BALB/c mice were exposed to biodiesel exhaust (derived from canola biodiesel or tallow biodiesel) and compared with control mice that were exposed to air or mineral diesel exhaust. Consistently with previous findings, the integrity of the BBB was significantly disrupted by exposure to mineral diesel exhaust. Tallow and canola biodiesel exhaust exposure resulted in no BBB disruption. Moreover, both tallow and canola biodiesels significantly attenuated oxidative stress in the brain. The data collectively suggest that biodiesel exhaust may exert significantly less detrimental effects on brain function, compared to mineral diesel.

Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy in humans. Early moderate PAE was sufficient to affect site-specific DNA methylation in newborn pups without altering behavioural outcomes in adult littermates. Whole-genome bisulfite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. DNA methylation differences were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. In our murine model, a maternal diet high in folate and choline protected against some of the damaging effects of early moderate PAE on DNA methylation. Our studies demonstrate that early moderate exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.

Host recognition of the pathogen-associated molecular pattern (PAMP), β-1,3-glucan, plays a major role in antifungal immunity. β-1,3-glucan is an essential component of the inner cell wall of the opportunistic pathogen Candida albicans. Most β-1,3-glucan is shielded by the outer cell wall layer of mannan fibrils, but some can become exposed at the cell surface. In response to host signals such as lactate, C. albicans shaves the exposed β-1,3-glucan from its cell surface, thereby reducing the ability of innate immune cells to recognise and kill the fungus. We have used sets of barcoded xog1 and eng1 mutants to compare the impacts of the secreted β-glucanases Xog1 and Eng1 upon C. albicans in vitro and in vivo. Flow cytometry of Fc-dectin-1-stained strains revealed that Eng1 plays the greater role in lactate-induced β-1,3-glucan masking. Transmission electron microscopy and stress assays showed that neither Eng1 nor Xog1 are essential for cell wall maintenance, but the inactivation of either enzyme compromised fungal adhesion to gut and vaginal epithelial cells. Competitive barcode sequencing suggested that neither Eng1 nor Xog1 strongly influence C. albicans fitness during systemic infection or vaginal colonisation in mice. However, the deletion of XOG1 enhanced C. albicans fitness during gut colonisation. We conclude that both Eng1 and Xog1 exert subtle effects on the C. albicans cell surface that influence fungal adhesion to host cells and that affect fungal colonisation in certain host niches.

Abstract Background To develop effective public health policies, programs, and services tailored to the unique sexual health needs of migrant populations, it is essential to understand the myriad socio-ecological factors that influence their sexual health. This qualitative community-based participatory study aimed to explore factors influencing migrants’ sexual health at different socio-ecological levels in a Canadian setting. Methods Participants (n = 34) from African, Caribbean, Black; Latin American; South Asian; Middle Eastern, as well as East and Southeast Asian communities were recruited across Manitoba using printed flyers, community organizations, and social media. Individual interviews, conducted in English, French, Mandarin, Cantonese, Tagalog, Arabic, Swahili, and Tigrinya languages, explored questions relating to sexual health and experiences with service providers. Data were analyzed using reflexive thematic analysis and socio-ecological systems theory. Results The study uncovered a range of individual, interpersonal, institutional, and socio-structural factors that affect the sexual health of migrants in Manitoba. Individual factors such as sexual health knowledge and testing practices, interpersonal factors like the type of sexual partnerships, institutional factors such as sexual health information needs, language, and service access barriers, and structural-level factors like gender norms and HIV stigma exerted a significant influence on the sexual health practices of study respondents. Sexual health awareness was influenced by various factors including length of time in Canada and involvement in community-based services. Study respondents identified issues related to access to HIV testing and sexual health information, as well as language barriers, racism in healthcare, and HIV stigma. Gender and social norms played a significant role in discouraging communication about sex and safer sex practices. Conclusions The study highlights the complex interplay of factors that influence the sexual health of migrants, and the need for targeted sexual health awareness campaigns and provision of sexual health information in languages spoken by migrants. Public health interventions focused on improving the sexual health outcomes for migrants should consider the socio-ecological elements identified in this study. These findings can inform public health campaigns to increase access to services and address sexual health inequities among migrant communities in Canada.

Abstract The benefits of plant‐to‐plant facilitation in ecological restoration are well recognized, yet the potential for indirect trophic facilitation remains understudied. Nothofagus (southern beech; Nothofagaceae) is an iconic southern hemisphere tree genus that is frequently the focus of ecological restoration efforts. One aspect of Nothofagus ecology that may limit restoration success is the availability of appropriate ectomycorrhizal fungi. It has been suggested that pioneer dual‐mycorrhizal hosts such as Leptospermum species (Myrtaceae) could facilitate Nothofagus establishment by providing fungal inoculum, but the capacity for Nothofagus to use Leptospermum ectomycorrhizal fungi is unknown. To investigate potential indirect facilitation, we conducted a common garden pot trial to determine if Nothofagus cliffortioides (mountain beech) can use symbionts from Leptospermum scoparium (mānuka) ectomycorrhizal communities. Nothofagus and Leptospermum seedlings were grown in monoculture and mixed pairs with reciprocal “home” and “away” soil fungal inoculum. ITS2 metabarcoding of eDNA from hyphal ingrowth bags revealed that Nothofagus and Leptospermum inoculum contained different ectomycorrhizal fungal communities, but that half of the common ectomycorrhizal taxa identified were found in both soil types, suggesting generalist fungi exist. Nothofagus was able to form associations with some fungal species originating from Leptospermum inoculum, however, probable spore contamination meant that the proportion of root colonization associated with those species was ambiguous. Root ectomycorrhizal colonization rates were positively associated with seedling biomass, and there was some evidence of a home soil inoculum advantage in Nothofagus, but these effects were minor. Additionally, we found evidence that home inoculum provides a protective advantage against drought stress for Leptospermum seedlings. Our results indicate the potential for using Leptospermum to promote Nothofagus establishment in restoration plantings and highlight the possible benefits of considering fungal mutualists in ecological restoration projects.

Abstract Hospital-acquired diarrhoea (HAD) is common, and often associated with gut microbiota and metabolome dysbiosis following antibiotic administration. Clostridioides difficile is the most significant antibiotic-associated diarrhoeal (AAD) pathogen, but less is known about the microbiota and metabolome associated with AAD and C. difficile infection (CDI) with contrasting antibiotic treatment. We characterised faecal microbiota and metabolome for 169 HAD patients (33 with CDI and 133 non-CDI) to determine dysbiosis biomarkers and gain insights into metabolic strategies C. difficile might use for gut colonisation. The specimen microbial community was analysed using 16 S rRNA gene amplicon sequencing, coupled with untargeted metabolite profiling using gas chromatography-mass spectrometry (GC-MS), and short-chain fatty acid (SCFA) profiling using GC-MS. AAD and CDI patients were associated with a spectrum of dysbiosis reflecting non-antibiotic, short-term, and extended-antibiotic treatment. Notably, extended antibiotic treatment was associated with enterococcal proliferation (mostly vancomycin-resistant Enterococcus faecium) coupled with putative biomarkers of enterococcal tyrosine decarboxylation. We also uncovered unrecognised metabolome dynamics associated with concomitant enterococcal proliferation and CDI, including biomarkers of Stickland fermentation and amino acid competition that could distinguish CDI from non–CDI patients. Here we show, candidate metabolic biomarkers for diagnostic development with possible implications for CDI and vancomycin-resistant enterococci (VRE) treatment.

ABSTRACT: Acquired arteriovenous malformations (AVM) of the uterus can cause life-threatening vaginal bleeding and are associated with previous pregnancy, abortion or pelvic trauma. The pathophysiology is not well understood and the diagnosis is usually made by greyscale ultrasound often with nonspecific imaging findings, hence making it difficult to establish a correct diagnosis and therefore also the true incidence. However, case reports have previously described a connection between AVM formation and placental invasive disorders. In this report we demonstrate a case of a woman diagnosed with an AVM by ultrasound, presenting with menorrhagia after a termination of pregnancy, resulting in an emergency hysterectomy where subsequently a vascular malformation was found in conjunction with a remnant of a placenta increta and a placental site nodule. We hence suggest the hypothesis that these conditions are part of the same pathological process in the spectrum of abnormal invasive placental disorders, and that in the setting of previous trophoblastic processes, vascular malformations may mimic AVMs and ought not in fact to be considered as true AVMs.

​​​​​​​Electronic cigarettes (e-cigarettes) lack regulatory status as therapeutic products in all jurisdictions worldwide. They are potentially unsafe consumer products, with significant evidence they pose a risk to human health. Therefore, developing rapid, economical test methods to assess the chemical composition of e-liquids in heated and unheated forms and the aerosols produced by e-cigarettes is crucial. Four different e-liquids were heated using two different methods: (1) “typical” vaping using an e-cigarette device, by cycling “on” for 3 s every minute for 2 h (e-liquid obtained from remainder in the tank and aerosol collected in an impinger), and (2) “accelerated” heating, using an e-cigarette coil submerged in e-liquid and heating in short 20 s bursts on then 20 s off for 2 min only (liquid traps aerosol produced). All e-liquids were then analysed to test for the presence and quantity of 13 chemicals by gas chromatography–mass spectrometry and compared to an unheated sample. E-liquids heated with the accelerated method showed a comparable trend to the typical heating method, i.e. increase or decrease in chemical compound quantity, for more than two-thirds of the detected compounds analysed over all e-liquids. Six chemicals were detected as aerosol from the impinger fluid with the typical heating method at negligible levels. We propose that this accelerated version of the typical vaping method could form the basis of a standardized screening tool to test heated e-liquids (and e-cigarette aerosols) for harmful or banned substances. This will ensure that only approved products reach the consumer and reduce potential e-cigarette harm.

ABSTRACT Microbial species capable of co-existing with healthy individuals, such as the commensal fungus Candida albicans, exploit multifarious strategies to evade our immune defenses. These strategies include the masking of immunoinflammatory pathogen-associated molecular patterns (PAMPs) at their cell surface. We reported previously that C. albicans actively reduces the exposure of the proinflammatory PAMP, β-1,3-glucan, at its cell surface in response to host-related signals such as lactate and hypoxia. Here, we show that clinical isolates of C. albicans display phenotypic variability with respect to their lactate- and hypoxia-induced β-1,3-glucan masking. We have exploited this variability to identify responsive and non-responsive clinical isolates. We then performed RNA sequencing on these isolates to reveal genes whose expression patterns suggested potential association with lactate- or hypoxia-induced β-1,3-glucan masking. The deletion of two such genes attenuated masking: PHO84 and NCE103. We examined NCE103-related signaling further because NCE103 has been shown previously to encode carbonic anhydrase, which promotes adenylyl cyclase-protein kinase A (PKA) signaling at low CO2 levels. We show that while CO2 does not trigger β-1,3-glucan masking in C. albicans, the Sch9-Rca1-Nce103 signaling module strongly influences β-1,3-glucan exposure in response to hypoxia and lactate. In addition to identifying a new regulatory module that controls PAMP exposure in C. albicans, our data imply that this module is important for PKA signaling in response to environmental inputs other than CO2.IMPORTANCEOur innate immune defenses have evolved to protect us against microbial infection in part via receptor-mediated detection of “pathogen-associated molecular patterns” (PAMPs) expressed by invading microbes, which then triggers their immune clearance. Despite this surveillance, many microbial species are able to colonize healthy, immune-competent individuals, without causing infection. To do so, these microbes must evade immunity. The commensal fungus Candida albicans exploits a variety of strategies to evade immunity, one of which involves reducing the exposure of a proinflammatory PAMP (β-1,3-glucan) at its cell surface. Most of the β-1,3-glucan is located in the inner layer of the C. albicans cell wall, hidden by an outer layer of mannan fibrils. Nevertheless, some β-1,3-glucan can become exposed at the fungal cell surface. However, in response to certain specific host signals, such as lactate or hypoxia, C. albicans activates an anticipatory protective response that decreases β-1,3-glucan exposure, thereby reducing the susceptibility of the fungus to impending innate immune attack. Here, we exploited the natural phenotypic variability of C. albicans clinical isolates to identify strains that do not display the response to β-1,3-glucan masking signals observed for the reference isolate, SC5314. Then, using genome-wide transcriptional profiling, we compared these non-responsive isolates with responsive controls to identify genes potentially involved in β-1,3-glucan masking. Mutational analysis of these genes revealed that a sensing module that was previously associated with CO2 sensing also modulates β-1,3-glucan exposure in response to hypoxia and lactate in this major fungal pathogen of humans.

Background. Local health services make limited use of economic evaluation to inform decisions to fund new health service interventions. One barrier is the relevance of published intervention effects to the local setting, given these effects can strongly reflect the original evaluation context. Expert elicitation methods provide a structured approach to explicitly and transparently adjust published effect estimates, which can then be used in local-level economic evaluations to increase their local relevance. Expert elicitation was used to adjust published effect estimates for 2 interventions targeting the prevention of inpatient hypoglycemia. Methods. Elicitation was undertaken with 6 clinical experts. They were systematically presented with information regarding potential differences in patient characteristics and quality of care between the published study and local contexts, and regarding the design and application of the published study. The experts then assessed the intervention effects and provided estimates of the most realistic, most pessimistic, and most optimistic intervention effect sizes in the local context. Results. The experts estimated both interventions would be less effective in the local setting compared with the published effect estimates. For one intervention, the experts expected the lower complexity of admitted patients in the local setting would reduce the intervention’s effectiveness. For the other intervention, the reduced effect was largely driven by differences in the scope of implementation (hospital-wide in the local setting compared with targeted implementation in the evaluation). Conclusions. The pragmatic elicitation methods reported in this article provide a feasible and acceptable approach to assess and adjust published intervention effects to better reflect expected effects in the local context. Further development and application of these methods is proposed to facilitate the use of local-level economic evaluation. Highlights Local health services make limited use of economic evaluation to inform their decisions on the funding of new health service interventions. One barrier to use is the relevance of published intervention evaluations to the local setting. Expert elicitation methods provide a structured way to consider differences between the evaluation and local settings and to explicitly and transparently adjust published effect estimates for use in local economic evaluations. The pragmatic elicitation methods reported in this article offer a feasible and acceptable approach to adjusting published intervention effects to better reflect the effects expected in the local context. This increases the relevance of economic evaluations for local decision makers.

ABSTRACT There has been a decrease in healthcare-associated Clostridioides difficile infection (CDI) in Australia, coupled with an increase in the genetic diversity of strains isolated in these settings, and an increase in community-associated cases. To explore this changing epidemiology, we studied the genetic relatedness of C. difficile isolated from patients at a major hospital in Melbourne, Australia. Whole-genome sequencing of C. difficile isolates from symptomatic (n = 61) and asymptomatic (n = 10) hospital patients was performed. Genomic comparisons were made using single-nucleotide polymorphism (SNP) analysis, ribotyping, and toxin, resistome, and mobilome profiling. C. difficle clade 1 strains were found to be predominant (64/71), with most strains (63/71) encoding both toxins A and B (A+B+). Despite these similarities, only two isolates were genetically related (≤2 SNPs) and a diverse range of ribotypes was detected, with those predominating including ribotypes commonly found in community-associated cases. Five non-toxigenic (A−B−CDT−) clade 1 strains were identified, all in asymptomatic patients. Three clade 4 (A−B+CDT−) and four clade 5 (A+B+CDT+) strains were detected also, with these strains more likely to carry antimicrobial resistance determinants, many of which were associated with mobile genetic elements. Overall, within a single hospital, C. difficile-associated disease was caused by a diverse range of strains, including many strain types associated with community and environmental sources. While strains carried asymptomatically were more likely to be non-toxigenic, toxigenic strains were isolated also from asymptomatic patients, which together suggest the presence of diverse sources of transmission, potentially including asymptomatic patients. IMPORTANCE There has been a decrease in healthcare-associated Clostridioides difficile infection in Australia, but an increase in the genetic diversity of infecting strains, and an increase in community-associated cases. Here, we studied the genetic relatedness of C. difficile isolated from patients at a major hospital in Melbourne, Australia. Diverse ribotypes were detected, including those associated with community and environmental sources. Some types of isolates were more likely to carry antimicrobial resistance determinants, and many of these were associated with mobile genetic elements. These results correlate with those of other recent investigations, supporting the observed increase in genetic diversity and prevalence of community-associated C. difficile, and consequently the importance of sources of transmission other than symptomatic patients. Thus, they reinforce the importance of surveillance for in both hospital and community settings, including asymptomatic carriage, food, animals, and other environmental sources to identify and circumvent important sources of C. difficile transmission.

ABSTRACTMany Indigenous communities in Canada experience endemic tuberculosis with superimposed periodic epidemic outbreaks. Failures in outbreak management have resulted in the “seeding” of future infection and disease. In this paper we present a model that may be used in planning, implementation and review of tuberculosis outbreak management in Cree Indigenous communities in Canada, based on the Medicine Wheel, a paradigm for holistic living. In the context of tuberculosis management, the Medicine Wheel provides a path for the establishment of respectful cross-cultural relationships, the expression of values through action, true community engagement and partnership, and the establishment of culture-based processes of transparency, accountability and change.

Objectives: Ethnic minorities (EM) are still underrepresented in research recruitment. Despite wide literature outlining the barriers, enablers and recommendations for driving inclusion and diversity in research, there is still little evidence for successful diversity in research participation, which has a direct impact on the quality of care provided to ethnically diverse individuals. A new, comprehensive approach to recruitment strategies is therefore necessary. Study design: service improvement initiative. Methods: In the light of the Covid-19 pandemic and the key public health need to address the disparity in care provided to non-white populations, we used a novel, comprehensive approach (The King's Model) comprising of local and community actions to promote inclusive research recruitment. We then compared rates of diverse recruitment in studies where the novel approach, was applied to studies which had been closed to recruitment at the time of analysis and where ethnicity data was available. Results: Our results demonstrate that following the introduction of the King's Model for diverse recruitment, commercial interventional study diverse recruitment increased from 6.4% to 16.1%, and for non-commercial studies, from 30.2% to 41.0% and 59.2% in the selected studies. Conclusions: King's Model is potentially a useful tool in enhancing non-Caucasian recruitment to clinical research. Enriched by additional recommendations based on our experiences during the Covid-19 research recruitment drive, we propose the King's Model is used to support ethnically diverse research recruitment. Further evidence is needed to replicate our findings, although this preliminary evidence provides granular details necessary to address the key unmet need of validating clinical research outcomes in non-white populations.

Prevalence studies indicate that higher degree research (Master's and Doctoral) students experience high rates of psychological distress. As a result, universities are seeking evidence-based interventions to better support the mental wellbeing of this student cohort. The present study contributes to that evidence base by asking higher degree research students (HDRs) from a large Australian research-intensive university what they think should be done to improve their wellbeing. After inductively analysing 595 open-ended survey responses, nine themes emerged. The four most prominent themes were culture and community, support services, supervisors and supervision practices, and peer engagement and networking. These themes are interpreted by drawing on the Job Demands-Resources theory of occupational stress. We also compare our findings with typologies of 'doctoral challenges' developed in prior research to extend and refine the 'roadmap' for policy, action and research to better understand and address the high levels of psychological distress that HDRs experience. Overall, the findings of this study suggest that HDRs are likely to benefit from a whole-of-university approach to supporting their wellbeing, and from an academic research culture that values the wellbeing of all its members.

Although high PhD attrition rates are a matter of international concern, the factors that lead doctoral researchers to leave their programmes are not well understood. The present study addresses that issue by exploring factors that prompted thoughts of discontinuing among 1017 PhD researchers (PhDRs) at a public, research-intensive Australian university. We analyse the prevalence, strength and clustering of the most frequently identified factors, including mental health difficulties, financial pressures, and problems with supervision. The investigated factors were all strongly associated with thoughts of discontinuing; mental health difficulties were among the strongest factors, and financial stress was the most prevalent. An exploratory cluster analysis revealed that the risk factors co-present in distinctive ways such that six discrete groups of PhDRs are identifiable with varying risk profiles and socio-demographic characteristics. We discuss the research, policy and practice implications of these findings.

University students are known to be at heightened risk among their peers for experiencing psychological distress and mental health difficulties. To date, there have been few interventions designed to reduce stressors in the educational environment. This may be due to limited research investigating course-related correlates of students' distress. The present study addresses that gap by identifying and exploring the extent to which six common elements of coursework programmes predict students' scores on measures of depression, anxiety, stress, wellbeing and satisfaction with life. It finds that the investigated coursework experiences account for more variance in students' wellbeing scores than factors such as financial strain, worry about future employment, English language difficulties and minority group status. It is hoped these findings assist university course coordinators and academic educators to design and develop curricula, teaching approaches and learning environments likely to mitigate students' high levels of distress and actively support positive mental wellbeing.

γδ T-cells provide immune surveillance against cancer, straddling both innate and adaptive immunity. G115 is a clonal γδ T-cell receptor (TCR) of the Vγ9Vδ2 subtype which can confer responsiveness to phosphoantigens (PAgs) when genetically introduced into conventional αβ T-cells. Cancer immunotherapy using γδ TCR-engineered T-cells is currently under clinical evaluation. In this study, we sought to broaden the cancer specificity of the G115 γδ TCR by insertion of a tumour-binding peptide into the complementarity-determining region (CDR) three regions of the TCR δ2 chain. Peptides were selected from the foot and mouth disease virus A20 peptide which binds with high affinity and selectivity to αvβ6, an epithelial-selective integrin that is expressed by a range of solid tumours. Insertion of an A20-derived 12mer peptide achieved the best results, enabling the resulting G115 + A12 T-cells to kill both PAg and αvβ6-expressing tumour cells. Cytolytic activity of G115 + A12 T-cells against PAg-presenting K562 target cells was enhanced compared to G115 control cells, in keeping with the critical role of CDR3 δ2 length for optimal PAg recognition. Activation was accompanied by interferon (IFN)-γ release in the presence of either target antigen, providing a novel dual-specificity approach for cancer immunotherapy.

Retrotransposons are mobile genetic elements normally repressed by DNA methylation in differentiated cells. Here, the authors show that DNA hypomethylation in mouse induced pluripotent stem cells allows retrotransposons to jump, but this can be blocked with a reverse transcriptase inhibitor.

Introduction In Manitoba, Canada, there has been an increase in the number of people newly diagnosed with HIV and those not returning for regular HIV care. The COVID-19 pandemic resulted in increased sex and gender disparities in disease risk and mortalities, decreased harm reduction services and reduced access to healthcare. These health crises intersect with increased drug use and drug poisoning deaths, houselessness and other structural and social factors most acutely among historically underserved groups. We aim to explore the social and structural barriers and facilitators to HIV care and harm reduction services experienced by people living with HIV (PLHIV) in Manitoba.Methods and analysis Our study draws on participatory action research design. Guiding the methodological design are the lived experiences of PLHIV. In-depth semi-structured face-to-face interviews and quantitative questionnaires will be conducted with two groups: (1) persons aged ≥18 years living or newly diagnosed with HIV and (2) service providers who work with PLHIV. Data collection will include sex, gender, sociodemographic information, income and housing, experiences with the criminal justice system, sexual practices, substance use practices and harm reduction access, experiences with violence and support, HIV care journey (since diagnosis until present), childhood trauma and a decision-making questionnaire. Data will be analysed intersectionally, employing grounded theory for thematic analysis, sex-based and gender-based analysis and social determinants of health and syndemic framework to understand the experiences of PLHIV in Manitoba.Ethics and dissemination We received approval from the University of Manitoba Health Ethics Research Board (HS25572; H2022:218), First Nations Health and Social Secretariat of Manitoba, Nine Circles Community Health Centre, Shared Health Manitoba (SH2022:194) and 7th Street Health Access Centre. Findings will be disseminated using community-focused knowledge translation strategies identified by participants, peers, community members and organisations, and reported in conferences, peer-reviewed journals and a website (www.alltogether4ideas.org).

Abstract Background Various washout policies are widely used in adults living with long-term catheters (LTC). There is currently insufficient evidence on the benefits and potential harms of prophylactic LTC washout policies in the prevention of blockages and other LTC-related adverse events, such as urinary tract infections. CATHETER II tests the hypothesis that weekly prophylactic LTC washouts (normal saline or citric acid) in addition to standard LTC care reduce the incidence of catheter blockage requiring intervention compared to standard LTC care only in adults living with LTC. Methods CATHETER II is a pragmatic three-arm open multi-centre superiority randomised controlled trial with an internal pilot, economic analysis, and embedded qualitative study. Eligible participants are adults aged ≥ 18 years, who have had a LTC in use for ≥ 28 days, have no plans to discontinue the use of the catheter, are able to undertake the catheter washouts, and complete trial documentation or have a carer able to help them. Participants are identified from general practitioner practices, secondary/tertiary care, community healthcare, care homes, and via public advertising strategies. Participants are randomised 1:1:1 to receive a weekly saline (0.9%) washout in addition to standard LTC care, a weekly citric acid (3.23%) washout in addition to standard LTC care or standard LTC care only. Participants and/or carers will receive training to administer the washouts. Patient-reported outcomes are collected at baseline and for 24 months post-randomisation. The primary clinical outcome is catheter blockage requiring intervention up to 24 months post-randomisation expressed per 1000 catheter days. Secondary outcomes include symptomatic catheter-associated urinary tract infection requiring antibiotics, catheter change, adverse events, NHS/ healthcare use, and impact on quality of life. Discussion This study will guide treatment decision-making and clinical practice guidelines regarding the effectiveness of various prophylactic catheter washout policies in men and women living with LTC. This research has received ethical approval from Wales Research Ethics Committee 6 (19/WA/0015). Trial registration ISRCTN ISRCTN17116445 . Registered prospectively on 06 November 2019

Asthma is a complex medical problem for which currently available treatment can be incompletely effective. This case report describes a 49 year old woman who had suffered from asthma since her teenage years that resolved after she took up regular open water swimming. After sharing this case report with an international open water swimming community on social media, over one hundred people with asthma commented that their symptoms had also improved after taking up this activity. The mechanism whereby open water swimming might alleviate asthma has not been established. Possibilities include benefits to mental health, anti-inflammatory effects, being more fit, improved immune function and suppression of the bronchoconstrictive component of the diving reflex. Further research might usefully confirm or refute these clinical observations.

We evaluate if the iconic Australian Zebra Finch (Taeniopygia guttata) has a unique physiology or if its metabolic, thermal and hygric physiology are similar to other Australian poephiline finches, by comparing it with three other species, the arid-habitat Painted Finch (Emblema pictum) and the mesic-habitat Double-barred (Taeniopygia bichenovii) and Red-browed (Neochmia temporalis) Finches. All physiological variables responded to ambient temperature as expected. There were no species differences for any of the standard physiological variables, consistent with the hypotheses that birds are pre-adapted to arid habitats, the recent development of Australian deserts has limited opportunity for physiological adaptation, and all four species share similar behavioural and ecological traits. Nevertheless, the ambient temperature where metabolic water production equals evaporative water loss (point of relative water economy) was highest for the Zebra (19.1 °C), lower for Double-barred (16.4 °C) and Painted (15.2 °C) and lowest for Red-Browed (4.1 °C) Finches, corresponding with their general patterns of habitat aridity. The point of relative water economy may be a sensitive index for assessing a species’ tolerance of aridity because it integrates individual physiological variables. We conclude that the Zebra Finch is not a physiological outlier amongst Australian finches, but is at the end of a continuum of aridity tolerance for the four study species.

Intracellular pathogens construct their environmental niche, and influence disease susceptibility, by deploying factors that manipulate infected host cell gene expression. Theileria annulata is an important tick-borne parasite of cattle that causes tropical theileriosis. Excellent candidates for modulating host cell gene expression are DNA binding proteins bearing AT-hook motifs encoded within the TashAT gene cluster of the parasite genome. In this study, TashAT2 was transfected into bovine BoMac cells to generate three expressing and three non-expressing (opposite orientation) cell lines. RNA-Seq was conducted and differentially expressed (DE) genes identified. The resulting dataset was compared with genes differentially expressed between infected cells and non-infected cells, and DE genes between infected cell lines from susceptible Holstein vs tolerant Sahiwal cattle. Over 800 bovine genes displayed differential expression associated with TashAT2, 209 of which were also modulated by parasite infection. Network analysis showed enrichment of DE genes in pathways associated with cellular adhesion, oncogenesis and developmental regulation by mammalian AT-hook bearing high mobility group A (HMGA) proteins. Overlap of TashAT2 DE genes with Sahiwal vs Holstein DE genes revealed that a significant number of shared genes were associated with disease susceptibility. Altered protein levels encoded by one of these genes (GULP1) was strongly linked to expression of TashAT2 in BoMac cells and was demonstrated to be higher in infected Holstein leucocytes compared to Sahiwal. We conclude that TashAT2 operates as an HMGA analogue to differentially mould the epigenome of the infected cell and influence disease susceptibility.

Abstract Transcription factors (TFs) are the master regulators of cellular identity, capable of driving cell fate transitions including differentiations, reprogramming, and transdifferentiations. Pioneer TFs recognize partial motifs exposed on nucleosomal DNA, allowing for TF‐mediated activation of repressed chromatin. Moreover, there is evidence suggesting that certain TFs can repress actively expressed genes either directly through interactions with accessible regulatory elements or indirectly through mechanisms that impact the expression, activity, or localization of other regulatory factors. Recent evidence suggests that during reprogramming, the reprogramming TFs initiate opening of chromatin regions rich in somatic TF motifs that are inaccessible in the initial and final cellular states. It is postulated that analogous to a sponge, these transiently accessible regions “soak up” somatic TFs, hence lowering the initial barriers to cell fate changes. This indirect TF‐mediated gene regulation event, which is aptly named the “sponge effect,” may play an essential role in the silencing of the somatic transcriptional network during different cellular conversions.

ABSTRACT Candida albicans exists as a commensal of mucosal surfaces and the gastrointestinal tract without causing pathology. However, this fungus is also a common cause of mucosal and systemic infections when antifungal immune defenses become compromised. The activation of antifungal host defenses depends on the recognition of fungal pathogen-associated molecular patterns (PAMPs), such as β-1,3-glucan. In C. albicans, most β-1,3-glucan is present in the inner cell wall, concealed by the outer mannan layer, but some β-1,3-glucan becomes exposed at the cell surface. In response to host signals, such as lactate, C. albicans induces the Xog1 exoglucanase, which shaves exposed β-1,3-glucan from the cell surface, thereby reducing phagocytic recognition. We show here that β-1,3-glucan is exposed at bud scars and punctate foci on the lateral wall of yeast cells, that this exposed β-1,3-glucan is targeted during phagocytic attack, and that lactate-induced masking reduces β-1,3-glucan exposure at bud scars and at punctate foci. β-1,3-Glucan masking depends upon protein kinase A (PKA) signaling. We reveal that inactivating PKA, or its conserved downstream effectors, Sin3 and Mig1/Mig2, affects the amounts of the Xog1 and Eng1 glucanases in the C. albicans secretome and modulates β-1,3-glucan exposure. Furthermore, perturbing PKA, Sin3, or Mig1/Mig2 attenuates the virulence of lactate-exposed C. albicans cells in Galleria. Taken together, the data are consistent with the idea that β-1,3-glucan masking contributes to Candida pathogenicity. IMPORTANCE Microbes that coexist with humans have evolved ways of avoiding or evading our immunological defenses. These include the masking by these microbes of their “pathogen-associated molecular patterns” (PAMPs), which are recognized as “foreign” and used to activate protective immunity. The commensal fungus Candida albicans masks the proinflammatory PAMP β-1,3-glucan, which is an essential component of its cell wall. Most of this β-1,3-glucan is hidden beneath an outer layer of the cell wall on these microbes, but some can become exposed at the fungal cell surface. Using high-resolution confocal microscopy, we examine the nature of the exposed β-1,3-glucan at C. albicans bud scars and at punctate foci on the lateral cell wall, and we show that these features are targeted by innate immune cells. We also reveal that downstream effectors of protein kinase A (Mig1/Mig2, Sin3) regulate the secretion of major glucanases, modulate the levels of β-1,3-glucan exposure, and influence the virulence of C. albicans in an invertebrate model of systemic infection. Our data support the view that β-1,3-glucan masking contributes to immune evasion and the virulence of a major fungal pathogen of humans.

The immunogenicity of Candida albicans cells is influenced by changes in the exposure of microbe-associated molecular patterns (MAMPs) on the fungal cell surface. Previously, the degree of exposure on the C. albicans cell surface of the immunoinflammatory MAMP β-(1,3)-glucan was shown to correlate inversely with colonisation levels in the gastrointestinal (GI) tract. This is important because life-threatening systemic candidiasis in critically ill patients often arises from translocation of C. albicans strains present in the patient’s GI tract. Therefore, using a murine model, we have examined the impact of gut-related factors upon β-glucan exposure and colonisation levels in the GI tract.The degree of β-glucan exposure was examined by imaging flow cytometry of C. albicans cells taken directly from GI compartments, and compared with colonisation levels. Fungal β-glucan exposure was lower in the cecum than the small intestine, and fungal burdens were correspondingly higher in the cecum. This inverse correlation did not hold for the large intestine.The gut fermentation acid, lactate, triggers β-glucan masking in vitro, leading to attenuated anti-Candida immune responses. Additional fermentation acids are present in the GI tract, including acetate, propionate, and butyrate. We show that these acids also influence β-glucan exposure on C. albicans cells in vitro and, like lactate, they influence β-glucan exposure via Gpr1/Gpa2-mediated signalling. Significantly, C. albicans gpr1Δ gpa2Δ cells displayed elevated β-glucan exposure in the large intestine and a corresponding decrease in fungal burden, consistent with the idea that Gpr1/Gpa2-mediated β-glucan masking influences colonisation of this GI compartment. Finally, extracts from the murine gut and culture supernatants from the mannan grazing gut anaerobe Bacteroides thetaiotaomicron promote β-glucan exposure at the C. albicans cell surface. Therefore, the local microbiota influences β-glucan exposure levels directly (via mannan grazing) and indirectly (via fermentation acids), whilst β-glucan masking appears to promote C. albicans colonisation of the murine large intestine.

Biodiesel, which can be made from a variety of natural oils, is currently promoted as a sustainable, healthier replacement for commercial mineral diesel despite little experimental data supporting this. The aim of our research was to investigate the health impacts of exposure to exhaust generated by the combustion of diesel and two different biodiesels. Male BALB/c mice (n = 24 per group) were exposed for 2 h/day for 8 days to diluted exhaust from a diesel engine running on ultra-low sulfur diesel (ULSD) or Tallow or Canola biodiesel, with room air exposures used as control. A variety of respiratory-related end-point measurements were assessed, including lung function, responsiveness to methacholine, airway inflammation and cytokine response, and airway morphometry. Exposure to Tallow biodiesel exhaust resulted in the most significant health impacts compared to Air controls, including increased airway hyperresponsiveness and airway inflammation. In contrast, exposure to Canola biodiesel exhaust resulted in fewer negative health effects. Exposure to ULSD resulted in health impacts between those of the two biodiesels. The health effects of biodiesel exhaust exposure vary depending on the feedstock used to make the fuel.

Despite their increasing popularity, and Australia’s unique regulatory environment, how and why Australian adults use e-cigarettes and their perceptions of their safety, efficacy and regulation have not been extensively reported before. In this study, we screened 2217 adult Australians with the aim of assessing these questions in a sample of current or former e-cigarette users. A total of 505 out of 2217 respondents were current or former e-cigarette users, with only these respondents completing the full survey. Key findings of this survey included the high proportion of respondents who indicated they were currently using e-cigarettes (307 out of 2217 = 13.8%), and the high proportion of current e-cigarette users that were also smokers (74.6%). The majority of respondents used e-liquids containing nicotine (70.3%), despite it being illegal in Australia without a prescription, and the majority bought their devices and liquids in Australia (65.7%). Respondents reported using e-cigarettes in a variety of places, including inside the home, inside public places (where it is illegal to smoke tobacco cigarettes), and around other people—which has implications for second and third hand exposures. A significant proportion of current e-cigarette users (30.6%) thought that e-cigarettes were completely safe to use long-term, although in general, there was a large amount of uncertainty/ambivalence with respect to perceptions of e-cigarette safety and efficacy as smoking cessation tools. This study shows that e-cigarette use is common in Australia, and that appropriate dissemination of unbiased research findings on their safety and efficacy in smoking cessation is urgently required.

Co-stimulation is critical to the function of chimeric antigen receptor (CAR) T-cells. Previously, we demonstrated that dual co-stimulation can be effectively harnessed by a parallel (p)CAR architecture in which a CD28-containing second generation CAR is co-expressed with a 4-1BB containing chimeric co-stimulatory receptor (CCR). When compared to linear CARs, pCAR-engineered T-cells elicit superior anti-tumor activity in a range of pre-clinical models. Since CD19 is the best validated clinical target for cellular immunotherapy, we evaluated a panel of CD19-specific CAR and pCAR T-cells in this study. First, we generated a panel of single chain antibody fragments (scFvs) by alanine scanning mutagenesis of the CD19-specific FMC63 scFv (VH domain) and these were incorporated into second generation CD28+CD3ζ CARs. The resulting panel of CAR T-cells demonstrated a broad range of CD19 binding ability and avidity for CD19-expressing tumor cells. Each scFv-modified CAR was then converted into a pCAR by co-expression of an FMC63 scFv-targeted CCR with a 4-1BB endodomain. When compared to second generation CARs that contained an unmodified or mutated FMC63 scFv, each pCAR demonstrated a significant enhancement of tumor re-stimulation potential and IL-2 release, reduced exhaustion marker expression and enhanced therapeutic efficacy in mice with established Nalm-6 leukemic xenografts. These data reinforce the evidence that the pCAR platform delivers enhanced anti-tumor activity through effective provision of dual co-stimulation. Greatest anti-tumor activity was noted for intermediate avidity CAR T-cells and derived pCARs, raising the possibility that effector to target cell avidity is an important determinant of efficacy.

Schuster et al. make the important observation that small numbers of trypanosomes can infect tsetse flies, and further argue that this can occur whether the infecting parasites are developmentally ‘slender’ or ‘stumpy’(Schuster et al., 2021). We welcome their careful experiments but disagree that they require a rethink of the trypanosome life-cycle. Instead, the study reveals that stumpy forms are more likely to successfully infect flies, the key limit on parasite transmission, and we predict this advantage would be greatly amplified in tsetse infections in the field. Further, we argue that stumpy forms are defined by a suite of molecular adaptations for life-cycle progression, with morphology being a secondary feature. Finally, their dominance in chronic infections means most natural tsetse infections would involve stumpy forms, even in small numbers. Our interpretation does not require re-evaluation of the obligatory life cycle of the parasite, where stumpy forms are selected to sustain transmission.

This study examined the relationship between loss of income due to the COVID-19 pandemic and worsening mental health among a sample of 366 Two-Spirit, gay, bisexual, queer (2SGBQ+) men in Manitoba. Data were drawn from a cross-sectional online survey among 2SGBQ+ men in Manitoba. Logistic regression assessed the relationship between sociodemographics, loss of income due to COVID-19 (independent variable) and worsening of mental health (analytic outcome). Among all respondents in the sample (N = 366), 55% indicated worsening of their mental health. In logistic regression, compared to participants who did not experience any loss of income, those who experienced loss of income due to the COVID-19 pandemic were significantly more likely to report worsening mental health (Adjusted Odds Ratio [AOR] = 8.32, 95% Confidence Interval[CI] = 3.54-19.54). Compared to participants who self-identified as gay, bisexual-identifying participants were less likely to report worsening mental health (AOR = .35, 95%CI = 0.13-0.96). Finally, as compared to participants who were married or partnered, participants who were dating (AOR = 3.14, 95%CI = 1.60-6.17), single (AOR = 4.08, 95%CI = 1.75-9.52), and separated/divorced/widowed (AOR = 15.08, 95%CI = 2.22-102.51) were all significantly more likely to report experiencing a worsening of mental health due to the COVID-19 pandemic. This study highlights the need to develop robust public strategies for sub-populations of 2SGBQ+ men (non-gay identified sexual minorities and 2SGBQ+ men who may be more socially isolated). Specific targeted and tailored public health interventions designed with the unique needs of 2SGBQ+ men in Manitoba may be required to increase their access to socio-economic and mental health supports.

Introduction: The shift to remote working/learning to slow transmission of the SARS-CoV-2 virus has had widespread mental health impacts. We aimed to describe how the COVID-19 pandemic impacted the mental health of students and faculty within a health sciences faculty at a central Canadian university. Methods: Via an online survey, we queried mental health in the first four months of the COVID-19 pandemic quantitatively (scale: 1 (most negative)-100 (most positive)) and qualitatively. Results: The sample (n = 110) was predominantly women (faculty 39/59; [66.1%]; students 46/50; [92.0%]). Most faculty were married/common law (50/60; [84.8%]) and had children at home (36/60; [60.0%]); the opposite was true for most students. Faculty and students self-reported comparable mental health (40.47±24.26 and 37.62±26.13; respectively). Amongst women, those with vs. without children at home, reported significantly worse mental health impacts (31.78±23.68 vs. 44.29±27.98; respectively, p = 0.032). Qualitative themes included: “Sharing resources,” “spending money,” “few changes,” for those without children at home; “working at home can be isolating,” including the subtheme, “balancing act”: “working in isolation,” “working more,” for those with children at home. Discussion: Amongst women in academia, including both students and faculty, those with children at home have disproportionately worse mental health than those without children at home.

Background Knowledge of factors that influence the outcome of infection are crucial for determining the risk of severe disease and requires the characterisation of pathogen-host interactions that have evolved to confer variable susceptibility to infection. Cattle infected by Theileria annulata show a wide range in disease severity. Native (Bos indicus) Sahiwal cattle are tolerant to infection, whereas exotic (Bos taurus) Holstein cattle are susceptible to acute disease. Methodology/Principal findings We used RNA-seq to assess whether Theileria infected cell lines from Sahiwal cattle display a different transcriptome profile compared to Holstein and screened for altered expression of parasite factors that could generate differences in host cell gene expression. Significant differences (Conclusions/Significance We conclude that divergent pathogen-host molecular interactions that influence chromatin architecture of the infected cell are a major determinant in the generation of gene expression differences linked to disease susceptibility.