An integrated knowledge translation (iKT) approach to advancing community-based depression care in Vietnam: lessons from an ongoing research-policy collaboration.

BACKGROUND: Evidence-based mental health policies are key to supporting the expansion of community-based mental health care and are increasingly being developed in low and middle-income countries (LMICs). Despite this, research on the process of mental health policy development in LMICs is limited. Engagement between researchers and policy makers via an integrated Knowledge Translation (iKT) approach can help to facilitate the process of evidence-based policy making. This paper provides a descriptive case study of a decade-long policy and research collaboration between partners in Vietnam, Canada and Australia to advance mental health policy for community-based depression care in Vietnam. METHODS: This descriptive case study draws on qualitative data including team meeting minutes, a focus group discussion with research team leaders, and key informant interviews with two Vietnamese policy makers. Our analysis draws on Murphy et al.'s (2021) findings and recommendations related to stakeholder engagement in global mental health research. RESULTS: Consistent with Murphy et al.'s findings, facilitating factors across three thematic categories were identified. Related to 'the importance of understanding context', engagement between researchers and policy partners from the formative research stage provided a foundation for engagement that aligned with local priorities. The COVID-19 pandemic acted as a catalyst to further advance the prioritization of mental heath by the Government of Vietnam. 'The nature of engagement' is also important, with findings demonstrating that long-term policy engagement was facilitated by continuous funding mechanisms that have enabled trust-building and allowed the research team to respond to local priorities over time. 'Communication and dissemination' are also crucial, with the research team supporting mental health awareness-raising among policy makers and the community, including via capacity building initiatives. CONCLUSIONS: This case study identifies factors influencing policy engagement for mental health system strengthening in an LMIC setting. Sustained engagement with policy leaders helps to ensure alignment with local priorities, thus facilitating uptake and scale-up. Funding agencies can play a crucial role in supporting mental health system development through longer term funding mechanisms. Increased research related to the policy engagement process in global mental health will further support policy development and improvement in mental health care in LMICs.

Assistive Technology Workplace Accommodation and Employment among Diverse Populations with Disabilities: Does Race/Ethnicity Matter?

The purpose of this study was to examine the relationship between assistive technology workplace accommodation (AT-WA) usage and employment status among racial/ethnic populations with disabilities. Chi-square tests and logistic regression were used to analyze secondary data from the 2015 Kessler Foundation National Employment and Disability Survey (KFNEDS). Results indicated that significantly more consumers who used AT-WA were currently working, and a significantly greater proportion of them were White. Moreover, a significantly lower proportion of those who did not use AT-WA had less expected odds of being currently employed. Specific implications are discussed to inform practices, policy, and/or future research.

Tissue-specific roles for sonic hedgehog signaling in establishing thymus and parathyroid organ fate.

The thymus and parathyroids develop from third pharyngeal pouch (3rd pp) endoderm. Our previous studies show that Shh null mice have smaller, aparathyroid primordia in which thymus fate specification extends into the pharynx. SHH signaling is active in both dorsal pouch endoderm and neighboring neural crest (NC) mesenchyme. It is unclear which target tissue of SHH signaling is required for the patterning defects in Shh mutants. Here, we used a genetic approach to ectopically activate or delete the SHH signal transducer Smo in either pp endoderm or NC mesenchyme. Although no manipulation recapitulated the Shh null phenotype, manipulation of SHH signaling in either the endoderm or NC mesenchyme had direct and indirect effects on both cell types during fate specification and organogenesis. SHH pathway activation throughout pouch endoderm activated ectopic Tbx1 expression and partially suppressed the thymus-specific transcription factor Foxn1, identifying Tbx1 as a key target of SHH signaling in the 3rd pp. However, ectopic SHH signaling was insufficient to expand the GCM2-positive parathyroid domain, indicating that multiple inputs, some of which might be independent of SHH signaling, are required for parathyroid fate specification. These data support a model in which SHH signaling plays both positive and negative roles in patterning and organogenesis of the thymus and parathyroids.

Underutilized and undertheorized: the use of hospitalization for ambulatory care sensitive conditions for assessing the extent to which primary healthcare services are meeting needs in British Columbia First Nation communities.

BACKGROUND: Since the 1960s, the federal government has been providing or funding a selection of community-based primary healthcare (PHC) programs on First Nations reserves. A key question is whether local access to PHC can help address health inequities in First Nations on-reserve communities in British Columbia (BC). OBJECTIVES: This paper examines whether hospitalization for Ambulatory Care Sensitive Conditions (1) can be used as a proxy measure for the organization of PHC in First Nations reserve areas; and (2) is associated with premature mortality rates. METHODS: In this descriptive correlational study, we used administrative data available through Population Data BC, including demographic and ecological information (i.e. geo-codes indicating location of residence). We used two different measures of hospitalization: rates of episodic hospital care and rates of length of stay. We correlated hospitalization rates with premature mortality rates and the level of care available in First Nations communities, which depends on a federal funding formula based upon community size and, more specifically, the level of isolation from a provincial point of care. RESULTS: First Nations communities in BC that have local 24/7 access to PHC services have similar rates of hospitalization for ACSC to those living in urban centres. This is demonstrated by the similarities in the strengths of the correlation between premature mortality rates and rates of avoidable hospitalization for conditions treatable in a PHC setting. This is not the case for communities served by a Health Centre (weaker correlation) and for communities serviced by a Health Station or with no on-reserve point of care (no correlation). CONCLUSIONS: Improving access to PHC services in First Nations communities can be associated with a significant reduction in avoidable hospitalization and premature mortality rates. The method we tested is an important tool that could serve health care planning decisions in small communities.

The RNA-binding protein Tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome.

The NLRP3 inflammasome is a central regulator of inflammation in many common diseases, including atherosclerosis and type 2 diabetes, driving the production of pro-inflammatory mediators such as IL-1ß and IL-18. Due to its function as an inflammatory gatekeeper, expression and activation of NLRP3 need to be tightly regulated. In this study, we highlight novel post-transcriptional mechanisms that can modulate NLRP3 expression. We have identified the RNA-binding protein Tristetraprolin (TTP) as a negative regulator of NLRP3 in human macrophages. TTP targets AU-rich elements in the NLRP3 3'-untranslated region (UTR) and represses NLRP3 expression. Knocking down TTP in primary macrophages leads to an increased induction of NLRP3 by LPS, which is also accompanied by increased Caspase-1 and IL-1ß cleavage upon NLRP3, but not AIM2 or NLRC4 inflammasome activation. Furthermore, we found that human NLRP3 can be alternatively polyadenylated, producing a short 3'-UTR isoform that excludes regulatory elements, including the TTP- and miRNA-223-binding sites. Because TTP also represses IL-1ß expression, it is a dual inhibitor of the IL-1ß system, regulating expression of the cytokine and the upstream controller NLRP3.

Hospitalization for mental health related ambulatory care sensitive conditions: what are the trends for First Nations in British Columbia?

BACKGROUND: Indigenous peoples globally experience a disproportionate burden of mental illness due to forced policies and practices of colonization and cultural disruption. The objective of this study was to provide a baseline profile of hospitalization rates for mental health-related Ambulatory Care Sensitive Conditions among First-Nations living both on and off reserve in British Columbia, Canada, and explore the relationship between local access to health services and mental health-related hospitalization rates. METHODS: A population-based time trend analysis of mental health-related Ambulatory Care Sensitive Conditions hospitalizations was conducted using de-identified administrative health data. The study population included all residents eligible under the universal British Columbia Medical Services Plan and living on and off First Nations reserves between 1994/95 and 2009/10. The definition of mental health-related Ambulatory Care Sensitive Conditions included mood disorders and schizophrenia, and three different change measures were used to operationalize avoidable hospitalizations: 1) rates of episodes of hospital care, 2) rates of length of stay, and 3) readmission rates. Data were analyzed using generalized estimating equations approach, controlling for age, sex, and socio-economic status, to account for change over time. RESULTS: Our findings show that First Nations living on reserve have higher hospitalization rates for mental disorders compared to other British Columbia residents up until 2008. Those living off reserve had significantly higher hospitalization rates throughout the study period. On-reserve communities served by nursing stations had the lowest rates of hospitalization whereas communities with limited local services had the highest rates. Compared to other British Columbia residents, all First Nations have a shorter length of stay and lower readmission rates. CONCLUSIONS: This study suggests that despite reduced rates of hospitalization for mental-health related Ambulatory Care Sensitive Conditions over time for First Nations, gaps in mental health care still exist. We argue greater investments in primary mental health care are needed to support First Nations health. However, these efforts should place equal importance on prevention and the social determinants of health.

Dominant Suppression of Inflammation via Targeted Mutation of the mRNA Destabilizing Protein Tristetraprolin.

In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two specific phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inflammatory mediators. Mice expressing only the mutant form of TTP were healthy and fertile, and their systemic inflammatory responses to LPS were strongly attenuated. Adaptive immune responses and protection against infection by Salmonella typhimurium were spared. A single allele encoding the mutant form of TTP was sufficient for enhanced mRNA degradation and underexpression of inflammatory mediators. Therefore, the equilibrium between unphosphorylated and phosphorylated TTP is a critical determinant of the inflammatory response, and manipulation of this equilibrium may be a means of treating inflammatory pathologies.

Managing Matajoosh: determinants of first Nations' cancer care decisions.

BACKGROUND: Accessing cancer treatment requires First Nation peoples living in rural and remote communities to either commute to care, or to relocate to an urban centre for the length or part of the treatment. While Canadians living in rural and remote communities must often make difficult decisions following a cancer diagnosis, such decisions are further complicated by the unique policy and socio-historical contexts affecting many First Nation peoples in Canada. These contexts often intersect with negative healthcare experiences which can be related to jurisdictional confusion encountered when seeking care. Given the rising incidence of cancer within First Nation populations, there is a growing potential for negative health outcomes. METHODS: The analysis presented in this paper focuses on the experience of First Nation peoples' access to cancer care in the province of Manitoba. We analyzed policy documents and government websites; interviewed individuals who have experienced relocation (N = 5), family members (N = 8), healthcare providers and administrators (N = 15). RESULTS: Although the healthcare providers (social workers, physicians, nurses, patient navigators, and administrators) we interviewed wanted to assist patients and their families, the focus of care remained informed by patients' clinical reality, without recognition of the context which impacts and constrains access to cancer care services. Contrasting and converging narratives identify barriers to early diagnosis, poor coordination of care across jurisdictions and logistic complexities that result in fatigue and undermine adherence. Providers and decision-makers who were aware of this broader context were not empowered to address system's limitations. CONCLUSIONS: We argue that a whole system's approach is required in order to address these limitations.

Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo.

Human embryonic stem cells (hESCs) are considered a potential alternative to cadaveric islets as a source of transplantable cells for treating patients with diabetes. We previously described a differentiation protocol to generate pancreatic progenitor cells from hESCs, composed of mainly pancreatic endoderm (PDX1/NKX6.1-positive), endocrine precursors (NKX2.2/synaptophysin-positive, hormone/NKX6.1-negative), and polyhormonal cells (insulin/glucagon-positive, NKX6.1-negative). However, the relative contributions of NKX6.1-negative versus NKX6.1-positive cell fractions to the maturation of functional ß-cells remained unclear. To address this question, we generated two distinct pancreatic progenitor cell populations using modified differentiation protocols. Prior to transplant, both populations contained a high proportion of PDX1-expressing cells (~85%-90%) but were distinguished by their relatively high (~80%) or low (~25%) expression of NKX6.1. NKX6.1-high and NKX6.1-low progenitor populations were transplanted subcutaneously within macroencapsulation devices into diabetic mice. Mice transplanted with NKX6.1-low cells remained hyperglycemic throughout the 5-month post-transplant period whereas diabetes was reversed in NKX6.1-high recipients within 3 months. Fasting human C-peptide levels were similar between groups throughout the study, but only NKX6.1-high grafts displayed robust meal-, glucose- and arginine-responsive insulin secretion as early as 3 months post-transplant. NKX6.1-low recipients displayed elevated fasting glucagon levels. Theracyte devices from both groups contained almost exclusively pancreatic endocrine tissue, but NKX6.1-high grafts contained a greater proportion of insulin-positive and somatostatin-positive cells, whereas NKX6.1-low grafts contained mainly glucagon-expressing cells. Insulin-positive cells in NKX6.1-high, but not NKX6.1-low grafts expressed nuclear MAFA. Collectively, this study demonstrates that a pancreatic endoderm-enriched population can mature into highly functional ß-cells with only a minor contribution from the endocrine subpopulation.

Advancing equitable access to digital mental health in the Asia-Pacific region in the context of the COVID-19 pandemic and beyond: A modified Delphi consensus study.

The COVID-19 pandemic had an unprecedented impact on global mental health and well-being, including across the Asia-Pacific. Efforts to mitigate virus spread led to far-reaching disruption in the delivery of health and social services. In response, there was a rapid shift to the use of digital mental health (DMH) approaches. Though these technologies helped to improve access to care for many, there was also substantial risk of access barriers leading to increased inequities in access to mental health care, particularly among at-risk and equity-deserving populations. The objective of this study was to conduct a needs assessment and identify priorities related to equitable DMH access among at-risk and equity-deserving populations in the Asia Pacific region during the first year of the COVID-19 pandemic. The study consisted of a modified Delphi consensus methodology including two rounds of online surveys and online consultations with stakeholders from across the region. Study participants included policy makers, clinicians and service providers, and people with lived experience of mental health conditions. Results demonstrate that vulnerabilities to negative mental health impacts and access barriers were compounded during the pandemic. Access barriers included a lack of linguistically and culturally appropriate DMH options, low mental health literacy and poor access to technological infrastructure and devices, low levels of awareness and trust of DMH options, and lack of policies and guidelines to support effective and equitable delivery of DMH. Recommendations to improve equitable access include ensuring that diverse people with lived experience are engaged in research, co-design and policy development, the development and implementation of evidence-based and equity-informed guidelines and frameworks, clear communication about DMH evidence and availability, and the integration of DMH into broader health systems. Study results can inform the development and implementation of equitable DMH as its use becomes more widespread across health systems.

Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice.

AIMS/HYPOTHESIS: Islet transplantation is a promising cell therapy for patients with diabetes, but it is currently limited by the reliance upon cadaveric donor tissue. We previously demonstrated that human embryonic stem cell (hESC)-derived pancreatic progenitor cells matured under the kidney capsule in a mouse model of diabetes into glucose-responsive insulin-secreting cells capable of reversing diabetes. However, the formation of cells resembling bone and cartilage was a major limitation of that study. Therefore, we developed an improved differentiation protocol that aimed to prevent the formation of off-target mesoderm tissue following transplantation. We also examined how variation within the complex host environment influenced the development of pancreatic progenitors in vivo. METHODS: The hESCs were differentiated for 14 days into pancreatic progenitor cells and transplanted either under the kidney capsule or within Theracyte (TheraCyte, Laguna Hills, CA, USA) devices into diabetic mice. RESULTS: Our revised differentiation protocol successfully eliminated the formation of non-endodermal cell populations in 99% of transplanted mice and generated grafts containing >80% endocrine cells. Progenitor cells developed efficiently into pancreatic endocrine tissue within macroencapsulation devices, despite lacking direct contact with the host environment, and reversed diabetes within 3 months. The preparation of cell aggregates pre-transplant was critical for the formation of insulin-producing cells in vivo and endocrine cell development was accelerated within a diabetic host environment compared with healthy mice. Neither insulin nor exendin-4 therapy post-transplant affected the maturation of macroencapsulated cells. CONCLUSIONS/INTERPRETATION: Efficient differentiation of hESC-derived pancreatic endocrine cells can occur in a macroencapsulation device, yielding glucose-responsive insulin-producing cells capable of reversing diabetes.

Vocational rehabilitation services and employment outcomes for adults with cerebral palsy in the United States.

AIM: The aim of this study was to examine the relationship between vocational rehabilitation services provided and work outcomes among people with cerebral palsy (CP), taking in to account demographic characteristics. METHOD: From the US Department of Education Rehabilitation Service Administration Case Service Report (RSA-911) database, data from 3162 individuals with CP (1820 males [57.6%] and 1342 females [42.4% age range 16-54 y) whose cases were closed in 2009, were used in this study. A total of 1567 cases (49.6%) were closed with clients being categorized as 'successful employment' and 1595 cases (50.4%) were closed with clients being classified as unemployed. RESULTS: Multivariate logistic regression was used to examine the relationship between services provided and work outcomes with regard to demographic characteristics. Males aged between 26 and 54 years old with higher education attainment were more likely to be employed. Individuals receiving disability benefits were less likely to be employed. After controlling for the effect of demographic and work disincentive variables, five vocational rehabilitation services significantly predicted employment outcomes (p<0.05), including (1) on-the-job training; (2) job placement assistance; (3) on-the-job support; (4) maintenance services; and (5) rehabilitation technology. INTERPRETATION: Medical and health professionals need to be aware of vocational rehabilitation agencies as a resource for providing medical, psychological, educational, and vocational interventions for adults with CP to help them maximize their employability, to address their much needed work adjustment skills, to establish independent living, and to eventually reach their full potential in participation in society.

Adapting and Scaling a Digital Health Intervention to Improve Maternal and Child Health Among Ethnic Minority Women in Vietnam Amid the COVID-19 Context: Protocol for the dMOM Project.

BACKGROUND: Due to interconnected structural determinants including low maternal health knowledge, economic marginalization, and remoteness from low-capacity health centers, ethnic minority women in remote areas of Vietnam face severe maternal, newborn, and child health (MNCH) inequities. As ethnic minorities represent 15% of the Vietnamese population, these disparities are significant. mMOM-a pilot mobile health (mHealth) intervention using SMS text messaging to improve MNCH outcomes among ethnic minority women in northern Vietnam-was implemented from 2013-2016 with promising results. Despite mMOM's findings, exacerbated MNCH inequities, and digital health becoming more salient amid COVID-19, mHealth has not yet been scaled to address MNCH among ethnic minority women in Vietnam. OBJECTIVE: We describe the protocol for adapting, expanding, and exponentially scaling the mMOM intervention qualitatively through adding COVID-19-related MNCH guidance and novel technological components (mobile app and artificial intelligence chatbots) and quantitatively through broadening the geographical area to reach exponentially more participants, within the evolving COVID-19 context. METHODS: dMOM will be conducted in 4 phases. (1) Drawing on a review of international literature and government guidelines on MNCH amid COVID-19, mMOM project components will be updated to respond to COVID-19 and expanded to include a mobile app and artificial intelligence chatbots to more deeply engage participants. (2) Using an intersectionality lens and participatory action research approach, a scoping study and rapid ethnographic fieldwork will explore ethnic minority women's unmet MNCH needs; acceptability and accessibility of digital health; technical capacity of commune health centers; gendered power dynamics and cultural, geographical, and social determinants impacting health outcomes; and multilevel impacts of COVID-19. Findings will be applied to further refine the intervention. (3) dMOM will be implemented and incrementally scaled across 71 project communes. (4) dMOM will be evaluated to assess whether SMS text messaging or mobile app delivery engenders better MNCH outcomes among ethnic minority women. The documentation of lessons learned and dMOM models will be shared with Vietnam's Ministry of Health for adoption and further scaling up. RESULTS: The dMOM study was funded by the International Development Research Centre (IDRC) in November 2021, cofacilitated by the Ministry of Health, and is being coimplemented by provincial health departments in 2 mountainous provinces. Phase 1 was initiated in May 2022, and phase 2 is planned to begin in December 2022. The study is expected to be complete in June 2025. CONCLUSIONS: dMOM research outcomes will generate important empirical evidence on the effectiveness of leveraging digital health to address intractable MNCH inequities among ethnic minority women in low-resource settings in Vietnam and provide critical information on the processes of adapting mHealth interventions to respond to COVID-19 and future pandemics. Finally, dMOM activities, models, and findings will inform a national intervention led by the Ministry of Health. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/44720.

Evaluating the effectiveness and cost-effectiveness of a digital, app-based intervention for depression (VMood) in community-based settings in Vietnam: Protocol for a stepped-wedge randomized controlled trial.

The COVID-19 pandemic has amplified mental health problems and highlighted inequitable gaps in care worldwide. In response there has been an explosion of digital interventions such as smartphone applications ("apps") to extend care. The objective of this trial is to evaluate the effectiveness and cost-effectiveness of a digital depression intervention (VMood), delivered via a smartphone app. VMood is adapted from an in-person intervention that was delivered by non-specialist providers and shown to be effective in the Vietnamese context in our previous trial (2016-2019). A stepped-wedge, randomized controlled trial will be conducted across eight provinces in Vietnam. Adults aged 18 years and over will be recruited through community-based primary care centres and screened for depression using the embedded Patient Health Questionnaire-9 (primary outcome measure). Participants scoring 10-19, indicating depression caseness, will be randomly allocated to the intervention or control group until the target of 336 is reached. Secondary outcome measures will examine the effect of the intervention on commonly co-occuring anxiety, quality of life and work productivity, along with use of alcohol and tobacco products. Assessments will be administered through an online survey platform (REDCap) at baseline, and at every 3 months until 3 months post-intervention. Intervention-group participants will receive VMood for a 3-month period, with online support provided by social workers. Control-group participants will receive a limited version of the app until they cross into the intervention group. Generalized Linear Mixed-effect Models for clustered measures will be used for all outcomes data. We will conduct a cost-effectiveness analysis alongside the trial to capture VMood's costs and benefits. This trial will provide evidence on the effectiveness and cost-effectiveness of a digital mental health intervention adapted from an in-person intervention. This trial will also contribute important information to the growing and promising field of digital mental health. Trail regulation. Registered at ClinicalTrials.gov, identifier [NCT05783531].

Fibroblasts Derived From Vestibular Schwannoma Express Protumorogenic Markers.

BACKGROUND AND AIM: Vestibular schwannomas (VSs), despite being histologically benign, cause significant morbidity because of their challenging intracranial location and the propensity for growth. The role of the stroma and particularly fibroblasts, in the progression of VS, is not completely understood. This study examines the profile of fibroblasts in VS. METHODS: Seventeen patients undergoing surgical excision of VS were recruited into the study. Reverse transcription with quantitative polymerase chain reaction (RT-qPCR) was performed on VS tissue samples and fibroblast-associated molecules examined. Immunofluorescence and immunohistochemistry in VS tissue were used to study the expression of fibroblast markers CD90 and podoplanin in situ. Fibroblast cultures were established from VS, and RT-qPCR analysis was performed on a panel of fibroblast markers on VS and control tissue fibroblasts. RESULTS: Several fibroblast-associated molecules including members of galectin family and matrix metalloproteinases were found to be expressed in VS tissue on RT-qPCR analysis. In situ, expression of CD90 and podoplanin was observed in VS tissue both on immunohistochemistry and immunofluorescence. RT-qPCR analysis of fibroblasts from VS and control vestibular neuroepithelium (NE) showed a higher expression of several molecules of the galectin and matrix metalloproteinases family on VS fibroblasts compared with NE fibroblasts. CONCLUSION: This work examines fibroblasts from VS and shows qualitative differences from NE fibroblasts on RT-qPCR. Further understanding of the fibroblast function in the progression of VS will potentially unveil new targets to manage VS growth.

Dexamethasone impairs the expression of antimicrobial mediators in lipopolysaccharide-activated primary macrophages by inhibiting both expression and function of interferon ß.

Glucocorticoids potently inhibit expression of many inflammatory mediators, and have been widely used to treat both acute and chronic inflammatory diseases for more than seventy years. However, they can have several unwanted effects, amongst which immunosuppression is one of the most common. Here we used microarrays and proteomic approaches to characterise the effect of dexamethasone (a synthetic glucocorticoid) on the responses of primary mouse macrophages to a potent pro-inflammatory agonist, lipopolysaccharide (LPS). Gene ontology analysis revealed that dexamethasone strongly impaired the lipopolysaccharide-induced antimicrobial response, which is thought to be driven by an autocrine feedback loop involving the type I interferon IFNß. Indeed, dexamethasone strongly and dose-dependently inhibited the expression of IFNß by LPS-activated macrophages. Unbiased proteomic data also revealed an inhibitory effect of dexamethasone on the IFNß-dependent program of gene expression, with strong down-regulation of several interferon-induced antimicrobial factors. Surprisingly, dexamethasone also inhibited the expression of several antimicrobial genes in response to direct stimulation of macrophages with IFNß. We tested a number of hypotheses based on previous publications, but found that no single mechanism could account for more than a small fraction of the broad suppressive impact of dexamethasone on macrophage type I interferon signaling, underlining the complexity of this pathway. Preliminary experiments indicated that dexamethasone exerted similar inhibitory effects on primary human monocyte-derived or alveolar macrophages.

The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages.

Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on the alteration of glucose utilization.

Closing the health equity gap: evidence-based strategies for primary health care organizations.

INTRODUCTION: International evidence shows that enhancement of primary health care (PHC) services for disadvantaged populations is essential to reducing health and health care inequities. However, little is known about how to enhance equity at the organizational level within the PHC sector. Drawing on research conducted at two PHC Centres in Canada whose explicit mandates are to provide services to marginalized populations, the purpose of this paper is to discuss (a) the key dimensions of equity-oriented services to guide PHC organizations, and (b) strategies for operationalizing equity-oriented PHC services, particularly for marginalized populations. METHODS: The PHC Centres are located in two cities within urban neighborhoods recognized as among the poorest in Canada. Using a mixed methods ethnographic design, data were collected through intensive immersion in the Centres, and included: (a) in-depth interviews with a total of 114 participants (73 patients; 41 staff), (b) over 900 hours of participant observation, and (c) an analysis of key organizational documents, which shed light on the policy and funding environments. RESULTS: Through our analysis, we identified four key dimensions of equity-oriented PHC services: inequity-responsive care; trauma- and violence-informed care; contextually-tailored care; and culturally-competent care. The operationalization of these key dimensions are identified as 10 strategies that intersect to optimize the effectiveness of PHC services, particularly through improvements in the quality of care, an improved 'fit' between people's needs and services, enhanced trust and engagement by patients, and a shift from crisis-oriented care to continuity of care. Using illustrative examples from the data, these strategies are discussed to illuminate their relevance at three inter-related levels: organizational, clinical programming, and patient-provider interactions. CONCLUSIONS: These evidence- and theoretically-informed key dimensions and strategies provide direction for PHC organizations aiming to redress the increasing levels of health and health care inequities across population groups. The findings provide a framework for conceptualizing and operationalizing the essential elements of equity-oriented PHC services when working with marginalized populations, and will have broad application to a wide range of settings, contexts and jurisdictions. Future research is needed to link these strategies to quantifiable process and outcome measures, and to test their impact in diverse PHC settings.

'Trying to make it all come together': structuration and employed mothers' experience of family food provisioning in Canada.

This research examined the aetiology of employed mothers' food choice and food provisioning decisions using a qualitative, grounded theory methodology. Semi-structured interviews using the Food Choice Map were conducted with eleven middle-income employed mothers of elementary school-age children. Results demonstrated that the women exhibited conflicting identities with respect to food choice and provisioning. As 'good mothers' they were the primary food and nutrition caregivers for the family, desiring to provide healthy, homemade foods their families preferred at shared family meals. They also sought to be independent selves, working outside the home, within the context of a busy modern family. Increased food autonomy of children, and lack of time due to working outside the home and children's involvement in extracurricular activities, were significant influences on their food choice and provisioning. This resulted in frequently being unable to live up to their expectations of consistently providing healthy homemade foods and having shared family meals. To cope, the women frequently relied on processed convenience and fast foods despite their acknowledged inferior nutritional status. Using Giddens' structuration theory, the dynamic relationships between the women's food choice and provisioning actions, their identities and larger structures including socio-cultural norms, conditions of work and the industrial food system were explored. The ensuing dietary pattern of the women and their families increases the risk of poor health outcomes, including obesity. These results have implications for public health responses to improve population health by shifting the focus from individual-level maternal influences to structural influences on diet.

Mindset as a resilience resource and perceived wellness of first responders in a South African context.

The global increase in frequency and intensity of disasters and emergency situations has a major disruptive effect on societies that is especially visible in Africa, where conflict, poverty, diseases and social unrest are some of the biggest factors contributing to societal vulnerability. Developing countries such as South Africa are vulnerable to the impact of disaster situations that strain the society's ability to deal with these emergencies. First responders play an important function responding to disasters but are exposed to work-related stressors that could impact their performance. Several international studies make a link between wellness, performance and resilience and the use of resilience resources in the development and enhancement of wellness, indicating that resilience resources such as a resilient mindset are an indicator of good mental health and performance amongst first responders, despite being exposed to traumatic situations. However, very little research has been carried out on first responders in South Africa, making this study an important stepping stone towards gaining an understanding of the relationship between mindset as a resilience resource and perceived wellness of first responders in a South African context. Data were collected from 52 first responders using a structured questionnaire. The results indicate a statistically significant relationship between mindset and perceived wellness, with all the wellness factors indicating that the mindset of first responders plays a crucial role in their resilience and perception of wellness, necessitating additional research in this specialised field of disaster response.