Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction.

Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA-mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2(+)CD8(+) T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.

CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy.

Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFNγ expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.

The Implementation of Federated Digital Identifiers in Health Care: Rapid Review.

BACKGROUND: Federated digital identifiers (FDIs) have been cited to improve the interoperability of data and information management while enhancing the privacy of individuals verifying their identity on the web. Many countries around the world have implemented FDIs in various sectors, such as banking and government. Similarly, FDIs could improve the experience for those wanting to access their health care information; however, they have only been introduced in a few jurisdictions around the world, and their impact remains unclear. OBJECTIVE: The main objective of this environmental scan was to describe how FDIs have been established and implemented to enable patients' access to health care. METHODS: We conducted this study in 2 stages, with the primary stage being a rapid review, which was supplemented by a targeted gray literature search. Specifically, the rapid review was conducted through a database search of MEDLINE and Embase, which generated a list of countries and their services that use FDIs in health care. This list was then used to conduct a targeted gray literature search using the Google search engine. RESULTS: A total of 93 references from the database and targeted Google searches were included in this rapid review. FDIs were implemented in health care in 11 countries (Australia, Belgium, Canada, Denmark, Estonia, Finland, Iceland, Norway, Singapore, Sweden, and Taiwan) and exclusively used with a patient-accessible electronic health record system through a single sign-on interface. The most common FDIs were implemented nationally or provincially, and establishing them usually required individuals to visit a bank or government office in person. In contrast, some countries, such as Australia, allow individuals to verify their identities entirely on the web. We found that despite the potential of FDIs for use in health care to facilitate the amalgamation of health information from different data sources into one platform, the adoption of most health care services that use FDIs remained below 30%. The exception to this was Australia, which had an adoption rate of 90%, which could be correlated with the fact that it leveraged an opt-out consent model. CONCLUSIONS: This rapid review highlights key features of FDIs across regions and elements associated with higher adoption of the patient-accessible electronic health record systems that use them, like opt-out registration. Although FDIs have been reported to facilitate the collation of data from multiple sources through a single sign-on interface, there is little information on their impact on care or patient experience. If FDIs are used to their fullest potential and implemented across sectors, adoption rates within health care may also improve.

Mapping Theories, Models, and Frameworks to Evaluate Digital Health Interventions: Scoping Review.

BACKGROUND: Digital health interventions (DHIs) are a central focus of health care transformation efforts, yet their uptake in practice continues to fall short of their potential. In order to achieve their desired outcomes and impact, DHIs need to reach their target population and need to be used. Many factors can rapidly intersect between this dynamic of users and interventions. The application of theories, models, and frameworks (TMFs) can facilitate the systematic understanding and explanation of the complex interactions between users, practices, technology, and health system factors that underpin research questions. There remains a gap in our understanding of how TMFs have been applied to guide the evaluation of DHIs with real-world health system operations. OBJECTIVE: This study aims to map TMFs used in studies to guide the evaluation of DHIs. The objectives are to (1) describe the TMFs and the constructs they target, (2) identify how TMFs have been prospectively used (ie, their roles) in primary studies to evaluate DHIs, and (3) to reflect on the relevance and utility of our findings for knowledge users. METHODS: This scoping review was conducted in partnership with knowledge users using an integrated knowledge translation approach. We included papers (eg, reports; empirical quantitative, qualitative, and mixed methods studies; conference proceedings; and dissertations) if primary insights resulting from the application of TMFs were presented. Any type of DHI was eligible. Papers published from 2000 and onward were mainly identified from the following databases: MEDLINE (Ovid), CINAHL Complete (EBSCOhost), PsycINFO (Ovid), EBM Reviews (Ovid), and Embase (Ovid). RESULTS: A total of 156 studies published between 2000 and 2022 were included. A total of 68 distinct TMFs were identified across 85 individual studies. In more than half (85/156, 55%) of the included studies, 1 of following 6 prevailing TMFs were reported: Consolidated Framework for Implementation Research (n=39); the Reach, Effectiveness, Adoption, Implementation, and Maintenance Framework (n=17); the Technology of Acceptance Model (n=16); the Unified Theory on Acceptance and Use of Technology (n=12); the Diffusion of Innovation Theory (n=10); and Normalization Process Theory (n=9). The most common intended roles of the 6 TMFs were to inform data collection (n=86), to inform data analysis (n=69), and to identify key constructs that may serve as barriers and facilitators (n=52). CONCLUSIONS: As TMFs are most often reported to be applied to support data collection and analysis, researchers should consider more clearly synthesizing key insights as practical use cases to both increase the relevance and digestibility of their findings. There is also a need to adapt or develop guidelines for better reporting DHIs and the use of TMFs to guide evaluation. Hence, it would contribute to ensuring ongoing technology transformation efforts are evidence and theory informed rather than anecdotally driven.

Gastrointestinal Dysmotility in Critically Ill Patients: Bridging the Gap Between Evidence and Common Misconceptions.

Disruption of normal gastrointestinal (GI) function in critical illness is linked to increased morbidity and mortality, and GI dysmotility is frequently observed in patients who are critically ill. Despite its high prevalence, the diagnosis and management of GI motility problems in the intensive care unit remain very challenging, given that critically ill patients often cannot verbalize symptoms and the general lack of understanding of underlying pathophysiology. Common clinical presentations of GI dysmotility issues among critically ill patients include: (1) high gastric residual volumes, acid reflux, and vomiting, (2) abdominal distention, and (3) diarrhea. In this review, we discuss the differential diagnosis for intensive care unit patients with symptoms and signs concerning GI motility issues. There are many myths and longstanding misconceptions about the diagnosis and management of GI dysmotility in critical illness. Here, we uncover these myths and discuss relevant evidence in each subject area, with the goal of re-conceptualizing GI motility disorders in critical care and providing evidence-based recommendations for clinical care.

Towards a global partnership model in interprofessional education for cross-sector problem-solving.

OBJECTIVES: A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available. METHODS: This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in students' data. RESULTS: We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretest-posttest differences in students' readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in students' social interaction anxiety after the IPE simulation. CONCLUSIONS: The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education.

Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2.

Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are important cellular components in the cancer microenvironment and may affect cancer phenotype and patient outcome. The nature of MDSCs and their interaction with CSCs in ovarian carcinoma are unclear. We examined the interaction between MDSCs and CSCs in patients with ovarian carcinoma and showed that MDSCs inhibited T cell activation and enhanced CSC gene expression, sphere formation, and cancer metastasis. MDSCs triggered miRNA101 expression in cancer cells. miRNA101 subsequently repressesed the corepressor gene C-terminal binding protein-2 (CtBP2), and CtBP2 directly targeted stem cell core genes resulting in increased cancer cell stemness and increasing metastatic and tumorigenic potential. Increased MDSC density and tumor microRNA101 expression predict poor survival, as does decreased tumor CtBP2 expression, independent of each other. Collectively, our work identifies an immune-associated cellular, molecular, and clinical network involving MDSCs-microRNA101-CtBP2-stem cell core genes, which extrinsically controls cancer stemness and impacts patient outcome.

Hyoscine butylbromide in pain reduction associated with ultrasound-guided manual vacuum aspiration: a randomized placebo-controlled trial.

RESEARCH QUESTION: What is the effect of adding an anti-spasmodic drug to an existing ultrasound-guided manual vacuum aspiration (USG-MVA) protocol to alleviate immediate post-procedure abdominal cramping pain in women treated for early pregnancy loss? DESIGN: Double-blind, placebo-controlled, randomized controlled trial conducted between February 2018 and January 2020. Participants were assigned to receive a 1-ml intravenous injection containing 20-mg hyoscine butylbromide (HBB) (n=55) or saline (n =56) as a control immediately before USG-MVA. Primary outcome was reduced abdominal pain after adding a 20-mg dose of HBB to the current pain control regimen. Secondary outcomes were vaginal pain, complications and side-effects, women's pre- and post-procedure psychological state, physiological stress (saliva alpha-amylase) and procedure pain control satisfaction. Two-way mixed ANOVA was used to evaluate the main effects and interactions. RESULTS: VAS abdominal pain scores in the HBB group were 16% lower immediately after and 21% lower 2 h after surgery (not statistically significant). Two-way ANOVA indicated that time (F[1108] = 83.41, P < 0.001) was the only significant main effect for reduced abdominal pain after the procedure and vaginal pain score (F[1108] = 180.1, P < 0.0001) but not drug received. No adverse events were reported. No significant difference was found for psychological state, physiological stress and procedure pain control satisfaction between the two groups. CONCLUSIONS: Anti-spasmodic drugs can help to reduce abdominal cramping pain associated with USG-MVA; HBB produced an insignificant decrease in abdominal pain score. Further studies with longer acting or larger doses of anti-spasmodic drugs are warranted.

Exploring weight bias internalization in pregnancy.

BACKGROUND: Recent research has shown that pregnant individuals experience weight stigma throughout gestation, including negative comments and judgement associated with gestational weight gain (GWG). Weight bias internalization (WBI) is often a result of exposure to weight stigma and is detrimental to biopsychological health outcomes. The purpose of this study was to explore WBI in pregnancy and compare scores based on maternal weight-related factors including pre-pregnancy body mass index (BMI), obesity diagnosis and excessive GWG. METHODS: Pregnant individuals in Canada and USA completed a modified version of the Adult Weight Bias Internalization Scale. Self-reported pre-pregnancy height and weight were collected to calculate and classify pre-pregnancy BMI. Current weight was also reported to calculate GWG, which was then classified as excessive or not based on Institute of Medicine (2009) guidelines. Participants indicated if they were diagnosed with obesity by a healthcare provider. Inferential analyses were performed comparing WBI scores according to pre-pregnancy BMI, excessive GWG, and obesity diagnosis. Significance was accepted as p < 0.05 and effect sizes accompanied all analyses. RESULT: 336 pregnant individuals completed the survey, with an average WBI score of 3.9 ± 1.2. WBI was higher among those who had a pre-pregnancy BMI of obese than normal weight (p = 0.04, η2 = 0.03), diagnosed with obesity than not diagnosed (p < 0.001, Cohen's d = 1.3), and gained excessively versus not (p < 0.001, Cohen's d = 1.2). CONCLUSIONS: Pregnant individuals who have a higher BMI, obesity and gain excessively may experience WBI. Given that weight stigma frequently occurs in pregnancy, effective person-oriented strategies are needed to mitigate stigma and prevent and care for WBI.

Team cohesiveness and collective efficacy explain outcomes in interprofessional education.

BACKGROUND: Team cohesiveness and collective efficacy have been construed as important characteristics of a high-functioning team. However, the psychological mechanism through which they promote positive outcomes remains unknown. Understanding this psychological process is important to teachers and programme implementers to yield actionable interventions that can be used to craft effective practices for optimizing team outcomes. This is especially true in interprofessional education (IPE) in medical education, where a team-based approach to patient management is promoted. Drawing from the social-cognitive theory, we examined a hypothesized model where team cohesiveness predicts collaboration outcomes (teamwork satisfaction, overall satisfaction with the team experience, and IPE goal attainment) via collective efficacy. METHODS: We used data from Chinese medicine, medicine, nursing, and social work students in Hong Kong (n = 285) who were enrolled in IPE. They were invited to respond to scales in two time points. We performed mediation analysis using structural equations modelling to test the indirect effect model: team cohesiveness → collective efficacy → outcomes. RESULTS: Results of structural equation modelling revealed that collective efficacy fully mediated the relationships between team cohesiveness and all three team outcomes, providing support for the hypothesised model [RMSEA = 0.08, NFI = 0.90, CFI = 0.93, IFI = 0.93, TLI = 0.93]. Team cohesiveness predicted the achievement of collaboration outcomes via collective efficacy. CONCLUSION: The findings demonstrated the important roles of team cohesiveness and collective efficacy in promoting successful team collaboration. Team cohesiveness predicted collective efficacy, and collective efficacy, in turn, predicted collaboration outcomes. This study contributed to theorising the pathways towards successful team collaboration outcomes.

Virtual Primary Care Implementation During COVID-19 in High-Income Countries: A Scoping Review.

Background: The purpose of this scoping review was to map the challenges, strategies, and lessons learned from high-income countries that can be mobilized to inform decision-makers on how to best implement virtual primary care services during and after the COVID-19 pandemic. Findings of our scoping review identified the barriers and strategies within the Quadruple Aim components, which may prove to be an effective implementation strategy for virtual care adoption in primary care settings. Materials and Methods:The two concepts of virtual care and COVID-19 were searched in MEDLINE, EMBASE, and CINAHL on August 10, 2020, and Scopus was searched on August 15, 2020. The database searches returned 10,549 citations and an additional 766 citations were retrieved from searching the citations from the reference lists of articles that met all inclusion criteria. A total of 1,260 full-text articles were reviewed of which 38 articles met the eligibility criteria for inclusion in the review. Results: Seven key barriers and strategies were identified for the implementation of virtual primary care. Of the 38 articles included, the key barriers identified were equitable access to care (n = 20; 53%), lack of funding for virtual care (n = 14; 37%), negative patient and clinician perception (n = 11, 29%), lack of regulatory policies (n = 10, 26%), inadequate clinical workflows (n = 9, 21), lack of virtual care infrastructure (n = 8, 21%), and insufficient virtual care training and education (n = 5, 13%). Strategies included the following: increased funding (n = 15, 39%), improving clinical workflows (n = 13, 34%), appropriate education and training (n = 11, 29%), improving virtual care infrastructure and patient equity (n = 7, 18%), establishing regulatory policies (n = 5, 13%), and improving patient and clinician perceptions (n = 3, 7%). Conclusions: As many countries enter potential subsequent waves of the COVID-19 pandemic, applying early lessons learned to mitigate implementation barriers can help with the transition to equitable and appropriate virtual primary care services.

Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy.

Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.

The effects of intervening with physical activity in the early years (ages 3-5) on health-related quality of life: a secondary analysis of the Activity Begins in Childhood (ABC) trial.

PURPOSE: Limited research has measured the effect of physical activity (PA) interventions on health-related quality of life (HRQoL) among pre-school-aged children. This study evaluates the effect of the Activity Begins in Childhood (ABC) cluster-randomized controlled trial designed to increase PA in the ages 3-5 years on HRQoL. METHODS: This was a cluster-randomized controlled trial where the intervention group included PA education delivered to daycare providers only, or daycare providers and parents. In the current study, the two PA intervention groups were combined. The comparator group received standard daycare curriculum (COM). A total of 215 children were included (PA n = 161, COM n = 54). Parents completed the proxy Pediatric Quality of Life Inventory Generic Core Scale (PedsQL™ 4.0) to measure HRQoL at baseline and the end of the 6-month trial. HRQoL scores were analyzed as physical, psychosocial, and total domains. Baseline and 6-months measurements were compared for PA and COM groups, and mean changes in scores (95% confidence intervals) were measured using absolute values. RESULTS: No between-group differences were observed for the physical (p = 0.17), psychosocial (p = 0.95) or total scores (p = 0.20). Paired comparisons showed that only the PA group improved psychosocial- (PA mean difference = 2.18 (0.20, 4.15), p = 0.03; COM mean difference = 2.05 (- 1.03, 5.13), p = 0.19) and total-HRQoL scores (PA mean difference = 2.83 (1.83, 3.84), p < 0.001; COM mean difference = 0.19 (- 1.78, 2.16), p = 0.84) after 6 months. CONCLUSION: Although the within-PA group analysis showed an improvement in psychosocial and total HRQoL scores from baseline, no between-group differences were observed in the HRQoL over time among children aged 3-5 years.

Utilization of Asynchronous and Synchronous Teledermatology in a Large Health Care System During the COVID-19 Pandemic.

Background: Teledermatology offers an opportunity to continually deliver care during the coronavirus disease 2019 pandemic. Objective: To provide quantitative data about the use of teledermatology. Methods: Retrospective analysis of teledermatology consultations was performed from March 16 to May 1, 2020. The number/type of encounters, differences in diagnoses, and prescriptions between asynchronous and synchronous teledermatology visits were analyzed. Results: A total of 951 visits (36.2%) were asynchronous whereas 1,672 visits (63.8%) were synchronous. Only 131 (<5%) visits required an acute in-person follow-up. The diagnosis of acne was more frequent with asynchronous visits (p < 0.002, Bonferroni corrected). Antibiotics and nonretinoid acne medications were prescribed more with asynchronous visits, whereas immunomodulators and biologics were more commonly prescribed with synchronous visits (p < 0.02, Bonferroni corrected). Providers at our institution were split on preferred mode (54.2% synchronous, 45.8% asynchronous); however, synchronous visits were preferred for complex medical dermatology patients and return patients (p < 0.05). Limitations: This study is limited by being a single-center study. Conclusions: Asynchronous teledermatology was used more for acne management, whereas synchronous teledermatology was preferable to providers for complex medical dermatology. Postanalysis of the data collected led us to institute a hybridization of our asynchronous and synchronous teledermatology.

Endothelial cell-secreted MIF reduces pericyte contractility and enhances neutrophil extravasation.

Dysregulated neutrophil extravasation contributes to the pathogenesis of many inflammatory disorders. Pericytes (PCs) have been implicated in the regulation of neutrophil transmigration, and previous work demonstrates that endothelial cell (EC)-derived signals reduce PC barrier function; however, the signaling mechanisms are unknown. Here, we demonstrate a novel role for EC-derived macrophage migration inhibitory factor (MIF) in inhibiting PC contractility and facilitating neutrophil transmigration. With the use of micro-ELISAs, RNA sequencing, quantitative PCR, and flow cytometry, we found that ECs secrete MIF, and PCs upregulate CD74 in response to TNF-α. We demonstrate that EC-derived MIF decreases PC contractility on 2-dimensional silicone substrates via reduction of phosphorylated myosin light chain. With the use of an in vitro microvascular model of the human EC-PC barrier, we demonstrate that MIF decreases the PC barrier to human neutrophil transmigration by increasing intercellular PC gap formation. For the first time, an EC-specific MIF knockout mouse was used to investigate the effects of selective deletion of EC MIF. In a model of acute lung injury, selective deletion of EC MIF decreases neutrophil infiltration to the bronchoalveolar lavage and tissue and simultaneously decreases PC relaxation by increasing myosin light-chain phosphorylation. We conclude that paracrine signals from EC via MIF decrease PC contraction and enhance PC-regulated neutrophil transmigration.-Pellowe, A. S., Sauler, M., Hou, Y., Merola, J., Liu, R., Calderon, B., Lauridsen, H. M., Harris, M. R., Leng, L., Zhang, Y., Tilstam, P. V., Pober, J. S., Bucala, R., Lee, P. J., Gonzalez, A. L. Endothelial cell-secreted MIF reduces pericyte contractility and enhances neutrophil extravasation.

Inpatient eDermatology (Teledermatology) Can Help Meet the Demand for Inpatient Skin Disease.

Background: Currently, the number of inpatient dermatology providers cannot meet the overall burden of inpatient skin disease in the United States. Introduction: We seek to determine whether inpatient eDermatology can meet the need for inpatient skin disease in hospitals without access to a dermatology hospitalist. Methods: This retrospective cohort study reviewed inpatient eDermatology consults at the University of Pittsburgh eDermatology Consult Service between July 1, 2014 and June 30, 2018. This included a diverse group of 1,320 patients admitted to 10 different community hospitals. Study data were reviewed for demographics, diagnostic impressions, time to discharge, and diagnostic discordance between referring and consultant physicians. Results: Forty percent of inpatient eDermatology consults were admitted with a primary dermatologic diagnosis. Referring diagnosis most commonly was rash not otherwise specified. eDermatology consulting impressions, conversely, were specific and varied. Ninety-one percent of patients received a consultant impression by the end of day, or within 8 hours. Overall, 89.3% of patients with a referring diagnosis of "cellulitis" were given a different diagnosis by the consultant. Discussion: Although this study lacked concordance data to compare the Inpatient eDermatologist with a live Inpatient Dermatologist, overall, eDermatology consultants were able to provide rapid consult recommendations that aided patient management. Conclusions: Inpatient eDermatology appears to be an effective medium to provide dermatologic care to patients at hospitals without a dermatology presence. This delivery of health care can help prevent misdiagnosis, unnecessary costs, and inappropriate systemic therapies.

Tumor Necrosis Factor-α and IL-17A Activation Induces Pericyte-Mediated Basement Membrane Remodeling in Human Neutrophilic Dermatoses.

Sweet syndrome (SS) is a prototypical neutrophilic dermatosis, a class of inflammatory diseases marked by elevated levels of tumor necrosis factor (TNF)-α and IL-17A, pathologic neutrophil recruitment, and microvascular remodeling. Histologic analyses of four matrix proteins-collagen I and IV, laminin, and fibronectin-in skin biopsies of patients with SS reveal that the basement membrane of dermal postcapillary venules undergoes changes in structure and composition. Increased neutrophil recruitment in vivo was associated with increases in collagen IV, decreases in laminin, and varied changes in fibronectin. In vitro studies using TNF-α and IL-17A were conducted to dissect basement membrane remodeling. Prolonged dual activation of cultured human pericytes with TNF-α and IL-17A augmented collagen IV production, similar to in vivo remodeling. Co-activation of pericytes with TNF-α and IL-17A also elevated fibronectin levels with little direct effect on laminin. However, the expression of fibronectin- and laminin-specific matrix metalloproteinases (MMPs), particularly MMP-3, was significantly up-regulated. Interactions between pericytes and neutrophils in culture yielded even higher levels of active MMPs, facilitating fibronectin and laminin degradation, and likely contributing to the varied levels of detectable fibronectin and the decreases in laminin observed in vivo. These data indicate that pericyte-neutrophil interactions play a role in mediating microvascular changes in SS and suggest that targeting MMP-3 may be effective in protecting vascular wall integrity.

IL-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium.

A classical hallmark of acute inflammation is neutrophil infiltration of tissues, a multistep process that involves sequential cell-cell interactions of circulating leukocytes with IL-1- or TNF-activated microvascular endothelial cells (ECs) and pericytes (PCs) that form the wall of the postcapillary venules. The initial infiltrating cells accumulate perivascularly in close proximity to PCs. IL-17, a proinflammatory cytokine that acts on target cells via a heterodimeric receptor formed by IL-17RA and IL-17RC subunits, also promotes neutrophilic inflammation but its effects on vascular cells are less clear. We report that both cultured human ECs and PCs strongly express IL-17RC and, although neither cell type expresses much IL-17RA, PCs express significantly more than ECs. IL-17, alone or synergistically with TNF, significantly alters inflammatory gene expression in cultured human PCs but not ECs. RNA sequencing analysis identifies many IL-17-induced transcripts in PCs encoding proteins known to stimulate neutrophil-mediated immunity. Conditioned media from IL-17-activated PCs, but not ECs, induce pertussis toxin-sensitive neutrophil polarization, likely mediated by PC-secreted chemokines, and they also stimulate neutrophil production of proinflammatory molecules, including TNF, IL-1α, IL-1ß, and IL-8. Furthermore, IL-17-activated PCs, but not ECs, can prolong neutrophil survival by producing G-CSF and GM-CSF, delaying the mitochondrial outer membrane permeabilization and caspase-9 activation. Importantly, neutrophils exhibit enhanced phagocytic capacity after activation by conditioned media from IL-17-treated PCs. We conclude that PCs, not ECs, are the major target of IL-17 within the microvessel wall and that IL-17-activated PCs can modulate neutrophil functions within the perivascular tissue space.

Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+ NIK+ signalosome on Rab5+ endosomes.

Complement membrane attack complexes (MACs) promote inflammatory functions in endothelial cells (ECs) by stabilizing NF-κB-inducing kinase (NIK) and activating noncanonical NF-κB signaling. Here we report a novel endosome-based signaling complex induced by MACs to stabilize NIK. We found that, in contrast to cytokine-mediated activation, NIK stabilization by MACs did not involve cIAP2 or TRAF3. Informed by a genome-wide siRNA screen, instead this response required internalization of MACs in a clathrin-, AP2-, and dynamin-dependent manner into Rab5(+)endosomes, which recruited activated Akt, stabilized NIK, and led to phosphorylation of IκB kinase (IKK)-α. Active Rab5 was required for recruitment of activated Akt to MAC(+) endosomes, but not for MAC internalization or for Akt activation. Consistent with these in vitro observations, MAC internalization occurred in human coronary ECs in vivo and was similarly required for NIK stabilization and EC activation. We conclude that MACs activate noncanonical NF-κB by forming a novel Akt(+)NIK(+) signalosome on Rab5(+) endosomes.

Development and pilot evaluation of a pregnancy-specific mobile health tool: a qualitative investigation of SmartMoms Canada.

BACKGROUND: Mobile technology is ubiquitous. Women of childbearing age have embraced health information technology for pregnancy-related counsel as prenatal care provider communication is increasingly scarce and brief. Pregnant women and new mothers place high value in the use of online sources to support their pregnancy information needs. In Canada, over 300,000 women are pregnant annually, with approximately 60% exceeding evidence-based weight gain recommendations. Mobile health (mHealth) tools, such as mobile applications (app), have the potential to reduce excessive gestational weight gain, offering pregnant women trustworthy guidance, ultimately improving the health outcomes of mothers and infants. Therefore, the primary aim of this study was to implement a qualitative, descriptive research design to assess the receptiveness, functionality, and future prospective of the SmartMoms Canada mHealth app. METHODS: Two focus groups (n = 13) involving both currently pregnant and recently postpartum women were organized on the same day. Focus groups were transcribed verbatim and thematic analysis was undertaken using manual coding and NVivo software. Participants who took part in the focus groups (n = 13) and those who could not attend (n = 4) were asked to complete a Likert-scale survey. All survey responses (n = 17) were analyzed using simple tabulation and percentage analysis. RESULTS: Participants were technologically proficient and interacted with several mHealth tools prior to testing the SmartMoms Canada app. Six major themes emerged from thematic analysis: knowledge of pregnancy-specific mHealth services, knowledge and attitudes of weight gain guidelines, weight tracking, strengths of the app, critique and lastly, future suggestions for the app. CONCLUSIONS: Our thematic analysis found that women positively viewed the future potential of our app and offered constructive feedback to improve the next version. Participants sought more personalization and enhanced app interactivity, along with promotion of overall maternal health including nutrition and mental health, in addition to weight tracking.