Helminth egg derivatives as proregenerative immunotherapies.

The immune system is increasingly recognized as an important regulator of tissue repair. We developed a regenerative immunotherapy from the helminth Schistosoma mansoni soluble egg antigen (SEA) to stimulate production of interleukin (IL)-4 and other type 2-associated cytokines without negative infection-related sequelae. The regenerative SEA (rSEA) applied to a murine muscle injury induced accumulation of IL-4-expressing T helper cells, eosinophils, and regulatory T cells and decreased expression of IL-17A in gamma delta (γδ) T cells, resulting in improved repair and decreased fibrosis. Encapsulation and controlled release of rSEA in a hydrogel further enhanced type 2 immunity and larger volumes of tissue repair. The broad regenerative capacity of rSEA was validated in articular joint and corneal injury models. These results introduce a regenerative immunotherapy approach using natural helminth derivatives.

KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis.

Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation, disruption of which may drive carcinogenesis. The epigenetic regulator KMT2D (MLL4) is one of the most frequently mutated genes in all cancers, particularly epithelial cancers, yet its normal function in these tissues is unknown. Here, we identify a novel role for KMT2D in coordinating this fine balance, as depletion of KMT2D from undifferentiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification. Genome-wide, KMT2D interacts with p63 and is enriched at its target enhancers. Depletion of KMT2D results in a broad loss of enhancer histone modifications H3 Lys 4 (H3K4) monomethylation (H3K4me1) and H3K27 acetylation (H3K27ac) as well as reduced expression of p63 target genes, including key genes involved in epithelial development and adhesion. Together, these results reveal a critical role for KMT2D in the control of epithelial enhancers and p63 target gene expression, including the requirement of KMT2D for the maintenance of epithelial progenitor gene expression and the coordination of proper terminal differentiation.

Monitoring immunE DysregulAtion foLLowing Immune checkpOint-inhibitioN (MEDALLION): protocol for an observational cancer immunotherapy cohort study.

BACKGROUND: Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel. METHODS: MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a "significant IrAE" (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs. DISCUSSION: The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment. TRIAL REGISTRATION: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).

What's luck got to do with it? A generative model for examining the role of stochasticity in age-at-death, with implications for bioarchaeology.

INTRODUCTION: The role of "luck" in determining individual exposure to health insults is a critical component of the processes that shape age-at-death distributions in mortality samples but is difficult to address using traditional bioarcheological analysis of skeletal materials. The present study introduces a computer simulation approach to modeling stochasticity's contribution to the mortality schedule of a simulated cohort. METHODS: The present study employs an agent-based model of 15,100 individuals across a 120 year period to examine the predictive value of birth frailty on age-at-death when varying the likelihood of exposure to health insults. RESULTS: Birth frailty, when accounting for varying exposure likelihood scenarios, was found to account for 18.7% of the observed variation in individual age-at-death. Analysis stratified by exposure likelihood demonstrated that birth frailty alone explains 10.2%-12.1% of the variation observed across exposure likelihood scenarios, with the stochasticity associated with exposure to health insults (i.e., severity of health insult) and mortality likelihood driving the majority of variation observed. CONCLUSIONS: Stochasticity of stressor exposure and intrinsic stressor severity are underappreciated but powerful drivers of mortality in this simulation. This study demonstrates the potential value of simulation modeling for bioarchaeological research.

Cultural humility development in adults serving as mentors for youth: A qualitative evidence synthesis.

This qualitative review synthesizes evidence regarding how cultural humility (i.e., critical self-reflection, challenging inequity) may be influenced by the experience of serving as a mentor in a youth program. A systematic search identified 35 qualitative studies with findings that address this question. Thematic synthesis of extracted data identified the following six themes, all but one of which pertains to ways in which serving as a mentor appeared to have enhanced the cultural humility of the adults involved: (1) humanizing others: awareness of experiential differences, (2) reflecting inward on one's own identity, biases, and opportunities, (3) connecting with others, (4) recognizing environmental influences on human development, (5) envisioning contributions to community change, and (6) counterevidence: deficit-oriented attributions. Findings indicate that mentor cultural humility development primarily entailed individual and interpersonal awareness with relatively less evidence of increased awareness of and action to change inequality. The identified themes provide promising directions for future research as well as potentially useful avenues for incorporating consideration of cultural humility more intentionally in the development and evaluation of mentoring programs for youth.

Characterization of age-associated B cells in early drug-naïve rheumatoid arthritis patients.

Age-associated B cells (ABCs) are an immune cell subset linked to autoimmunity, infection and ageing, and whose pathophysiological importance was recently highlighted using single cell synovial tissue profiling. To elucidate their pathophysiological relevance, peripheral blood (PB) ABCs from early rheumatoid arthritis (eRA) patients naïve to disease-modifying anti-rheumatic drugs (DMARDs) were compared with their synovial fluid (SF) counterparts, and to PB ABCs from psoriatic arthritis patients and healthy controls. PB and SF B-cell subsets were phenotyped by multi-parameter flow cytometry, sorted and subjected to gene expression profiling (NanoString nCounter® Immunology V2 Panel) and functional characterization (stimulated cytokine measurements by immunoassay). PB ABCs of eRA patients, which are transcriptionally distinct from those of control cohorts, express chemokine receptors and adhesion molecules, such as CXCR3, that favour homing to inflammatory sites over lymphoid tissue. These cells are an activated, class-switched B-cell subset expressing high levels of HLA-DR, co-stimulatory molecules and T-bet. Their secretion profile includes IL-12p70 and IL-23 but low levels of IL-10. High surface expression of FcRL family members, including FcRL3, furthermore suggests a role for these cells in autoimmunity. Finally, and unlike in the periphery where they are rare, ABCs are the predominant B-cell subsets in SF. These observations indicate the predilection of ABCs for inflammatory tissue in RA, where their propensity for antigen presentation and pro-inflammatory phenotype may support autoimmune pathology. Their potential as a therapeutic target therefore warrants further study.

Characteristics associated with receipt of treatment among patients diagnosed with chronic hepatitis C virus.

Although current guidelines recommend that nearly all patients with chronic hepatitis C virus (HCV) infection receive treatment, a substantial proportion remain untreated. We conducted an administrative claims analysis to provide real-world data on treatment patterns and characteristics of treated versus untreated patients among individuals with HCV in the United States. Adults with an HCV diagnosis from 01 July 2016 through 30 September 2020 and continuous health plan enrolment for 12 months before and ≥1 month after the diagnosis date were identified in the Optum Research Database. Descriptive and multivariable analyses were conducted to evaluate the association between patient characteristics and the rate of treatment. Of 24,374 patients identified with HCV, only 30% initiated treatment during follow-up. Factors associated with increased rate of treatment included younger age versus age 75+ (hazard ratio [HR] 1.50-1.83 depending on age group), commercial versus Medicare insurance (HR 1.32), and diagnosis by a specialist versus a primary care physician (HR 2.56 and 2.62 for gastroenterology and infectious disease or hepatology, respectively) (p < .01 for all). Several baseline comorbidities were associated with decreased rate of treatment, including psychiatric disorders (HR 0.87), drug use disorders (HR 0.85) and cirrhosis (HR 0.42) (p < .01 for all). These findings highlight existing HCV treatment inequities, particularly among older patients and those with psychiatric disorders, substance use disorders or chronic comorbidities. Targeted efforts to increase treatment uptake in these populations could mitigate a considerable future burden of HCV-related morbidity, mortality and healthcare costs.

Micro-RNA content of circulating extracellular vesicles in early rheumatoid arthritis as biomarkers and mediators of methotrexate efficacy.

OBJECTIVES: Extracellular vesicles (EVs) are abundant in body fluids, contributing to intercellular signalling by transferring cargo that includes microRNAs (miRs) - themselves implicated in pathobiology. For the first time we evaluated the potential of EV miRs to contribute diagnostic information in early RA, predict methotrexate (MTX) efficacy or shed light on the drug's mechanism of action. METHODS: 798 miRs isolated from serum-derived EVs of 46 patients with untreated RA, 23 with untreated polymyalgia rheumatica (PMR; inflammatory disease control group) and 12 in whom significant inflammatory disease had been excluded (non-inflammatory controls; NICs) were profiled (Nanostring); the same measurements were made for RA patients after 6 months' MTX treatment. Analyses took multiple testing into account. RESULTS: 28 EV miRs were robustly differentially expressed between early RA (but not PMR) patients and NICs after correction for age and sex, suggesting discriminatory value. Cross-validated partial least squared-discriminant analysis also indicated the predictive potential of a distinct baseline EV miR signature with respect to MTX-induced remission at 6 months. The change in expression of 13 miRs over the course of MTX treatment differed significantly between responders and non-responders, and four of those exhibiting increased relative abundance amongst responders have known roles in regulating the pathogenic potential of synovial fibroblasts, namely miR-212-3p, miR-338-5p, miR-410-3p, and miR-537. CONCLUSION: Our data highlight the potential of serum EV miRs as diagnostic and therapeutic biomarkers, highlighting a novel potential mechanism via which MTX may exert its therapeutic effect in early RA that warrants further investigation.

Skeletal manifestations of disease experience: Length of illness and porous cranial lesion formation in a contemporary juvenile mortality sample.

OBJECTIVES: Porous lesions of the orbit (cribra orbitalia [CO]) and cranial vault (porotic hyperostosis [PH]) are used as skeletal indicators of childhood stress. Because they are understudied in contemporary populations, their relationship to disease experience is poorly understood. This paper examines the relationship between length of childhood illness and CO/PH formation in a clinically documented sample. "Turning points," which identify the window for lesion formation for CO/PH, are defined, implications for hidden heterogeneity in frailty are considered. METHODS: Data are from 333 (199 males; 134 females) pediatric postmortem computed tomography scans. Individuals died in New Mexico (2011-2019) and are 0.5 to 15.99 years (mean = 7.1). Length of illness was estimated using information from autopsy and field reports. Logistic regression was used to estimate predicted probabilities, odds ratios, and the temporal window for lesion formation. RESULTS: Illness, single bouts, or cumulative episodes lasting over 1 month is associated with higher odds of CO; individuals who were never sick have lower odds of having PH. This relationship was consistent for fatal and incidental illnesses that did not cause death. The developmental window for CO formation appears to close at 8 years. CONCLUSIONS: Those ill for over 1 month are more likely to have CO/PH than those with acute illnesses. Some individuals lived sufficiently long to form CO/PH but died of illness. Others with lesions died of circumstances unrelated to disease. This indicates hidden variation in robusticity even among ill individuals with CO/PH, which is vital in interpreting lesion frequencies in the archeological record.

Striving for safety, impact, and equity: A critical consideration of AJCP publications on formal youth mentoring programs.

In this virtual special issue (VSI) we curate and reflect upon 22 articles on formal youth mentoring previously published in the American Journal of Community Psychology (AJCP). First, we provide historical context and highlight AJCP's 2002 special issue on mentoring, which played an important role in establishing youth mentoring as a vibrant area of research. Next, we review and discuss findings from subsequent AJCP studies in three interrelated lines of inquiry: (1) the importance of facilitating high-quality mentoring relationships; (2) associations among youth's presenting needs, relationship quality, and outcomes; and (3) program practices leading to stronger, more impactful relationships. Throughout, we highlight and expand upon critical commentary from AJCP contributors, calling on the field to move away from paternalistic models that overly localize risk with youth and families without interrogating structural oppression. Our recommendations include: (1) centering critical consciousness, racial equity, and social justice in program curricula and mentor trainings; (2) respectfully engaging grassroots programs developed for and by communities of color that are underrepresented in research; (3) making meaningful efforts to recruit mentors from marginalized communities and removing barriers to their participation; and (4) examining youth's racial, ethnic, and other areas of identity development processes during mentoring.

Are adults influenced by the experience of mentoring youth? A scoping review.

AIMS: A relatively large body of research exists on the effectiveness of mentoring programs directed at youth and numerous syntheses of this literature have proven useful for advancing both research and practice. Less studied, but also important is the potential for adults serving in the role of mentor to young persons to be influenced by this experience. A scoping review was conducted with the aim of identifying and critically assessing major trends in the methods and findings in this literature. METHODS: Included sources were empirical studies reporting findings that address potential influences on adults (18+) serving as mentors to youth (<18) in formal programs designed for this purpose. The initial search resulted in 3155 records and 96 were included in the review. RESULTS: Approximately half of the studies (58%) focused on younger adults (ages 18-22 years old, e.g., college students) serving as mentors; only a small minority of studies focused on adults over 35 years old (10%). Most studies were qualitative (n = 54). Studies with a quantitative component (n = 18 quantitative only; n = 24 mixed methods) exhibited a significant risk of bias for inferring effects on mentors due to limitations in study design (e.g., lack of comparison group). Studies most often addressed potential outcomes for mentors in academic/career (55%) and social (45%) domains, when findings suggested possible effects on mentors, they were nearly universally in a positive direction. CONCLUSION: Existing research, although consistent with the potential for adults to benefit from the experience of mentoring youth, has insufficient rigor and representativeness to adequately address this question. Future research should utilize more rigorous quantitative designs and samples with greater representativeness of the different stages of adult development.

Identifying predictors of psychological well-being among volunteer mentors in Big Brothers Big Sisters.

Big Brothers Big Sisters (BBBS) facilitates mentoring relationships between youth and volunteer mentors. Although research has examined outcomes for youth in BBBS, relatively less investigation has been undertaken for volunteer outcomes. This study explored factors associated with changes in psychological well-being among BBBS volunteer mentors. Participants included 593 mentors (Mage = 31) surveyed at study baseline and 15-month follow-up. A classification and regression decision tree approach was used to predict residualized change in psychological well-being from study baseline with match length included as the first split variable, and demographic, individual, and relationship variables included as candidate predictors. Analyses indicated that mentors with longer relationships (>4.5 months) reported more positive change in psychological well-being compared with mentors with shorter relationships. Perceived quality of program supervision was a further predictor within both groups of volunteers. Findings suggest that longer relationships and greater program support may contribute to mentor well-being.

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming.

OBJECTIVES: An interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action. METHODS: In a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes. RESULTS: We reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α). CONCLUSIONS: Our data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.

The Relationship Between Objectively Measured Step Count, Clinical Characteristics, and Quality of Life Among Depressed Patients Recently Hospitalized With Systolic Heart Failure.

OBJECTIVE: Physical activity (PA) can improve symptoms of both depression and heart failure (HF), but objective activity data among recently hospitalized HF patients with comorbid depression are lacking. We examined PA and the relationship between daily step counts and mood, health-related quality of life (HRQoL), and heart health among patients enrolled in a clinical trial treating HF and comorbid depression. METHODS: We screened hospitalized patients with systolic HF (left ventricular ejection fraction [LVEF] ≤45%) and New York Heart Association class II-IV symptoms for depression using the two-item Patient Health Questionnaire (PHQ-2) and telephoned screen-positive patients to administer the PHQ-9 2 weeks after discharge. If the patient scored PHQ-9 ≥10 and agreed to continue in our study, we administered our baseline assessment and mailed them an armband accelerometer. We instructed patients to wear the armbands for 7 days before returning them and classified their data as "usable" if they wore it ≥10 hours per day on ≥4 separate days. RESULTS: We mailed accelerometers to 531 depressed HF patients, and 222 (42%) returned them with usable data. Their median age was 64 years, 54% were women, 23% were non-White, and they walked a median of 1170 steps daily. Higher median daily step counts were associated with lower New York Heart Association class and better physical- and HF-specific HRQoL, but not mood symptoms, mental HRQoL, or LVEF. CONCLUSIONS: Patients with HF and comorbid depression are generally sedentary after hospital discharge. Although mood symptoms and LVEF were unrelated to objective PA, patients with higher step counts self-reported better HRQoL.Trial Registration:ClinicalTrials.gov identifier NCT02044211.

A Pilot Evaluation of a Social Justice and Race Equity Training for Volunteer Mentors.

Mentor training on cultural humility is an area of needed support in formal youth mentoring relationships. This pilot study used an experimental design to examine the role of a social justice and race equity training on volunteer mentors' cognitive and affective outcomes related to cultural humility in mentoring. The sample included 99 volunteer mentors paired with adolescent mentees in an established formal mentoring program. Mentors predominantly identified as White (89%), and the majority (72%) were paired with youth of color. Participants were randomly assigned to either the training or control condition. Findings from intention-to-treat analyses indicated that training group participants (n = 49) exhibited greater increases in self-efficacy to provide racial/ethnic support over time than participants in the control group (n = 50). As-treated analyses indicated that training attendees (n = 23) exhibited greater increases in self-efficacy to provide racial/ethnic support over time than participants who did not attend the training (n = 76). Results indicated no significant changes over time in participants' training content knowledge, awareness of racial privilege, ethnocultural empathy, or social justice interest and behavioral intentions. Analyses also indicated an attendance bias within the training condition, such that mentors who attended the training reported significantly more awareness of racial privilege, social justice interest, and social justice behavioral intentions compared to training condition mentors who were invited but did not attend the training. Implications for training volunteer mentors within formal mentoring programs are discussed.

Using a multimethod life history approach to navigate the osteological paradox: A case study from Prehispanic Nasca, Peru.

OBJECTIVES: We leverage recent bioarchaeological approaches and life history theory to address the implications of the osteological paradox in a study population. The goal of this article is to evaluate morbidity and mortality patterns as well as variability in the risk of disease and death during the Late Intermediate period (LIP; 950-1450 C.E.) in the Nasca highlands of Peru. We demonstrate how the concurrent use of multiple analytical techniques and life history theory can engage the osteological paradox and provide salient insights into the study of stress, frailty, and resilience in past populations. MATERIALS AND METHODS: Crania from LIP burial contexts in the Nasca highlands were examined for cribra orbitalia (n = 325) and porotic hyperostosis (n = 270). All age groups and both sexes are represented in the sample. Survivor/nonsurvivor analysis assessed demographic differences in lesion frequency and severity. Hazard models were generated to assess differences in survivorship. The relationship between dietary diversity and heterogeneity in morbidity was assessed using stable δ15 N and δ13 C isotope values for bone collagen and carbonate. One hundred and twenty-four crania were directly AMS radiocarbon dated, allowing for a diachronic analysis of morbidity and mortality. RESULTS: The frequency and expression of both orbital and vault lesions increases significantly during the LIP. Survivor/nonsurvivor analysis indicates cranial lesions co-vary with frailty rather than robusticity or longevity. Hazard models show (1) decreasing survivorship with the transition into the LIP, (2) significantly lower adult life expectancy for females compared to males, and (3) individuals with cranial lesions have lower survivorship across the life course. Stable isotope results show very little dietary diversity. Mortality risk and frequency of pathological skeletal lesions were highest during Phase III (1300-1450 C.E.) of the LIP. CONCLUSION: Results provide compelling evidence of increasing physiological stress and mortality in the Nasca highlands during the LIP, but also reveal substantial heterogeneity in frailty and the risk of death. Certain members of society experienced a heavier disease burden and higher mortality compared to their contemporaries. Elevated levels of disease and lethal trauma among females account for some of the sex differences in survivorship but cannot explain the large degree of female-biased mortality. We hypothesize that parental investment in males or increased female fertility rates may explain these differences.

Assessing the usability of wearable devices to measure gait and physical activity in chronic conditions: a systematic review.

BACKGROUND: The World Health Organisation's global strategy for digital health emphasises the importance of patient involvement. Understanding the usability and acceptability of wearable devices is a core component of this. However, usability assessments to date have focused predominantly on healthy adults. There is a need to understand the patient perspective of wearable devices in participants with chronic health conditions. METHODS: A systematic review was conducted to identify any study design that included a usability assessment of wearable devices to measure mobility, through gait and physical activity, within five cohorts with chronic conditions (Parkinson's disease [PD], multiple sclerosis [MS], congestive heart failure, [CHF], chronic obstructive pulmonary disorder [COPD], and proximal femoral fracture [PFF]). RESULTS: Thirty-seven studies were identified. Substantial heterogeneity in the quality of reporting, the methods used to assess usability, the devices used, and the aims of the studies precluded any meaningful comparisons. Questionnaires were used in the majority of studies (70.3%; n = 26) with a reliance on intervention specific measures (n = 16; 61.5%). For those who used interviews (n = 17; 45.9%), no topic guides were provided, while methods of analysis were not reported in over a third of studies (n = 6; 35.3%). CONCLUSION: Usability of wearable devices is a poorly measured and reported variable in chronic health conditions. Although the heterogeneity in how these devices are implemented implies acceptance, the patient voice should not be assumed. In the absence of being able to make specific usability conclusions, the results of this review instead recommends that future research needs to: (1) Conduct usability assessments as standard, irrespective of the cohort under investigation or the type of study undertaken. (2) Adhere to basic reporting standards (e.g. COREQ) including the basic details of the study. Full copies of any questionnaires and interview guides should be supplied through supplemental files. (3) Utilise mixed methods research to gather a more comprehensive understanding of usability than either qualitative or quantitative research alone will provide. (4) Use previously validated questionnaires alongside any intervention specific measures.

Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci.

BACKGROUND: Defining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in the post-genome-wide association study era. OBJECTIVES: With a focus on rheumatoid arthritis, we sought new insight into genetic mechanisms of adaptive immune dysregulation to help prioritize molecular pathways for targeting in this and related immune pathologies. METHODS: Whole-genome methylation and transcriptional data from isolated CD4+ T cells and B cells of more than 100 genotyped and phenotyped patients with inflammatory arthritis, all of whom were naive to immunomodulatory treatments, were obtained. Analysis integrated these comprehensive data with genome-wide association study findings across IMDs and other publicly available resources. RESULTS: We provide strong evidence that disease-associated DNA variants regulate cis-CpG methylation in CD4+ T and/or B cells at 37% RA loci. Using paired, cell-specific transcriptomic data and causal inference testing, we identify examples where site-specific DNA methylation in turn mediates gene expression, including FCRL3 in both cell types and ORMDL3/GSDMB, IL6ST/ANKRD55, and JAZF1 in CD4+ T cells. A number of genes regulated in this way highlight mechanisms common to RA and other IMDs including multiple sclerosis and asthma, in turn distinguishing them from osteoarthritis, a primarily degenerative disease. Finally, we corroborate the observed effects experimentally. CONCLUSIONS: Our observations highlight important mechanisms of genetic risk in RA and the wider context of immune dysregulation. They confirm the utility of DNA methylation profiling as a tool for causal gene prioritization and, potentially, therapeutic targeting in complex IMD.

Emerging Adults' Social Justice Engagement: Motivations, Barriers, and Social Identity.

This study examines emerging adults' perceived motivations and barriers to social justice engagement, and how their social identities shape involvement. We conducted in-depth interviews with service-learning students (n = 30). Thematic analysis of interview data revealed that participants perceived several motivations and barriers to engagement, including the following: (a) the current political climate, (b) self-efficacy to make small-scale changes, (c) social support in action, (d) proximity to the social issue, (e) knowledge of resources, and (f) limited personal resources. Participants also described how their identities shaped engagement such that participants reflected upon their multiple privileged and marginalized identities and how their identities influenced their approach to engaging with a particular social issue. Findings have implications for recruiting and sustaining emerging adults' involvement in activities aimed at changing social issues.