Plasma adiponectin levels are associated with circulating inflammatory cytokines in autoantibody positive first-degree relatives of rheumatoid arthritis patients

Background Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations. Methods We analyzed samples from 144 first-degree relatives (FDRs) of RA probands, of whom 23 were positive for anti-cyclic citrullinated peptide antibody and/or ≥ 2 rheumatoid factor isotypes (IgM, IgG or IgA). We called this phenotype the ‘high risk autoantibody profile (HRP)’ as it has been shown in prior work to be >96% specific for future RA. We measured adiponectin, cytokines, and high-sensitivity C-reactive protein (hsCRP). Using linear mixed effects models, we evaluated interaction between HRP positivity and adiponectin on inflammatory markers, adjusting for age, sex, ethnicity, body mass index, pack-years smoking, and use of cholesterol-lowering medications. Results In everyone, adiponectin concentration was inversely associated with hsCRP and IL-1β in adjusted models, where a 1% higher adiponectin was associated with a 26% lower hsCRP (p = 0.04) and a 26% lower IL-1β (p = 0.04). Significant interactions between HRP and adiponectin for associations with GM-CSF, IL-6, and IL-9 were detected in fully adjusted models (p = 0.0006, p = 0.006, p = 0.01, respectively). In HRP positive FDRs but not HRP negative FDRs, a 1% higher adiponectin was associated with 97% higher GM-CSF, 73% higher IL-6, and 54% higher IL-9 concentrations. Conclusions Adiponectin associates with inflammatory markers, and these associations differ in individuals with a high-risk autoantibody profile compared with those without. The interaction between adiponectin and autoimmunity warrants further investigation into the potential systemic effects of RA-related autoantibodies and adiponectin on inflammation in the absence of clinically apparent RA

Public mental health during and after the SARS-CoV-2 pandemic: Opportunities for intervention via emotional self-efficacy and resilience

ImportanceDuring the pandemic, the number of United States adults reporting clinically significant symptoms of anxiety and depression sky-rocketed, up from 11% in 2020 to more than 40% in 2021. Our current mental healthcare system cannot adequately accommodate the current crisis; it is therefore important to identify opportunities for public mental health interventions.ObjectiveAssess whether modifiable emotional factors may offer a point of intervention for the mental health crisis.Design, setting, and participantsFrom January 13 to 15, 2022, adults living in the United States were recruited via Amazon Mechanical Turk to complete an anonymous survey.Main outcomes and measuresLinear regressions tested whether the primary outcomes during the SARS-CoV-2 pandemic (depressive and anxiety symptoms, burnout) were associated with hypothesized modifiable risk factors (loneliness and need for closure) and hypothesized modifiable protective factors (the ability to perceive emotions and connect with others emotionally; emotion-regulation efficacy; and resilience, or the ability to “bounce back” after negative events).ResultsThe sample included 1,323 adults (mean [SD] age 41.42 [12.52] years; 636 women [48%]), almost half of whom reported clinically significant depressive (29%) and/or anxiety (15%) symptoms. Approximately 90% of participants indicated feeling burned out at least once a year and nearly half of participants (45%) felt burned out once a week or more. In separate analyses, depressive symptoms (Model A), anxiety symptoms (Model B), and burnout (Model C) were statistically significantly associated with loneliness (βModel A, 0.38; 95% CI, 0.33–0.43; βModel B, 0.30; 95% CI, 0.26–0.36; βModel C, 0.34; 95% CI, 0.28–0.41), need for closure (βModel A, 0.09; 95% CI, 1.03–1.06; βModel B, 0.13; 95% CI, 0.97–0.17; βModel C, 0.11; 95% CI, 0.07–0.16), recent stressful life events (βModel A, 0.14; 95% CI, 0.10–0.17; βModel B, 0.14; 95% CI, 0.11–0.18; βModel C, 0.10; 95% CI, 0.06–0.15), and resilience (βModel A, −0.10; 95% CI, −0.15 to −0.05; βModel B, −0.18; 95% CI, −0.23 to −0.13; βModel C, −0.11; 95% CI, −0.17 to −0.05). In addition, depressive and anxiety symptoms were associated with emotional self-efficacy (βModel A, −0.17; 95% CI, −0.22 to −0.12; βModel B, −0.11; 95% CI, −0.17 to −0.06), and beliefs about the malleability of emotions (βModel A, −0.08; 95% CI, −0.12 to −0.03; βModel B, −0.09; 95% CI, −0.13 to −0.04). Associations between loneliness and symptoms were weaker among those with more emotional self-efficacy, more endorsement of emotion malleability beliefs, and greater resilience, in separate models. Analyses controlled for recent stressful life events, optimism, and social desirability.Conclusion and relevancePublic mental health interventions that teach resilience in response to negative events, emotional self-efficacy, and emotion-regulation efficacy may protect against the development of depressive symptoms, anxiety, and burnout, particularly in the context of a collective trauma. Emotional self-efficacy and regulation efficacy may mitigate the association between loneliness and mental health, but loneliness prevention research is also needed to address the current mental health crisis

Designing a complex intervention for dementia case management in primary care

Background: Community-based support will become increasingly important for people with dementia, but currently services are fragmented and the quality of care is variable. Case management is a popular approach to care co-ordination, but evidence to date on its effectiveness in dementia has been equivocal. Case management interventions need to be designed to overcome obstacles to care co-ordination and maximise benefit. A successful case management methodology was adapted from the United States (US) version for use in English primary care, with a view to a definitive trial. Medical Research Council guidance on the development of complex interventions was implemented in the adaptation process, to capture the skill sets, person characteristics and learning needs of primary care based case managers. Methods: Co-design of the case manager role in a single NHS provider organisation, with external peer review by professionals and carers, in an iterative technology development process. Results: The generic skills and personal attributes were described for practice nurses taking up the case manager role in their workplaces, and for social workers seconded to general practice teams, together with a method of assessing their learning needs. A manual of information material for people with dementia and their family carers was also created using the US intervention as its source. Conclusions: Co-design produces rich products that have face validity and map onto the complexities of dementia and of health and care services. The feasibility of the case manager role, as described and defined by this process, needs evaluation in ‘real life’ settings

Fresh takes on five health data sharing domains: Quality, privacy, equity, incentives, and sustainability

As entities around the world invest in repositories and other infrastructure to facilitate health data sharing, scalable solutions to data sharing challenges are needed. We conducted semi-structured interviews with 24 experts to explore views on potential issues and policy options related to health data sharing. In this Perspective, we describe and contextualize unconventional insights shared by our interviewees relevant to issues in five domains: data quality, privacy, equity, incentives, and sustainability. These insights question a focus on granular quality metrics for gatekeeping; challenge enthusiasm for maximalist risk disclosure practices; call attention to power dynamics that potentially compromise the patient's voice; encourage faith in the sharing proclivities of new generations of scientists; and endorse accounting for personal disposition in the selection of long-term partners. We consider the merits of each insight with the broad goal of encouraging creative thinking to address data sharing challenges

Ethnic differences in oral health and use of dental services:cross-sectional study using the 2009 Adult Dental Health Survey

Background Oral health impacts on general health and quality of life, and oral diseases are the most common non-communicable diseases worldwide. Non-White ethnic groups account for an increasing proportion of the UK population. This study explores whether there are ethnic differences in oral health and whether these are explained by differences in sociodemographic or lifestyle factors, or use of dental services. Methods We used the Adult Dental Health Survey 2009 to conduct a cross-sectional study of the adult general population in England, Wales and Northern Ireland. Ethnic groups were compared in terms of oral health, lifestyle and use of dental services. Logistic regression analyses were used to determine whether ethnic differences in fillings, extractions and missing teeth persisted after adjustment for potential sociodemographic confounders and whether they were explained by lifestyle or dental service mediators. Results The study comprised 10,435 (94.6 %) White, 272 (2.5 %) Indian, 165 (1.5 %) Pakistani/Bangladeshi and 187 (1.7 %) Black participants. After adjusting for confounders, South Asian participants were significantly less likely, than White, to have fillings (Indian adjusted OR 0.25, 95 % CI 0.17-0.37; Pakistani/Bangladeshi adjusted OR 0.43, 95 % CI 0.26-0.69), dental extractions (Indian adjusted OR 0.33, 95 % CI 0.23-0.47; Pakistani/Bangladeshi adjusted OR 0.41, 95 % CI 0.26-0.63), and <20 teeth (Indian adjusted OR 0.31, 95 % CI 0.16-0.59; Pakistani/Bangladeshi adjusted OR 0.22, 95 % CI 0.08-0.57). They attended the dentist less frequently and were more likely to add sugar to hot drinks, but were significantly less likely to consume sweets and cakes. Adjustment for these attenuated the differences but they remained significant. Black participants had reduced risk of all outcomes but after adjustment for lifestyle the difference in fillings was attenuated, and extractions and tooth loss became non-significant. Conclusions Contrary to most health inequalities, oral health was better among non-White groups, in spite of lower use of dental services. The differences could be partially explained by reported differences in dietary sugar

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1–12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis