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Introduction Cardiovascular disease (CVD) is the leading cause of mortality worldwide, though it may be prevented by increasing physical activity (PA). When behaviour change techniques (BCTs) are bundled together, they increase PA, though which individual BCTs increase PA (and the behavioural mechanism of action (MoA) responsible for said increase) have not been studied. The aim of this study is to conduct a randomised factorial experiment to determine which of four BCTs significantly engage the proposed MoA—self-efficacy for PA—in adults at risk for CVD.Methods and analysis Eight hundred and twenty sedentary adults (18–74 years old) at risk for CVD will be recruited between September 2022 and June 2025 to a fully remote, 24-week randomised BCT intervention. To identify those who might benefit from this intervention, we define self-reported walking

BACKGROUND AND PURPOSE: Interventions are effective in promoting health behavior change to the extent that (a) intervention strategies modify targets (i.e., mechanisms of action), and (b) modifying targets leads to changes in behavior. To complement taxonomies that characterize the variety of strategies used in behavioral interventions, we outline a new principle that specifies how strategies modify targets and thereby promote behavior change. We distinguish two dimensions of targets-value (positive vs. negative) and accessibility (activation level)-and show that intervention strategies operate either by altering the value of what people think, feel, or want (target change) or by heightening the accessibility of behavior-related thoughts, feelings, and goals (target activation). METHODS AND RESULTS: We review strategies designed to promote target activation and find that nudges, cue-reminders, goal priming, the question-behavior effect, and if-then planning are each effective in generating health behavior change, and that their effectiveness accrues from heightened accessibility of relevant targets. We also identify several other strategies that may operate, at least in part, via target activation (e.g., self-monitoring, message framing, anticipated regret inductions, and habits). CONCLUSIONS: The Activation Vs. Change Principle (AVCP) offers a theoretically grounded and parsimonious means of distinguishing among intervention strategies. By focusing on how strategies modify targets, the AVCP can aid interventionists in deciding which intervention strategies to deploy and how to combine different strategies in behavioral trials. We outline a research agenda that could serve to further enhance the design and delivery of interventions to promote target activation.

Assessing perceived vulnerability to a health threat is essential to understanding how people conceptualize their risk, and to predicting how likely they are to engage in protective behaviors. However, there is limited consensus about which of many measures of perceived vulnerability predict behavior best. We tested whether the ability of different measures to predict protective intentions varies as a function of the type of information people learn about their risk. Online participants (N = 909) read information about a novel respiratory disease before answering measures of perceived vulnerability and vaccination intentions. Type-of-risk information was varied across three between-participant groups. Participants learned either: (1) only information about their comparative standing on the primary risk factors (comparative-only), (2) their comparative standing as well as the base-rate of the disease in the population (+ base-rate), or (3) their comparative standing as well as more specific estimates of their absolute risk (+ absolute-chart). Experiential and affective measures of perceived vulnerability predicted protective intentions well regardless of how participants learned about their risk, while the predictive ability of deliberative numeric and comparative measures varied based on the type of risk information provided. These results broaden the generalizability of key prior findings (i.e., some prior findings about which measures predict best may apply no matter how people learn about their risk), but the results also reveal boundary conditions and critical points of distinction for determining how to best assess perceived vulnerability., Author(s): Jillian O'Rourke Stuart [sup.1] , Paul D. Windschitl [sup.2] , Elaine Bossard [sup.3] , Kathryn Bruchmann [sup.4] , Andrew R. Smith [sup.5] , Jason P. Rose [sup.6] , Jerry [...]

Background Provoked anger is associated with an increased risk of cardiovascular disease events. The underlying mechanism linking provoked anger as well as other core negative emotions including anxiety and sadness to cardiovascular disease remain unknown. The study objective was to examine the acute effects of provoked anger, and secondarily, anxiety and sadness on endothelial cell health. Methods and Results Apparently healthy adult participants (n=280) were randomized to an 8‐minute anger recall task, a depressed mood recall task, an anxiety recall task, or an emotionally neutral condition. Pre−/post‐assessments of endothelial health including endothelium‐dependent vasodilation (reactive hyperemia index), circulating endothelial cell‐derived microparticles (CD62E+, CD31+/CD42−, and CD31+/Annexin V+) and circulating bone marrow‐derived endothelial progenitor cells (CD34+/CD133+/kinase insert domain receptor+ endothelial progenitor cells and CD34+/kinase insert domain receptor+ endothelial progenitor cells) were measured. There was a group×time interaction for the anger versus neutral condition on the change in reactive hyperemia index score from baseline to 40 minutes (P=0.007) with a mean±SD change in reactive hyperemia index score of 0.20±0.67 and 0.50±0.60 in the anger and neutral conditions, respectively. For the change in reactive hyperemia index score, the anxiety versus neutral condition group by time interaction approached but did not reach statistical significance (P=0.054), and the sadness versus neutral condition group by time interaction was not statistically significant (P=0.160). There were no consistent statistically significant group×time interactions for the anger, anxiety, and sadness versus neutral condition on endothelial cell‐derived microparticles and endothelial progenitor cells from baseline to 40 minutes. Conclusions In this randomized controlled experimental study, a brief provocation of anger adversely affected endothelial cell health by impairing endothelium‐dependent vasodilation.

Risk perception is an important construct in many health behavior theories. Smoking risk perceptions are thoughts and feelings about the harms associated with cigarette smoking. Wide variation in the terminology, definition, and assessment of this construct makes it difficult to draw conclusions about the associations of risk perceptions with smoking behaviors. To understand optimal methods of assessing adults' cigarette smoking risk perceptions (among both smokers and nonsmokers), we reviewed best practices from the tobacco control literature, and where gaps were identified, we looked more broadly to the research on risk perceptions in other health domains. Based on this review, we suggest assessments of risk perceptions (1) about multiple smoking-related health harms, (2) about harms over a specific timeframe, and (3) for the person affected by the harm. For the measurement of perceived likelihood in particular (ie, the perceived chance of harm from smoking based largely on deliberative thought), we suggest including (4) unconditional and conditional items (stipulating smoking behavior) and (5) absolute and comparative items and including (6) comparisons to specific populations through (7) direct and indirect assessments. We also suggest including (8) experiential (ostensibly automatic, somatic perceptions of vulnerability to a harm) and affective (emotional reactions to a potential harm) risk perception items. We also offer suggestions for (9) response options and (10) the assessment of risk perception at multiple time points. Researchers can use this resource to inform the selection, use, and future development of smoking risk perception measures.ImplicationsIncorporating the measurement suggestions for cigarette smoking risk perceptions that are presented will help researchers select items most appropriate for their research questions and will contribute to greater consistency in the assessment of smoking risk perceptions among adults.

Abstract Background Transcriptome profiling of blood cells is an efficient tool to study the gene expression signatures of rheumatic diseases. This study aims to improve the early diagnosis of pediatric rheumatic diseases by investigating patients’ blood gene expression and applying machine learning on the transcriptome data to develop predictive models. Methods RNA sequencing was performed on whole blood collected from children with rheumatic diseases. Random Forest classification models were developed based on the transcriptome data of 48 rheumatic patients, 46 children with viral infection, and 35 controls to classify different disease groups. The performance of these classifiers was evaluated by leave-one-out cross-validation. Analyses of differentially expressed genes (DEG), gene ontology (GO), and interferon-stimulated gene (ISG) score were also conducted. Results Our first classifier could differentiate pediatric rheumatic patients from controls and infection cases with high area-under-the-curve (AUC) values (AUC = 0.8 ± 0.1 and 0.7 ± 0.1, respectively). Three other classifiers could distinguish chronic recurrent multifocal osteomyelitis (CRMO), juvenile idiopathic arthritis (JIA), and interferonopathies (IFN) from control and infection cases with AUC ≥ 0.8. DEG and GO analyses reveal that the pathophysiology of CRMO, IFN, and JIA involves innate immune responses including myeloid leukocyte and granulocyte activation, neutrophil activation and degranulation. IFN is specifically mediated by antibacterial and antifungal defense responses, CRMO by cellular response to cytokine, and JIA by cellular response to chemical stimulus. IFN patients particularly had the highest mean ISG score among all disease groups. Conclusion Our data show that blood transcriptomics combined with machine learning is a promising diagnostic tool for pediatric rheumatic diseases and may assist physicians in making data-driven and patient-specific decisions in clinical practice.

BackgroundBeing physically active is critical to successful aging, but most middle-aged and older adults do not move enough. Research has shown that even small increases in activity can have a significant impact on risk reduction and improve quality of life. Some behavior change techniques (BCTs) can increase activity, but prior studies on their effectiveness have primarily tested them in between-subjects trials and in aggregate. These design approaches, while robust, fail to identify those BCTs most influential for a given individual. In contrast, a personalized, or N-of-1, trial design can assess a person’s response to each specific intervention. ObjectiveThis study is designed to test the feasibility, acceptability, and preliminary effectiveness of a remotely delivered personalized behavioral intervention to increase low-intensity physical activity (ie, walking) in adults aged 45 to 75 years. MethodsThe intervention will be administered over 10 weeks, starting with a 2-week baseline period followed by 4 BCTs (goal-setting, self-monitoring, feedback, and action planning) delivered one at a time, each for 2 weeks. In total, 60 participants will be randomized post baseline to 1 of 24 intervention sequences. Physical activity will be continuously measured by a wearable activity tracker, and intervention components and outcome measures will be delivered and collected by email, SMS text messages, and surveys. The effect of the overall intervention on step counts relative to baseline will be examined using generalized linear mixed models with an autoregressive model that accounts for possible autocorrelation and linear trends for daily steps across time. Participant satisfaction with the study components and attitudes and opinions toward personalized trials will be measured at the intervention's conclusion. ResultsPooled change in daily step count will be reported between baseline and individual BCTs and baseline versus overall intervention. Self-efficacy scores will be compared between baseline and individual BCTs and between baseline and the overall intervention. Mean and SD will be reported for survey measures (participant satisfaction with study components and attitudes and opinions toward personalized trials). ConclusionsAssessing the feasibility and acceptability of delivering a personalized, remote physical activity intervention for middle-aged and older adults will inform what steps will be needed to scale up to a fully powered and within-subjects experimental design remotely. Examining the effect of each BCT in isolation will allow for their unique impact to be assessed and support design of future behavioral interventions. In using a personalized trial design, the heterogeneity of individual responses for each BCT can be quantified and inform later National Institutes of Health stages of intervention development trials. Trial Registrationclinicaltrials.gov NCT04967313; https://clinicaltrials.gov/ct2/show/NCT04967313 International Registered Report Identifier (IRRID)RR1-10.2196/43418

Introduction Fatigue is one of the most commonly recorded patient symptoms that can result in deficits in aspects of psychomotor functioning, cognition, work performance and mood. Research shows that bright light and dim light therapy may be an efficacious way to reduce symptoms of fatigue. Still, the feasibility, scalability, individual treatment effects and adverse event heterogeneity of these treatments are unknown.Methods and analysis The current study evaluates the feasibility, acceptability and effectiveness of a series of personalised (N-of-1) interventions for virtual delivery of bright light therapy and dim light therapy versus usual care treatment for fatigue in 60 participants. We hypothesise that this study will provide valuable information about implementing virtual, N-of-1 randomised controlled trials (RCTs) for fatigue. It will also offer results about determining participants’ ratings of usability and satisfaction with the virtual, personalised intervention delivery system; evaluating participants’ improvement of fatigue symptoms; and, in the long term, identify ways to integrate N-of-1 light therapy trials into patient care.Ethics and dissemination This trial was approved by the Northwell Health Institutional Review Board. The trial results will be published in a peer-reviewed journal. All publications resulting from this series of personalised trials will follow the Consolidated Standards of Reporting Trials extension for N-of-1 trials CENT 2015 reporting guidelines.Registration details This trial is registered in www.ClinicalTrials.gov (number NCT04707846).Trial registration number NCT04707846.

Background: Although dual independent review of search results by two reviewers is generally recommended for systematic reviews, there are not consistent recommendations regarding the timing of the use of the second reviewer. This study compared the use of a complete dual review approach, with two reviewers in both the title/abstract screening stage and the full-text screening stage, as compared with a limited dual review approach, with two reviewers only in the full-text stage. Methods: This study was performed within the context of a large systematic review. Two reviewers performed a complete dual review of 15,000 search results and a limited dual review of 15,000 search results. The number of relevant studies mistakenly excluded by highly experienced reviewers in the complete dual review was compared with the number mistakenly excluded during the full-text stage of the limited dual review. Results: In the complete dual review approach, an additional 6.6% to 9.1% of eligible studies were identified during the title/abstract stage by using two reviewers, and an additional 6.6% to 11.9% of eligible studies were identified during the full-text stage by using two reviewers. In the limited dual review approach, an additional 4.4% to 5.3% of eligible studies were identified with the use of two reviewers. Conclusions: Using a second reviewer throughout the entire study screening process can increase the number of relevant studies identified for use in a systematic review. Systematic review performers should consider using a complete dual review process to ensure all relevant studies are included in their review.

This study examined temporal and social comparisons of physical health status. Participants in two waves of the MIDUS cohort ranging in age from young adult to young-old (N = 2,408) rated current, past, and future physical health, as well as peer health. Past health was generally rated as better than current health (particularly among young adults). Young adults expected better future health; young-old adults expected declining health. All groups recalled their health as better than they reported a decade earlier. Middle-aged and young-old respondents expected more decline than they reported ten years later; young adults' ratings were consistent. The two older groups believed they were healthier than same-age peers, whereas younger respondents believed they were less healthy (though as healthy as the other age groups). The nature and trajectories of temporal and social comparisons of physical health across the lifespan suggest the need to examine their consequences for health behaviors., Author(s): Jerry Suls [sup.1] , Rebecca A. Ferrer [sup.2] , William M. P. Klein [sup.2] Author Affiliations: (1) grid.416477.7, 0000 0001 2168 3646, Feinstein Institutes for Medical Research, Northwell Health, [...]

The varicella-zoster virus (VZV) infects >95% of the population. VZV reactivation causes herpes zoster (HZ), known as shingles, primarily affecting the elderly and individuals who are immunocompromised. However, HZ can occur in otherwise healthy individuals. We analyzed the immune signature and risk profile in patients with HZ using a genome-wide association study across different UK Biobank HZ cohorts. Additionally, we conducted one of the largest HZ human leukocyte antigen association studies to date, coupled with transcriptomic analysis of pathways underlying HZ susceptibility. Our findings highlight the significance of the major histocompatibility complex locus for HZ development, identifying 5 protective and 4 risk human leukocyte antigen alleles. This demonstrates that HZ susceptibility is largely governed by variations in the major histocompatibility complex. Furthermore, functional analyses revealed the upregulation of type I interferon and adaptive immune responses. These findings provide fresh molecular insights into the pathophysiology and activation of innate and adaptive immune responses triggered by symptomatic VZV reactivation. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells are an innovative therapeutic for various equine orthopaedic diseases, including soft tissue injuries. Objectives: To evaluate the safety and efficacy of tenogenic primed equine allogeneic peripheral blood‐derived mesenchymal stem cells (tpMSCs) in horses with naturally occurring superficial digital flexor tendon (SDFT) and suspensory ligament (SL) injuries. Study design: Multicentre, blinded, randomised, placebo‐controlled clinical trial. Methods: One hundred client‐owned horses with SDFT and SL injuries were randomised to receive an intralesional tpMSC (66) or saline (34) injection. Clinical and ultrasonographic evaluation was performed before treatment and on Days 56 ± 3 and 112 ± 3 after treatment. Long‐term data on re‐injury was collected up to 2 years after treatment. Results: Significantly more tpMSC‐treated horses achieved improvement in fibre alignment score (FAS) (100% vs. 54.5%, p < 0.001) and echogenicity (97.0% vs. 57.6%, p < 0.001) on Day 112 ± 3, and their lesion size decreased significantly (−27.6 ± 25.91 vs. −4.6 ± 26.64 mm2, p < 0.001) compared to the placebo group. A FAS = 0 was achieved in 65% of tpMSC‐treated horses, as compared to 9% of placebo‐treated horses at Day 112 ± 3. The attending veterinarians reported no re‐injury in 41 of 53 tpMSC and in 2 of 26 saline‐treated horses available for long‐term follow‐up (p < 0.001). Main limitations: As this study consisted of client‐owned horses, no samples for histology were collected. Long‐term follow‐up was only available for a subset of enrolled horses. Conclusions: The intralesional administration of tpMSCs was safe and improved the quality of healing and long‐term outcomes in sports horses with naturally occurring SDFT and suspensory injuries. [ABSTRACT FROM AUTHOR]

Antigen recognition through the T cell receptor (TCR) αβ heterodimer is one of the primary determinants of the adaptive immune response. Vaccines activate naïve T cells with high specificity to expand and differentiate into memory T cells. However, antigen-specific memory CD4 T cells exist in unexposed antigen-naïve hosts. In this study, we use high-throughput sequencing of memory CD4 TCRβ repertoire and machine learning to show that individuals with preexisting vaccine-reactive memory CD4 T cell clonotypes elicited earlier and higher antibody titers and mounted a more robust CD4 T cell response to hepatitis B vaccine. In addition, integration of TCRβ sequence patterns into a hepatitis B epitope-specific annotation model can predict which individuals will have an early and more vigorous vaccine-elicited immunity. Thus, the presence of preexisting memory T cell clonotypes has a significant impact on immunity and can be used to predict immune responses to vaccination.

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

Abstract Background Meningitis can be caused by several viruses and bacteria. Identifying the causative pathogen as quickly as possible is crucial to initiate the most optimal therapy, as acute bacterial meningitis is associated with a significant morbidity and mortality. Bacterial meningitis requires antibiotics, as opposed to enteroviral meningitis, which only requires supportive therapy. Clinical presentation is usually not sufficient to differentiate between viral and bacterial meningitis, thereby necessitating cerebrospinal fluid (CSF) analysis by PCR and/or time-consuming bacterial cultures. However, collecting CSF in children is not always feasible and a rather invasive procedure. Methods In 12 Belgian hospitals, we obtained acute blood samples from children with signs of meningitis (49 viral and 7 bacterial cases) (aged between 3 months and 16 years). After pathogen confirmation on CSF, the patient was asked to give a convalescent sample after recovery. 3′ mRNA sequencing was performed to determine differentially expressed genes (DEGs) to create a host transcriptomic profile. Results Enteroviral meningitis cases displayed the largest upregulated fold change enrichment in type I interferon production, response and signaling pathways. Patients with bacterial meningitis showed a significant upregulation of genes related to macrophage and neutrophil activation. We found several significantly DEGs between enteroviral and bacterial meningitis. Random forest classification showed that we were able to differentiate enteroviral from bacterial meningitis with an AUC of 0.982 on held-out samples. Conclusions Enteroviral meningitis has an innate immunity signature with type 1 interferons as key players. Our classifier, based on blood host transcriptomic profiles of different meningitis cases, is a possible strong alternative for diagnosing enteroviral meningitis.

Abstract In addition to its implication in hereditary hearing loss, the Gasdermin E (GSDME) gene is also a tumor suppressor involved in cancer progression through programmed cell death. GSDME epigenetic silencing through methylation has been shown in some cancer types, but studies are yet to fully explore its diagnostic/prognostic potential in colorectal cancer on a large‐scale. We used public data from The Cancer Genome Atlas (TCGA) to investigate differences in GSDME methylation and expression between colorectal cancer and normal colorectal tissue, and between left‐ and right‐sided colorectal cancers in 432 samples. We also explored GSDME's diagnostic capacity as a biomarker for colorectal cancer. We observed differential methylation in all 22 GSDME CpGs between tumor and normal tissues, and in 18 CpGs between the left‐ and right‐sided groups. In the cancer tissue, putative promoter probes were hypermethylated and gene body probes were hypomethylated, while this pattern was inversed in normal tissues. Both putative promoter and gene body CpGs correlated well together but formed distinct methylation patterns with the putative promoter exhibiting the most pronounced methylation differences between tumor and normal tissues. Clinicopathological parameters, excluding age, did not show any effect on CpG methylation. Although the methylation of 5 distinct probes was a good predictor of gene expression, we could not identify an association between GSDME methylation and expression in general. Survival analysis showed no association between GSDME methylation and expression on 5‐year patient survival. Through logistic regression, we identified a combination of 2 CpGs, that can discriminate between cancer and normal tissue with high accuracy (AUC = 0.95) irrespective of age and tumor stage. We also validated our model in 3 external methylation datasets, from the Gene Expression Omnibus database, and similar results were reached. Our results suggest that GSDME is a promising biomarker for the detection of colorectal cancer.

BackgroundSmartphone apps promoting physical activity (PA) are abundant, but few produce substantial and sustained behavior change. Although many PA apps purport to induce users to compare themselves with others (by invoking social comparison processes), improvements in PA and other health behaviors are inconsistent. Existing literature suggests that social comparison may motivate PA for some people under some circumstances. However, 2 aspects of work that apply social comparison theory to PA apps remain unclear: (1) how comparison processes have been operationalized or harnessed in existing PA apps and (2) whether incorporating sources of variability in response to comparison have been used to tailor comparison features of apps, which could improve their effectiveness for promoting PA. ObjectiveThe aim of this meta-review was to summarize existing systematic, quantitative, and narrative reviews of behavior change techniques in PA apps, with an emphasis on social comparison features, to examine how social comparison is operationalized and implemented. MethodsWe searched PubMed, Web of Science, and PsycINFO for reviews of PA smartphone apps. Of the 3743 initial articles returned, 26 reviews met the inclusion criteria. Two independent raters extracted the data from these reviews, including the definition of social comparison used to categorize app features, the percentage of apps categorized as inducing comparison, specific features intended to induce comparison, and any mention of tailoring comparison features. For reference, these data were also extracted for related processes (such as behavioral modeling, norm referencing, and social networking). ResultsOf the included review articles, 31% (8/26) categorized app features as prompting social comparison. The majority of these employed Abraham and Michie’s earliest definition of comparison, which differs from versions in later iterations of the same taxonomy. Very few reviews specified what dimension users were expected to compare (eg, steps, physical fitness) or which features of the apps were used to induce comparison (eg, leaderboards, message boards). No review referenced tailoring of comparison features. In contrast, 54% (14/26) reviews categorized features for prompting behavioral modeling and 31% (8/26) referenced tailoring app features for users’ personal goals or preferences. ConclusionsThe heterogeneity across reviews of PA apps and the absence of relevant information (eg, about dimensions or features relevant for comparison) create confusion about how to best harness social comparison to increase PA and its effectiveness in future research. No evidence was found that important findings from the broader social comparison literature (eg, that people have differing preferences for and responses to social comparison information) have been incorporated in the design of existing PA apps. Greater integration of the mobile health (mHealth) and social comparison literatures may improve the effectiveness of PA apps, thereby increasing the public health impact of these mHealth tools. International Registered Report Identifier (IRRID)RR2-https://osf.io/nh4td/

Abstract Background Breast cancer is the most frequent cancer among women worldwide. Biomarkers for early detection and prognosis of these patients are needed. We hypothesized that deafness, autosomal dominant 5 (DFNA5) may be a valuable biomarker, based upon strong indications for its role as tumor suppressor gene and its function in regulated cell death. In this study, we aimed to analyze DFNA5 methylation and expression in the largest breast cancer cohort to date using publicly available data from TCGA, in order to further unravel the role of DFNA5 as detection and/or prognostic marker in breast cancer. We analyzed Infinium HumanMethylation450k data, covering 22 different CpGs in the DFNA5 gene (668 breast adenocarcinomas and 85 normal breast samples) and DFNA5 expression (Agilent 244K Custom Gene Expression: 476 breast adenocarcinomas and 56 normal breast samples; RNA-sequencing: 666 breast adenocarcinomas and 71 normal breast samples). Results DFNA5 methylation and expression were significantly different between breast cancer and normal breast samples. Overall, breast cancer samples showed higher DFNA5 methylation in the putative gene promoter compared to normal breast samples, whereas in the gene body and upstream of the putative gene promoter, the opposite is true. Furthermore, DFNA5 methylation, in 10 out of 22 CpGs, and expression were significantly higher in lobular compared to ductal breast cancers. An important result of this study was the identification of a combination of one CpG in the gene promoter (CpG07504598) and one CpG in the gene body (CpG12922093) of DFNA5, which was able to discriminate between breast cancer and normal breast samples (AUC = 0.93). This model was externally validated in three independent datasets. Moreover, we showed that estrogen receptor state is associated with DFNA5 methylation and expression. Finally, we were able to find a significant effect of DFNA5 gene body methylation on a 5-year overall survival time. Conclusions We conclude that DFNA5 methylation shows strong potential as detection and prognostic biomarker for breast cancer.

The article provides information on the National Institute on Aging Edward R. Roybal Centers which focused on supporting innovative research that fosters the health and independence of older adults while studying conditions that affect the most vulnerable among Americans aging population. Topics discussed include the primary aims of the iteration of the Royal Center foci, categories of the Roybal Center publications, and name and descriptions of Roybal Centers.