BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis

Introduction In colitis, macrophage functionality is altered compared to normal homeostatic conditions. Loss of IL-10 signaling results in an inappropriate chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice. Methods We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence and absence of lipopolysaccharide (LPS) with and without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization. Results Treatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo resulted in a mild reduction in colitis severity as compared with vehicle-treated mice. Conclusion We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis

Increased colonic expression of ACE2 associates with poor prognosis in Crohn’s disease

The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. We examined the expression of colonic ACE2 in 67 adult CD and 14 NIBD control patients using RNA-seq and quantitative (q) RT-PCR. We validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan–Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. Colonic ACE2 expression was significantly higher in a subset of adult CD patients which was defined as the ACE2-high CD subset. IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of CD diagnosis, and a Cox regression analysis found that high ACE2 levels is an independent risk factor for surgery (OR 2.17; 95% CI, 1.10–4.26; p = 0.025). Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that can impact CD disease-related outcomes

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation

Data from: Transcriptome profiles of sunflower reveal the potential role of microsatellites in gene expression divergence

The mechanisms by which natural populations generate adaptive genetic variation are not well understood. Some studies propose that microsatellites can function as drivers of adaptive variation. Here we tested a potentially adaptive role for transcribed microsatellites with natural populations of the common sunflower (Helianthus annuus L.) by assessing the enrichment of microsatellites in genes that show expression divergence across latitudes. Seeds collected from six populations at two distinct latitudes in Kansas and Oklahoma were planted and grown in a common garden. Morphological measurements from the common garden demonstrated that phenotypic variation among populations is largely explained by underlying genetic variation. An RNA–Seq experiment was conducted with 96 of the individuals grown in the common garden and differentially expressed (DE) transcripts between the two latitudes were identified. A total number of 825 DE transcripts were identified. DE transcripts and non-differentially expressed (NDE) transcripts were then scanned for microsatellites. The abundance of different motif lengths and types in both groups were estimated. Our results indicate that DE transcripts are significantly enriched with mononucleotide repeats and significantly depauperate in trinucleotide repeats. Further, the standardized mononucleotide repeat motif A and dinucleotide repeat motif AG were significantly enriched within DE transcripts while motif types, C, AT, ACC, and AAC in DE transcripts are significantly differentiated in microsatellite tract length between the two latitudes. The tract length differentiation at specific microsatellite motif types across latitudes and their enrichment within DE transcripts indicate a potential functional role for transcribed microsatellites in gene expression divergence in sunflower

Needs for Successful Engagement in Telemedicine Among Rural Older US Veterans and Their Caregivers: Qualitative Study

BackgroundTelemedicine is an important option for rural older adults who often must travel far distances to clinics or forgo essential care. In 2014, the Geriatric Research, Education, and Clinical Centers (GRECC) of the US Veterans Health Administration (VA) established a national telemedicine network called GRECC Connect. This network increased access to geriatric specialty care for the 1.4 million rural VA-enrolled veterans aged 65 years or older. The use of telemedicine skyrocketed during the COVID-19 pandemic, which disproportionately impacted older adults, exacerbating disparities in specialty care access as overburdened systems shut down in-person services. This surge presented a unique opportunity to study the supports necessary for those who would forgo telemedicine if in-person care were available. ObjectiveIn spring 2021, we interviewed veterans and their informal caregivers to (1) elicit their experiences attempting to prepare for a video visit with a GRECC Connect geriatric specialist and (2) explore facilitators and barriers to successful engagement in a telemedicine visit. MethodsWe conducted a cross-sectional qualitative evaluation with patients and their caregivers who agreed to participate in at least 1 GRECC Connect telemedicine visit in the previous 3 months. A total of 30 participants from 6 geographically diverse GRECC Connect hub sites agreed to participate. Semistructured interviews were conducted through telephone or the VA’s videoconference platform for home telemedicine visits (VA Video Connect) per participant preference. We observed challenges and, when needed, provided real-time technical support to facilitate VA Video Connect use for interviews. All interviews were recorded with permission and professionally transcribed. A team of 5 researchers experienced in qualitative research analyzed interview transcripts using rapid qualitative analysis. ResultsFrom 30 participant interviews, we identified the following 4 categories of supports participants described regarding successful engagement in telemedicine, as defined by visit completion, satisfaction, and willingness to engage in telemedicine in the future: (1) caregiver presence to facilitate technology setup and communication; (2) flexibility in visit modality (eg, video from home or a clinic or telephone); (3) technology support (eg, determining device compatibility or providing instruction and on-demand assistance); and (4) assurance of comfort with web-based communication, including orientation to features like closed captioning. Supports were needed at multiple points before the visit, and participants stressed the importance of eliciting the varying needs and preferences of each patient-caregiver dyad. Though many initially agreed to a telemedicine visit because of pandemic-related clinic closures, participants were satisfied with telemedicine and willing to use it for other types of health care visits. ConclusionsTo close gaps in telemedicine use among rural older adults, supports must be tailored to individuals, accounting for technology availability and comfort, as well as availability of and need for caregiver involvement. Comprehensive scaffolding of support starts well before the first telemedicine visit

Table1_Adaptation of a social risk screening and referral initiative across clinical populations, settings, and contexts in the Department of Veterans Affairs Health System.docx

Identifying and addressing social risks and social needs in healthcare settings is an important step towards achieving health equity. Assessing Circumstances and Offering Resources for Needs (ACORN) is a Department of Veterans Affairs (VA) social risk screening and referral model that aims to systematically identify and address social needs. Since initial piloting in 2018, our team has collaborated with clinical and operations partners to implement ACORN across multiple VA clinical settings while adapting and tailoring the initiative to meet the needs of different populations, specialties, and individuals administering screening. Given ACORN's complexity as a growing initiative with multiple partners and frequent real-time modifications within a large national healthcare system, we recognized a need to systematically document the rationale and process of adaptations over time. We looked to three implementation frameworks—RE-AIM, the Adaptome, and FRAME—to describe the rationale for adaptations, the nature of and context within which adaptations were made, and the details of each adaptation. In this manuscript, we uniquely interweave these three frameworks to document adaptations to ACORN across diverse VA clinical settings, with a focus on how adaptations support the promotion of heath equity in the Veteran population.</p

Linking gene expression to clinical outcomes in pediatric Crohn’s disease using machine learning

Abstract Pediatric Crohn’s disease (CD) is characterized by a severe disease course with frequent complications. We sought to apply machine learning-based models to predict risk of developing future complications in pediatric CD using ileal and colonic gene expression. Gene expression data was generated from 101 formalin-fixed, paraffin-embedded (FFPE) ileal and colonic biopsies obtained from treatment-naïve CD patients and controls. Clinical outcomes including development of strictures or fistulas and progression to surgery were analyzed using differential expression and modeled using machine learning. Differential expression analysis revealed downregulation of pathways related to inflammation and extra-cellular matrix production in patients with strictures. Machine learning-based models were able to incorporate colonic gene expression and clinical characteristics to predict outcomes with high accuracy. Models showed an area under the receiver operating characteristic curve (AUROC) of 0.84 for strictures, 0.83 for remission, and 0.75 for surgery. Genes with potential prognostic importance for strictures (REG1A, MMP3, and DUOX2) were not identified in single gene differential analysis but were found to have strong contributions to predictive models. Our findings in FFPE tissue support the importance of colonic gene expression and the potential for machine learning-based models in predicting outcomes for pediatric CD

Effectiveness of Ambulatory Telemedicine Care in Older Adults: A Systematic Review

BACKGROUND: Disparities in healthcare access and delivery, caused by transportation and health workforce difficulties, negatively impact individuals living in rural areas. These challenges are especially prominent in older adults. DESIGN: We systematically evaluated the feasibility, acceptability, and effectiveness in providing telemedicine (TMed), searching the English‐language literature for studies (January 2012 to July 2018) in the following databases: Medline (PubMed); Cochrane Library (Wiley); Web of Science; CINAHL; EMBASE (Ovid); and PsycINFO (EBSCO). PARTICIPANTS: Older adults (mean age = 65 years or older, and none were younger than 60 years). INTERVENTIONS: Interventions consisted of live, synchronous, two‐way videoconferencing communication in nonhospital settings. All medical interventions were included. MEASUREMENTS: Quality assessment, using the Cochrane Collaboration\u27s Risk‐of‐Bias Tool, was applied on all included articles, including a qualitative summary of all articles. RESULTS: Of 6,616 citations, we reviewed the full text of 1173 articles, excluding 1047 that did not meet criteria. Of the 17 randomized controlled trials, the United States was the country with the most trials (6 [35%]), with cohort sizes ranging from 3 to 844 (median = 35) participants. Risk of bias among included studies varied from low to high. Our qualitative analysis suggests that TMed can improve health outcomes in older adults and that it could be used in this population. CONCLUSIONS: TMed is feasible and acceptable in delivering care to older adults. Research should focus on well‐designed randomized trials to overcome the high degree of bias observed in our synthesis. Clinicians should consider using TMed in routine practice to overcome barriers of distance and access to care