Translating genome-wide association study (GWAS) loci into causal variants and genes requires accurate cell-type-specific enhancer-gene maps from disease-relevant tissues. Building enhancer-gene maps ...is essential but challenging with current experimental methods in primary human tissues. Here we developed a nonparametric statistical method, SCENT (single-cell enhancer target gene mapping), that models association between enhancer chromatin accessibility and gene expression in single-cell or nucleus multimodal RNA sequencing and ATAC sequencing data. We applied SCENT to 9 multimodal datasets including >120,000 single cells or nuclei and created 23 cell-type-specific enhancer-gene maps. These maps were highly enriched for causal variants in expression quantitative loci and GWAS for 1,143 diseases and traits. We identified likely causal genes for both common and rare diseases and linked somatic mutation hotspots to target genes. We demonstrate that application of SCENT to multimodal data from disease-relevant human tissue enables the scalable construction of accurate cell-type-specific enhancer-gene maps, essential for defining noncoding variant function.
Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; ...however, the epigenetic regulation of these states has yet to be defined. Here, we examine genome-wide open chromatin at single-cell resolution in 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identify 24 chromatin classes and predict their associated transcription factors, including a CD8 + GZMK+ class associated with EOMES and a lining fibroblast class associated with AP-1. By integrating with an RA tissue transcriptional atlas, we propose that these chromatin classes represent 'superstates' corresponding to multiple transcriptional cell states. Finally, we demonstrate the utility of this RA tissue chromatin atlas through the associations between disease phenotypes and chromatin class abundance, as well as the nomination of classes mediating the effects of putatively causal RA genetic variants.
This study examined the relationships between military stressors and supports, couple wellbeing, and the psychological outcomes of military wives. Systems focused theories, specifically the ABCX ...Model of Family Stress and the Marital Discord Model of Depression, were used to identify and explain such relationships. A structural equation model indicated that social support from the military community was directly associated with higher levels of personal wellbeing among military wives. In addition, military wives who were more satisfied with military life tended to indicate higher levels of couple wellbeing, suggesting an association with healthier interpersonal dynamics with their active duty partner, which also was associated with better psychological health, namely lower levels of depressive symptoms and higher levels of personal wellbeing. Results demonstrated that the couple relationship appeared to be the most salient resource and leverage point for intervention. Moreover, bivariate correlations indicated that military wives who were married longer tended to report greater community connections and that wives of enlisted service members reported being more dissatisfied with aspects of military life. The implications of these findings and areas of further research in the field of counseling and for the United States Armed Forces are discussed.
Abstract
Background and Aims
There are concerns regarding the potential impact of the COVID-19 outbreak on patients with inflammatory bowel disease IBD. We report on the impact of the COVID-19 ...outbreak in a European prospective cohort study of patients with IBD
Patients and Methods
We prospectively collected data from 5457 patients with IBD nested in the ongoing I-CARE project and still followed up in April 2020, with monthly online monitoring of clinical activity, treatment, imaging and endoscopy. Investigators were also contacted to report incidental cases.
Results
In total, 233 4.3% reported COVID-19 and 12 0.2% severe COVID-19, with no COVID-19 deaths. The risk of COVID-19 in patients with IBD was not increased compared to the general population (standardized incidence ratio SIR: 1.18, 95% confidence interval CI 1.03–1.34, p = 0.009), as well as the risk of severe COVID-19 (SIR: 0.69, 95% CI 0.35–1.20, p = 0.93). We did not observe any negative impact of the different IBD-related medication on the risk of either COVID-19 or severe COVID-19. In 2020, the COVID-19 outbreak resulted in a drastic decrease in endoscopic and imaging procedures from March to May 2020 compared to 2018 and 2019. No impacts on clinical IBD disease activity as well as ongoing treatment were noted.
Conclusion
No increases in either COVID-19 or severe COVID-19 incidences were observed in patients with IBD. There was no impact of COVID-19 on IBD-related medication and clinical activity. Access to endoscopy and imaging was restricted during the first months of the first COVID-19 outbreak.
The key political and strategic issues which need to be addressed for the future development of the Australian subject gateways are: continued quality of content creation, integration of access to ...print and electronic resources, archiving and persistent identification, sustainability of services and service integration. These isssues will be more effectively tackled internationally, and the Australian subject gateways are keen to work with international collaborators to achieve a mutually beneficial outcome.
Objective
Safer and more effective therapies are needed for the treatment of systemic lupus erythematosus (SLE). B lymphocytes have been shown to play fundamental pathogenic roles in SLE, and ...therefore, elimination of B cells with the use of rituximab may represent a new therapy for SLE.
Methods
A phase I/II dose‐escalation trial of rituximab added to ongoing therapy in SLE was conducted. Rituximab was administered as a single infusion of 100 mg/m2 (low dose), a single infusion of 375 mg/m2 (intermediate dose), or as 4 infusions (1 week apart) of 375 mg/m2 (high dose). CD19+ lymphocytes were measured to determine the effectiveness of B cell depletion. The Systemic Lupus Activity Measure (SLAM) score was used as the primary outcome for clinical efficacy.
Results
Rituximab was well tolerated in this patient population, with most experiencing no significant adverse effects. Only 3 serious adverse events, which were thought to be unrelated to rituximab administration, were noted. A majority of patients (11 of 17) had profound B cell depletion (to <5 CD19+ B cells/μl). In these patients, the SLAM score was significantly improved at 2 and 3 months compared with baseline (P = 0.0016 and P = 0.0022, respectively, by paired t‐test). This improvement persisted for 12 months, despite the absence of a significant change in anti–double‐stranded DNA antibody and complement levels. Six patients developed human antichimeric antibodies (HACAs) at a level ≥100 ng/ml. These HACA titers were associated with African American ancestry, higher baseline SLAM scores, reduced B cell depletion, and lower levels of rituximab at 2 months after initial infusion.
Conclusion
Rituximab therapy appears to be safe for the treatment of SLE and holds significant therapeutic promise, at least for the majority of patients experiencing profound B cell depletion. Based on these results, controlled trials of rituximab appear to be warranted.
The addition of long-acting beta(2)-adrenoceptor agonist (LABA) therapy to 'low dose' inhaled corticosteroids improves asthma outcomes in terms of lung function, exacerbation rates, and quality of ...life measures in asthmatic patients who remain symptomatic on low-dose inhaled corticosteroids alone. Such treatment is now included in guidelines of asthma therapy on the basis of class A evidence from large placebo-controlled trials. Data on the cost-benefit of such treatment is less compelling, but suggests that for patients with mild asthma this clinical improvement is gained at the expense of an increase in direct costs (mostly drug costs), whereas for patients with more severe asthma there may be a cost benefit, largely from reduced costs of exacerbations. Recently, combination inhalers containing both LABA and corticosteroid in the same device have been introduced. Although it is said that a single inhaler (with some immediate symptom relief) may aid patient adherence, there are no firm data to support this, nor are there any cost-effectiveness data on this point. Overall, these devices have been priced at less than the two drugs given separately, but prospective studies evaluating costs in clinical settings are required.
Controlled trials suggest that leukotriene receptor antagonists can improve lung function and reduce requirement for oral or inhaled corticosteroids in patients with asthma. We aimed to assess ...whether montelukast, a leukotriene receptor antagonist, can improve symptoms or lung function in patients with chronic asthma with symptoms already taking corticosteroids.
We did a double-blind, placebo-controlled, crossover, randomised add-on study in which 100 patients with asthma and symptoms despite treatment with inhaled corticosteroids and additional therapy were given 10 mg montelukast sodium for 14 days in an outpatient clinic setting. Outcome measures were symptoms and peak flow diaries.
72 patients had diary data for analysis. Compared with placebo, addition of montelukast did not result in any significant change in symptom scores (mean difference between the last 7 days of each treatment period 0·05; 95% CI −0·86 to 1·14), rescue inhaled (32 agonist use (mean difference in puffs per day 0·41; −0·29 to 0·57), or twice daily peak expiratory flow (PEF) measurements (mean difference in morning PEF 1·18 L/min; −14·29 to 17·14), and mean difference in evening peak flow (-0·50; −17·42 to 12·86). When treatment response was defined as a 15% or greater increase in mean peak flow readings, there were four responders to montelukast and seven responders to placebo.
Based on PEF data from our previous studies of a similar patient group we would have expected to detect changes of more than 5%. Used as additional therapy in a hospital outpatient clinic setting, montelukast did not provide such additional benefit in patients with moderate or severe asthma.
Context:Lack of awareness about diseases and associated risk factors could partially account for some rural health disparities. Health communications campaigns can be an effective means of increasing ...awareness in these areas.Purpose:To review findings and lessons learned from a rural health communications campaign.Methods:The health communications campaign titled "Physical Activity. The Arthritis Pain Reliever," developed by the Centers for Disease Control and Prevention, was implemented in a rural Arkansas county to promote awareness about arthritis and the beneficial effects of physical activity among residents 45-64 years of age with arthritis. The campaign was implemented through radio spots, print ads in local newspapers, and distribution of brochures and posters. A survey of 193 residents with arthritis assessed the reach of the campaign.Findings:Whereas 86% of respondents reported having seen or heard the messages related to arthritis during the 13-week period of the campaign, only 11% recalled messages from the "Physical Activity. The Arthritis Pain Reliever" campaign. Challenges faced during campaign implementation included limited fiscal resources, distrust, and staff and time constraints.Conclusion:Challenges to health communications campaigns in rural areas can decrease campaign reach and effectiveness. If resource constraints exist, leveraging partnerships and building trust among residents of the community are important for achieving campaign success.
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