To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow ...cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)
HLA-DRA
sublining fibroblasts, IL1B
pro-inflammatory monocytes, ITGAX
TBX21
autoimmune-associated B cells and PDCD1
peripheral helper T (T
) cells and follicular helper T (T
) cells. We defined distinct subsets of CD8
T cells characterized by GZMK
, GZMB
, and GNLY
phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1
HLA-DRA
fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.
The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, ...becomes inflamed and invasive, and destroys the joint
. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity
; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients-emanating from vascular endothelial cells outwards-in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.
Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction
. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments ...varies across patients, suggesting an undefined pathogenic diversity
. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.
Background
Enteral nutrition (EN) is often required in patients with head and neck cancer (HNSCC); however, initiation criteria is limited or inconsistent. This study aimed to describe the ...relationship of treatment toxicities and requirement for EN and investigate toxicity and baseline characteristics association with EN duration.
Methods
Acute toxicities and baseline characteristics were collected from patients with HNSCC (n = 110) undergoing H‐IMRT. Percentage EN contributing to estimated requirements and EN duration were measured.
Results
The threshold for patients needing ≥50% of estimated requirements via EN increased from week 3 to 4 for grade ≥2 oral/pharyngeal mucositis, dysgeusia, thick saliva and nausea, and for grade 3 dysphagia. Patients with grade 2–3 dysphagia had a reduced risk of ceasing EN compared to those with grade 0–1 dysphagia.
Conclusions
Using acute toxicities in clinical practice may be a useful tool to inform prompt initiation of EN prior to decline in nutritional status and anticipate EN duration.
We examined the prospective associations of COVID-19 fears and behavior, and daily physical activity and dysregulated eating. Adolescents (N = 31) aged 11–17 completed selected subscales of the Fear ...of Illness and Virus Evaluation and completed a 7-day health behavior diary. Greater fear of contamination was associated with lower daily physical activity. In contrast, greater COVID-19 precautionary behavior was associated with greater daily physical activity. COVID-19 fears and precautionary behaviors have differential associations with health promoting behavior engagement. Future studies should explore the mechanisms underlying these links to guide adaptation of health behavior interventions for this unique cohort.
The composition of the microbiome is shaped by both environment and host in most organisms, but in the mosquito Aedes aegypti the role of the host in shaping the microbiome is poorly understood. ...Previously, we had shown that four lines of Ae. aegypti harbored different microbiomes when reared in the same insectary under identical conditions. To determine whether these lines differed from each other across time and in different environments, we characterized the microbiome of the same four lines of Ae. aegypti reared in the original insectary and at another institution. While it was clear that the environment influenced the microbiomes of these lines, we did still observe distinct differences in the microbiome between lines within each insectary. Clear differences were observed in alpha diversity, beta diversity, and abundance of specific bacterial taxa. To determine if the line specific differences in the microbiome were maintained across environments, pair-wise differential abundances of taxa was compared between insectaries. Lines were most similar to other lines from the same insectary than to the same line reared in a different insectary. Additionally, relatively few differentially abundant taxa identified between pairs of lines were shared across insectaries, indicating that line specific properties of the microbiome are not conserved across environments, or that there were distinct microbiota within each insectary. Overall, these results demonstrate that mosquito lines under the same environmental conditions have different microbiomes across microbially- diverse environments and host by microbe interactions affecting microbiome composition and abundance is dependent on environmentally available bacteria.
Highlights • HNC patients undergoing helical IMRT experience a range of treatment related effects. • Symptoms peak in the final week of treatment and improve thereafter. • Most symptoms are better ...than baseline by 12 weeks post-treatment. • HNC patients undergoing helical IMRT continue to need speech pathology support.
To assess baseline factors that may predict fast tibiofemoral cartilage loss over a 30-month period.
The Multicenter Osteoarthritis (MOST) study is a longitudinal study of individuals who have or who ...are at high risk for knee osteoarthritis. The HIPAA-compliant protocol was approved by the institutional review boards of all participating centers, and written informed consent was obtained from all participants. Magnetic resonance (MR) images were read according to the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system. Only knees with minimal baseline cartilage damage (WORMS < or = 2.5) were included. Fast cartilage loss was defined as a WORMS of at least 5 (large full-thickness loss, less than 75% of the subregion) in any subregion at 30-month follow-up. The relationships of age, sex, body mass index (BMI), ethnicity, knee alignment, and several MR features (eg, bone marrow lesions, meniscal damage and extrusion, and synovitis or effusion) to the risk of fast cartilage loss were assessed by using a multivariable logistic regression model.
Of 347 knees, 90 (25.9%) exhibited cartilage loss, and only 20 (5.8%) showed fast cartilage loss. Strong predictors of fast cartilage loss were high BMI (adjusted odds ratio OR, 1.11; 95% confidence interval CI: 1.01, 1.23), the presence of meniscal tears (adjusted OR, 3.19; 95% CI: 1.13, 9.03), meniscal extrusion (adjusted OR, 3.62; 95% CI: 1.34, 9.82), synovitis or effusion (adjusted OR, 3.36; 95% CI: 0.91, 12.4), and any high-grade MR-depicted feature (adjusted OR, 8.99; 95% CI: 3.23, 25.1).
In participants with minimal baseline cartilage damage, the presence of high BMI, meniscal damage, synovitis or effusion, or any severe baseline MR-depicted lesions was strongly associated with an increased risk of fast cartilage loss. Patients with these risk factors may be ideal subjects for preventative or treatment trials.
Objectives To introduce a comprehensive and reliable scoring system for the assessment of whole-knee joint synovitis based on contrast-enhanced (CE) MRI. Methods Multicenter Osteoarthritis Study ...(MOST) is a cohort study of people with, or at high risk of, knee osteoarthritis (OA). Subjects are an unselected subset of MOST who volunteered for CE-MRI. Synovitis was assessed at 11 sites of the joint. Synovial thickness was scored semiquantitatively: grade 0 (<2 mm), grade 1 (2–4 mm) and grade 2 (>4 mm) at each site. Two musculoskeletal radiologists performed the readings and inter- and intrareader reliability was evaluated. Whole-knee synovitis was assessed by summing the scores from all sites. The association of Western Ontario and McMaster Osteoarthritis Index pain score with this summed score and with the maximum synovitis grade for each site was assessed. Results 400 subjects were included (mean age 58.8±7.0 years, body mass index 29.5±4.9 kg/m2, 46% women). For individual sites, intrareader reliability (weighted κ) was 0.67–1.00 for reader 1 and 0.60–1.00 for reader 2. Inter-reader agreement (κ) was 0.67–0.92. For the summed synovitis scores, intrareader reliability (intraclass correlation coefficient ( ICC)) was 0.98 and 0.96 for each reader and inter-reader agreement (ICC) was 0.94. Moderate to severe synovitis in the parapatellar subregion was associated with the higher maximum pain score (adjusted OR (95% CI), 2.8 (1.4 to 5.4) and 3.1 (1.2 to 7.9), respectively). Conclusions A comprehensive semiquantitative scoring system for the assessment of whole-knee synovitis is proposed. It is reliable and identifies knees with pain, and thus is a potentially powerful tool for synovitis assessment in epidemiological OA studies.
Diabetes distress among adolescents with type 1 diabetes has been associated with suboptimal diabetes outcomes, including lower quality of life, increased diabetes self-management challenges, and ...suboptimal glycemic outcomes.
This study examined the feasibility and acceptability of a scalable self-led mindfulness-based intervention to reduce diabetes distress in adolescents with type 1 diabetes.
Adolescents (N=25) aged between 14 and 18 years diagnosed with type 1 diabetes completed a baseline assessment. Participants were randomized to receive a 10-week self-guided mindfulness-based stress reduction workbook program (e-book or paper option) immediately (n=15) or after a 10-week wait (n=10). During the intervention period, participants completed weekly assignments and feedback surveys. At 10 weeks and 20 weeks, follow-up assessments were completed.
Findings indicated that participants did not find the original intervention feasible or acceptable. Adolescents reported barriers to completing the weekly material, such as that they forgot or that the material was not sufficiently related to their diabetes management. Adolescents also reported that a digital format rather than a workbook or e-book may be more acceptable. Results from weekly surveys provided the foundation for recommendations for future iterations of the mindfulness-based intervention for adolescents with type 1 diabetes.
Participant feedback informed recommendations for self-led mindfulness programs for youth with type 1 diabetes. Adolescents indicated that a shorter, digital mindfulness-based intervention focused on diabetes-specific behaviors may be more helpful.
ClinicalTrials.gov NCT05115175; https://clinicaltrials.gov/study/NCT05115175.
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