GRAPPA 2023: Major Projects, Key Advances, and Milestones.

At the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting, members were updated on a number of ongoing activities during the key project update session. These activities included the Axial Involvement in Psoriatic Arthritis (AXIS) cohort, the Axial Psoriatic Arthritis Molecular and Clinical Characterization study, the Diagnostic Ultrasound Enthesitis Tool (DUET) study, the Sex- and Gender-Based Analysis of the Effectiveness of Advanced Therapies in Psoriatic Arthritis (SAGE-PsA) study, the Health Initiatives in Psoriasis and Psoriatic Arthritis Consortium European States (HIPPOCRATES), the GRAPPA slide library, and the GRAPPA treatment recommendations.

Using Ultrasound to Improve Diagnostic Confidence and Management of Psoriatic Disease: Highlights From the GRAPPA 2023 Ultrasound Workshop.

The sensitivity of ultrasound (US) to detect, characterize, and monitor the relevant pathologies of psoriatic arthritis (PsA), including synovitis, enthesitis, tenosynovitis, and dactylitis, has made it an attractive tool for informing clinical decisions. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) US working group ran 2 sessions during the annual GRAPPA meeting held in July 2023 in Dublin, Ireland. During the first workshop, the group presented 2 topics, followed by a live demonstration and a group discussion. The 2 topics were (1) an overview of the Diagnostic Ultrasound Enthesitis Tool (DUET) enthesitis scoring methodology, and (2) small hand-held probes-will the promise deliver? The live demonstration that followed compared the performance of 2 hand-held US (HHUS) devices vs a console US machine in patients with PsA, and the interactive group discussion considered gaps in the literature and future research suggestions relating to HHUS and its application in psoriatic disease. During the second session, the US working group provided further updates regarding the GRAPPA US studies currently underway or recently completed.

Validation and incorporation of digital entheses into a preliminary GLobal OMERACT Ultrasound DActylitis Score (GLOUDAS) in psoriatic arthritis.

OBJECTIVES: The main objective was to generate a GLobal OMERACT Ultrasound DActylitis Score (GLOUDAS) in psoriatic arthritis and to test its reliability. To this end, we assessed the validity, feasibility and applicability of ultrasound assessment of finger entheses to incorporate them into the scoring system. METHODS: The study consisted of a stepwise process. First, in cadaveric specimens, we identified enthesis sites of the fingers by ultrasound and gross anatomy, and then verified presence of entheseal tissue in histological samples. We then selected the entheses to be incorporated into a dactylitis scoring system through a Delphi consensus process among international experts. Next, we established and defined the ultrasound components of dactylitis and their scoring systems using Delphi methodology. Finally, we tested the interobserver and intraobserver reliability of the consensus- based scoring systemin patients with psoriatic dactylitis. RESULTS: 32 entheses were identified in cadaveric fingers. The presence of entheseal tissues was confirmed in all cadaveric samples. Of these, following the consensus process, 12 entheses were selected for inclusion in GLOUDAS. Ultrasound components of GLOUDAS agreed on through the Delphi process were synovitis, tenosynovitis, enthesitis, subcutaneous tissue inflammation and periextensor tendon inflammation. The scoring system for each component was also agreed on. Interobserver reliability was fair to good (κ 0.39-0.71) and intraobserver reliability good to excellent (κ 0.80-0.88) for dactylitis components. Interobserver and intraobserver agreement for the total B-mode and Doppler mode scores (sum of the scores of the individual abnormalities) were excellent (interobserver intraclass correlation coefficient (ICC) 0.98 for B-mode and 0.99 for Doppler mode; intraobserver ICC 0.98 for both modes). CONCLUSIONS: We have produced a consensus-driven ultrasound dactylitis scoring system that has shown acceptable interobserver reliability and excellent intraobserver reliability. Through anatomical knowledge, small entheses of the fingers were identified and histologically validated.

Enthesitis in patients with psoriatic arthritis treated with secukinumab or adalimumab: a post hoc analysis of the EXCEED study.

OBJECTIVES: To evaluate enthesitis treatment response, including time to resolution and data from multiple enthesitis instruments, in patients with PsA treated with secukinumab or adalimumab for 52 weeks. METHODS: In this post hoc analysis of the EXCEED study, patients receiving secukinumab 300 mg or adalimumab 40 mg per the label were grouped by presence or absence of baseline enthesitis based on the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Efficacy was assessed according to several enthesitis-related instruments using non-responder imputation for the achievement of enthesitis resolution (LEI/SPARCC = 0), Kaplan-Meier analysis for time to resolution, and as-observed data for other outcomes. RESULTS: Enthesitis was present at baseline in 498 of 851 patients (58.5%) as assessed by LEI and in 632 of 853 patients (74.1%) as assessed by SPARCC. Patients with baseline enthesitis generally presented with greater disease activity. Similar proportions of patients receiving secukinumab or adalimumab achieved resolution of LEI and SPARCC at weeks 24 (secukinumab: LEI/SPARCC, 49.6%/45.8%; adalimumab: LEI/SPARCC, 43.6%/43.5%) and 52 (secukinumab: LEI/SPARCC, 60.7%/53.2%; adalimumab: LEI/SPARCC, 55.3%/51.4%), with comparable mean time to enthesitis resolution. Improvements were similar for both drugs at individual enthesitis sites. Resolution of enthesitis with secukinumab or adalimumab was associated with improvements in quality of life at week 52. CONCLUSION: Secukinumab and adalimumab showed similar efficacy, including time to resolution, with respect to resolution of enthesitis. Inhibition of IL-17 with secukinumab reduced clinical enthesitis similarly to TNF-α inhibition. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02745080.

Environment and taxonomy shape the genomic signature of prokaryotic extremophiles.

This study provides comprehensive quantitative evidence suggesting that adaptations to extreme temperatures and pH imprint a discernible environmental component in the genomic signature of microbial extremophiles. Both supervised and unsupervised machine learning algorithms were used to analyze genomic signatures, each computed as the k-mer frequency vector of a 500 kbp DNA fragment arbitrarily selected to represent a genome. Computational experiments classified/clustered genomic signatures extracted from a curated dataset of [Formula: see text] extremophile (temperature, pH) bacteria and archaea genomes, at multiple scales of analysis, [Formula: see text]. The supervised learning resulted in high accuracies for taxonomic classifications at [Formula: see text], and medium to medium-high accuracies for environment category classifications of the same datasets at [Formula: see text]. For [Formula: see text], our findings were largely consistent with amino acid compositional biases and codon usage patterns in coding regions, previously attributed to extreme environment adaptations. The unsupervised learning of unlabelled sequences identified several exemplars of hyperthermophilic organisms with large similarities in their genomic signatures, in spite of belonging to different domains in the Tree of Life.

Effects of Carboxymethylcellulose Artificial Tears on Ocular Surface Microbiome Diversity and Composition, A Randomized Controlled Trial.

Purpose: Carboxymethylcellulose is an artificial tear ingredient known to decrease gut microbiome diversity when ingested. This study examines the effect of carboxymethylcellulose on ocular surface microbiome diversity and composition. Methods: Healthy adult participants without significant ophthalmic disease or concurrent carboxymethylcellulose artificial tear use were allocated randomly to take carboxymethylcellulose or control polyethylene glycol artificial tears for seven days. Conjunctival swabs were collected before and after artificial tear treatment. This trial is registered at clinicaltrials.gov (NCT05292755). Primary outcomes included abundance of bacterial taxa and microbiome diversity as measured by the Chao-1 richness estimate, Shannon's phylogenetic diversity index, and UniFrac analysis. Secondary outcomes included Ocular Surface Disease Index scores and artificial tear compliance. Results: Of the 80 enrolled participants, 66 completed the trial. Neither intervention affected Chao-1 richness (analysis of variance [ANOVA], P = 0.231) or Shannon's diversity index (ANOVA, P = 0.224). Microbiome samples did not separate by time point (permutation multivariate analysis of variance [PERMANOVA], P = 0.223) or intervention group (PERMANOVA, P = 0.668). LEfSe taxonomic analysis revealed that carboxymethylcellulose depleted several taxa including Bacteroides and Lachnoclostridium, but enriched Enterobacteriaceae, Citrobacter, and Gordonia. Both interventions decreased OSDI scores (Wilcoxon signed rank test, P < 0.05), but there was no significant difference between interventions (Mann-Whitney U, P = 0.54). Conclusions: Carboxymethylcellulose artificial tears increased Actinobacteriota but decreased Bacteroides and Firmicutes bacteria. Carboxymethylcellulose artificial tears do not affect ocular surface microbiome diversity and are not significantly more effective than polyethylene glycol artificial tears for dry eye treatment. Translational Relevance: The 16S microbiome analysis has revealed small changes in the ocular surface microbiome associated with artificial tear use.

Seeing is believing: Smart use of musculoskeletal ultrasound in rheumatology practice.

Musculoskeletal ultrasonography has become an increasingly valuable tool as a complement to the physical exam in rheumatology practice. Its point-of-care access, low cost, safety, portability, and reliability in trained hands, make this technique especially useful in patients with inflammatory arthritis. Growing evidence has demonstrated the value of musculoskeletal ultrasound in the detection of inflammatory and structural changes in patients with joint pain without obvious joint swelling, in differentiating various inflammatory diagnoses, in the monitoring of inflammatory arthritis, and interventional procedures. The potential role of ultrasound guiding treat-to-target strategies or tapering treatment in inflammatory arthritis requires further research. However, musculoskeletal ultrasound can also have pitfalls and limitations that a clinician should be aware of.

Developing Ultrasound Measures for the Early Diagnosis of Psoriatic Arthritis.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) ultrasound (US) steering committee provided an update at GRAPPA's 2022 annual meeting on activities to enable earlier diagnosis of psoriatic arthritis. An update of the Diagnostic Ultrasound Enthesitis Tool (DUET) study included preliminary reliability results for US enthesitis elementary lesions. Common scanning pitfalls were reviewed. New projects included widening the scope of US beyond large entheses and validating small point-of-care US probes to evaluate enthesitis.

Smoking-induced subgingival dysbiosis precedes clinical signs of periodontal disease.

Smoking accelerates periodontal disease and alters the subgingival microbiome. However, the relationship between smoking-associated subgingival dysbiosis and progression of periodontal disease is not well understood. Here, we sampled 233 subgingival sites longitudinally from 8 smokers and 9 non-smokers over 6-12 months, analyzing 804 subgingival plaque samples using 16 rRNA sequencing. At equal probing depths, the microbial richness and diversity of the subgingival microbiome was higher in smokers compared to non-smokers, but these differences decreased as probing depths increased. The overall subgingival microbiome of smokers differed significantly from non-smokers at equal probing depths, which was characterized by colonization of novel minority microbes and a shift in abundant members of the microbiome to resemble periodontally diseased communities enriched with pathogenic bacteria. Temporal analysis showed that microbiome in shallow sites were less stable than deeper sites, but temporal stability of the microbiome was not significantly affected by smoking status or scaling and root planing. We identified 7 taxa-Olsenella sp., Streptococcus cristatus, Streptococcus pneumoniae, Streptococcus parasanguinis, Prevotella sp., Alloprevotella sp., and a Bacteroidales sp. that were significantly associated with progression of periodontal disease. Taken together, these results suggest that subgingival dysbiosis in smokers precedes clinical signs of periodontal disease, and support the hypothesis that smoking accelerates subgingival dysbiosis to facilitate periodontal disease progression.

Power doppler ultrasound signal predicts abnormal HDL function in patients with rheumatoid arthritis.

Active rheumatoid arthritis (RA) is associated with increased cardiovascular risk and impaired function of high-density lipoprotein (HDL). Previous work suggests that HDL may become dysfunctional through oxidative modifications within the RA joint. The current work evaluates an association of synovial power doppler ultrasound signal (PDUS) with HDL function and structure. Two open-label clinical therapeutic studies using PDUS as a disease outcome measure were included in this analysis, including a 12-month trial of subcutaneous abatacept in 24 RA patients and a 6-month trial of IV tocilizumab in 46 RA patients. Laboratory assays included assessments of HDL function and structure, HDL and total cholesterol levels, and a cytokine/chemokine panel. Patients with the highest baseline PDUS scores in both clinical studies, had worse HDL function, including suppression of paraoxonase 1 (PON1) activity as well as lower HDL-C levels. Associations between other disease assessments (DAS28 and CDAI) and HDL function/structure were noted but were generally of lesser magnitude and consistency than PDUS across the HDL profile. Treatment with tocilizumab for 6 months was associated with increases in cholesterol levels and improvements in the HDL function profile, which correlated with greater decreases in PDUS scores. Similar trends were noted following treatment with abatacept for 3 months. Higher baseline PDUS scores identified patients with worse HDL function. This data supports previous work suggesting a direct association of joint inflammation with abnormal HDL function.

Musculoskeletal Ultrasound in Childhood Arthritis Limited Examination: A Comprehensive, Reliable, Time-Efficient Assessment of Synovitis.

OBJECTIVE: To develop and initially validate a comprehensive pediatric musculoskeletal ultrasound (MSUS) joint-specific scoring system, and to determine the minimum number of joints needed to identify active disease. METHODS: A semiquantitative scoring system was developed by consensus and initially validated by interrater reliability using intraclass correlation coefficients (ICCs). Subsequently, newly diagnosed juvenile idiopathic arthritis patients with an active joint count of >4 had a 42-joint MSUS performed at baseline and 3 months using this protocol. A minimum set of joints needed to identify all patients with synovitis on MSUS was obtained through a data reduction process. Spearman's correlation (rs ) was calculated to determine the association between MSUS findings and clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10). Standardized response means (SMRs) were used to assess change over time. RESULTS: The final joint-specific scoring system revealed an excellent interrater reliability (ICC 0.81-0.96) for all joints. Thirty patients were enrolled. Scanning 5 joints bilaterally (wrists, second and third metacarpophalangeal joints, knees and ankles) captured 100% of children with B-mode synovitis and had moderate correlation with the cJADAS10 at baseline (rs  = 0.45). Mean ultrasound scores at baseline and follow-up were 28.3 and 22.3, with an SRM of 0.69 (P = 0.002) for 42 joints, and 36 and 27.7, with an SRM of 0.76 (P = 0.003) for the reduced joints, respectively. CONCLUSION: A limited MSUS examination called musculoskeletal ultrasound in childhood arthritis limited examination (MUSICAL) captures all patients with active synovitis, and our new joint-specific scoring system is highly reliable and sensitive to change.

Improved outcomes in rheumatoid arthritis with obesity after a weight loss intervention: randomized trial.

OBJECTIVE: To examine whether a weight loss intervention programme improves RA disease activity and/or musculoskeletal ultrasound synovitis measures in obese RA patients. METHODS: We conducted a proof-of-concept, 12-week, single-blind, randomized controlled trial of obese RA patients (BMI ≥ 30) with 28-joint DAS (DAS28) ≥ 3.2 and with evidence of power Doppler synovitis. Forty patients were randomized to the diet intervention (n = 20) or control group (n = 20). Diet intervention consisted of a hypocaloric diet of 1000-1500 kcal/day and high protein meal replacements. Co-primary outcomes included change in DAS28 and power Doppler ultrasound (PDUS)-34. Clinical disease activity, imaging, biomarkers, adipokines and patient-reported outcomes were monitored throughout the trial. Recruitment terminated early. All analyses were based on intent-to-treat for a significance level of 0.05. RESULTS: The diet intervention group lost an average 9.5 kg/patient, while the control group lost 0.5 kg (P < 0.001). Routine Assessment of Patient Index Data 3 (RAPID3) improved, serum leptin decreased and serum adiponectin increased significantly within the diet group and between the groups (all P < 0.03). DAS28 decreased, 5.2 to 4.2, within the diet group (P < 0.001; -0.51 [95% CI -1.01, 0.00], P = 0.056, between groups). HAQ-Disability Index (HAQ-DI) improved significantly within the diet group (P < 0.04; P = 0.065 between group). Ultrasound measures and the multi-biomarker disease activity score did not differ between groups (PDUS-34 -2.0 [95% CI -7.00, 3.1], P = 0.46 between groups). CONCLUSION: Obese RA patients on the diet intervention achieved weight loss. There were significant between group improvements for RAPID3, adiponectin and leptin levels, and positive trends for DAS28 and HAQ-DI. Longer-term, larger weight loss studies are needed to validate these findings, and will allow for further investigative work to improve the clinical management of obese RA patients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02881307.

Quality of Online Information for Esophageal Cancer.

The Internet is a readily available source of information, and patients in North America frequently access it. Esophageal cancer is the 7th most common cancer worldwide, but there is a lack of studies examining esophageal cancer website quality. This current study looks to systematically analyze the quality of websites accessed by patients with esophageal cancer. A previously validated website evaluation tool was used to analyze the quality of online esophageal cancer resources for patients. The term "esophagus cancer" was used to retrieve hits from the search engine Google and the meta-search engines Dogpile and Yippy. A 100 website list was compiled using pre-specified inclusion and exclusion criteria. Websites were evaluated regarding administration, accountability, authorship, organization, readability, content, and accuracy. The term "esophagus cancer" returned over 500 websites from the search engines. Of the 100 websites included for analysis, 97% disclosed ownership, sponsorship, and advertising. Only 35% identified an author and even fewer (31%) gave the author's credentials. Only 31% declared updates to their information within the past 2 years. Readability scores revealed only 9%, and 12% of sites scored at an elementary level, according to the Flesch-Kincaid (FK) and SMOG scoring scales, respectively. The average FK and SMOG scores were 12.6 and 11.0, respectively. Detection was the most accurately described (70%). However, few websites provided accurate incidence/prevalence (28%), stage-specific prognosis (27%), or preventative information (17%). The quality of websites offering information on esophageal cancer is variable. While they overwhelmingly disclose website ownership interests, most do not identify authors, poorly describe important domains of esophageal cancer, and overall readability exceeds the commonly accepted level for non-healthcare professionals.

Management of Dactylitis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: This literature review aimed to identify the most efficacious current interventions for dactylitis and provide up-to-date scientific evidence to support the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations on the management of psoriatic arthritis. METHODS: Original articles published from 2013 to 2020, registered in MEDLINE, Embase, and Cochrane Library, describing interventional trials and reporting dactylitis-related outcomes were included. The 20 members of the GRAPPA dactylitis group were divided into 9 subgroups according to treatment, and members of each group independently extracted data from articles/abstracts corresponding to their group by using a standardized data extraction form. RESULTS: Forty-nine publications were analyzed, representing 40 randomized clinical trials (RCTs) and including 16,752 patients. Dactylitis was assessed as a secondary outcome in 97.5% of these trials and more than 40% of RCTs did not employ a specific dactylitis measure or instrument. CONCLUSION: The emergence of agents with novel mechanisms of action in recent years, such as interleukin 17 (IL-17), IL-12/23, IL-23, and Janus kinase inhibitors, has significantly expanded the available treatment options for dactylitis. This article points out the lack of consensus regarding dactylitis assessment and the paucity of data concerning the effect of local steroid injections, nonsteroidal antiinflammatory drugs, and conventional disease-modifying antirheumatic drugs. Clinical trials evaluating the effect of these traditional and low-cost medications used to treat dactylitis should be encouraged.

Optimizing Reliability of Real-Time Sonographic Examination and Scoring of Joint Synovitis in Rheumatoid Arthritis.

OBJECTIVE: Musculoskeletal ultrasound real-time image acquisition and scoring are complex, and many factors affect reliability. Static image reliability does not guarantee real-time scoring. This study aimed to identify factors and solutions to improve real-time scoring reliability for the grey scale and power Doppler evaluation of synovitis. We also report on using a novel musculoskeletal ultrasound synovitis rule-based scoring atlas. METHODS: In four stages, we evaluated inter- and intra-reader reliability among three ultrasonographers (US1-3). Intra- and inter-reader reliability was calculated using weighted-kappa, intraclass correlation coefficient, and Spearman correlation. Reliability statistics were compared between stages using permutation tests to compute empirical distributions for differences in those statistics. At each stage, factors that diminished reliability were identified and addressed. After intensive reliability exercises, a RA MSUS atlas with in-depth scoring rules was generated to improve interpretive reliability. RESULTS: The three ultrasonographers had good to excellent intra-reader reliability for real-time acquisition scoring over 2432 views (weighted kappa 0.52-0.80, intraclass correlation coefficient 0.59-0.86, and Spearman correlation 0.64-0.86). Inter-reader reliability was good to excellent between US1/US2 and US1/US3 (weighted kappa 0.51-0.66, intraclass correlation coefficient 0.66-0.75, Spearman correlation 0.59-0.73). US1 achieved significant improvement in intra-reader reliability from stage 1 to stage 2 (p<0.05, weighted-kappa 0.63 to 0.80, intraclass correlation coefficient 0.71 to 0.86, Spearman 0.67 to 0.86) with use of the atlas.  Conclusion: This rheumatoid arthritis musculoskeletal ultrasound study addressed complex factors affecting musculoskeletal ultrasound acquisition-scoring reliability. Systematic identification and amelioration of many factors and using a novel rule-based scoring atlas significantly improved intra-reader reliability.

Collagen cross-link profiles and mineral are different between the mandible and femur with site specific response to perturbed collagen.

Compromises to collagen and mineral lead to a decrease in whole bone quantity and quality in a variety of systemic diseases, yet, clinically, disease manifestations differ between craniofacial and long bones. Collagen alterations can occur through post-translational modification via lysyl oxidase (LOX), which catalyzes enzymatic collagen cross-link formation, as well as through non-enzymatic advanced glycation end products (AGEs) such as pentosidine and carboxymethyl-lysine (CML). Characterization of the cross-links and AGEs, and comparison of the mineral and collagen modifications in craniofacial and long bones represent a critical gap in knowledge. However, alterations to either the mineral or collagen in bone may contribute to disease progression and, subsequently, the anatomical site dependence of a variety of diseases. Therefore, we hypothesized that collagen cross-links and AGEs differ between craniofacial and long bones and that altered collagen cross-linking reduces mineral quality in an anatomic location dependent. To study the effects of cross-link inhibition on mineralization between anatomical sites, beta-aminoproprionitrile (BAPN) was administered to rapidly growing, 5-8 week-old male mice. BAPN is a dose-dependent inhibitor of LOX that pharmacologically alters enzymatic cross-link formation. Long bones (femora) and craniofacial bones (mandibles) were compared for mineral quantity and quality, collagen cross-link and AGE profiles, and tissue level mechanics, as well as the response to altered cross-links via BAPN. A highly sensitive liquid chromatography/mass spectrometry (LC-MS) method was developed which allowed for quantification of site-dependent accumulation of the advanced glycation end-product, carboxymethyl-lysine (CML). CML was ∼8.3× higher in the mandible than the femur. The mandible had significantly higher collagen maturation, mineral crystallinity, and Young's modulus, but lower carbonation, than the femur. BAPN also had anatomic specific effects, leading to significant decreases in mature cross-links in the mandible, and an increase in mineral carbonation in the femur. This differential response of both the mineral and collagen composition to BAPN between the mandible and femur highlights the need to further understand how inherent compositional differences in collagen and mineral contribute to anatomic-site specific manifestations of disease in both craniofacial and long bones.

Matrix/mineral ratio and domain size variation with bone tissue age: A photothermal infrared study.

Atomic force microscopy-infrared spectroscopy (AFM-IR) and optical photothermal infrared spectroscopy (O-PTIR), which feature spectroscopic imaging spatial resolution down to âˆ¼ 50 nm and âˆ¼ 500 nm, respectively, were employed to characterize the nano- to microscale chemical compositional changes in bone. Since these changes are known to be age dependent, fluorescently labelled bone samples were employed. The average matrix/mineral ratio values decrease as the bone tissue matures as measured by both AFM-IR and O-PTIR, which agrees with previously published FTIR and Raman spectroscopy results. IR ratio maps obtained by AFM-IR reveal variation in matrix/mineral ratio-generating micron-scale bands running parallel to the bone surface as well as smaller domains within these bands ranging from âˆ¼ 50 to 700 nm in size, which is consistent with the previously published length scale of nanomechanical heterogeneity. The matrix/mineral changes do not exhibit a smooth gradient with tissue age. Rather, the matrix/mineral transition occurs sharply within the length scale of 100-200 nm. O-PTIR also reveals matrix/mineral band domains running parallel to the bone surface, resulting in waves of matrix/mineral ratios progressing from the youngest to most mature tissue. Both AFM-IR and O-PTIR show a greater variation in matrix/mineral ratio value for younger tissue as compared to older tissue. Together, this data confirms O-PTIR and AFM-IR as techniques that visualize bulk spectroscopic data consistent with higher-order imaging techniques such as Raman and FTIR, while revealing novel insight into how mineralization patterns vary as bone tissue ages.

Region-specific associations among tissue-level mechanical properties, porosity, and composition in human male femora.

Region-specific differences in age-related bone remodeling are known to exist. We therefore hypothesized that the decline in tissue-level strength and post-yield strain (PYS) with age is not uniform within the femur, but is driven by region-specific differences in porosity and composition. Four-point bending was conducted on anterior, posterior, medial, and lateral beams from male cadaveric femora (n = 33, 18-89 yrs of age). Mid-cortical porosity, composition, and mineralization were assessed using nano-computed tomography (nanoCT), Raman spectroscopy, and ashing assays. Traits between bones from young and elderly groups were compared, while multivariate analyses were used to identify traits that predicted strength and PYS at the regional level. We show that age-related decline in porosity and mechanical properties varied regionally, with highest positive slope of age vs. Log(porosity) found in posterior and anterior bone, and steepest negative slopes of age vs. strength and age vs. PYS found in anterior bone. Multivariate analyses show that Log(porosity) and/or Raman 1246/1269 ratio explained 46-51% of the variance in strength in anterior and posterior bone. Three out of five traits related to Log(porosity), mineral crystallinity, 1246/1269, mineral/matrix ratio, and/or hydroxyproline/proline (Hyp/Pro) ratio, explained 35-50% of the variance in PYS in anterior, posterior and lateral bones. Log(porosity) and Hyp/Pro ratio alone explained 13% and 19% of the variance in strength and PYS in medial bone, respectively. The predictive performance of multivariate analyses was negatively impacted by pooling data across all bone regions, underscoring the complexity of the femur and that the use of pooled analyses may obscure underlying region-specific differences.

SomaticSiMu: a mutational signature simulator.

SUMMARY: SomaticSiMu is an in silico simulator of single and double base substitutions, and single base insertions and deletions in an input genomic sequence to mimic mutational signatures. SomaticSiMu outputs simulated DNA sequences and mutational catalogues with imposed mutational signatures. The tool is the first mutational signature simulator featuring a graphical user interface, control of mutation rates and built-in visualization tools of the simulated mutations. Simulated datasets are useful as a ground truth to test the accuracy and sensitivity of DNA sequence classification tools and mutational signature extraction tools under different experimental scenarios. The reliability of SomaticSiMu was affirmed by (i) supervised machine learning classification of simulated sequences with different mutation types and burdens, and (ii) mutational signature extraction from simulated mutational catalogues. AVAILABILITY AND IMPLEMENTATION: SomaticSiMu is written in Python 3.8.3. The open-source code, documentation and tutorials are available at https://github.com/HillLab/SomaticSiMu under the terms of the CreativeCommonsAttribution4.0InternationalLicense. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Toward a Sonographic Composite Index for Diagnosis in Psoriatic Arthritis: Highlights From the GRAPPA Ultrasound Workshop.

The ability to visualize musculoskeletal structures with high-resolution ultrasound is an asset to understanding the complexity of psoriatic arthritis (PsA). During the 2021 Annual Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) meeting, 3 topics were presented and discussed in the ultrasound workshop: (1) the progress on the Diagnostic Ultrasound Enthesitis Tool (DUET) project; (2) the sonographic evaluation of joints in PsA-GRAPPA joint project; and (3) extrasynovial lesions in PsA. The ultrasound group aims to develop sonographic tools that are feasible and can be used in standard care to diagnose PsA early. The discussions around these topics will shape the group's work toward developing a composite index to diagnose PsA early.