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Patients with diffuse cutaneous systemic sclerosis (dcSSc) display a complex clinical phenotype. Transcriptional profiling of whole blood or tissue from patients are affected by changes in cellular composition that drive gene expression and an inability to detect minority cell populations. Here, we focused on the two main subtypes of circulating monocytes, classical (CM) and non-classical (NCM).SSc patients were recruited from the Prospective Registry for Early SSc registry. Clinical data were collected as well as peripheral blood for isolation of CM and NCM. Age-, sex-, and race-matched healthy volunteers were recruited as controls. Bulk macrophages were isolated from skin in a separate cohort. All samples were assayed by RNA-seq.We used an unbiased approach to cluster patients into three groups (A-C) based on their transcriptional signatures of CM relative to controls. Further, each group maintained their characteristic transcriptional signature in NCM. Genes upregulated in Group C demonstrated the highest signature compared to the other groups in skin macrophages. Patients from Group B and C exhibited worse lung function than Group A, although there was no difference in skin disease at baseline. We validated our approach by applying our group classifications to published bulk monocyte RNA-seq data on SSc patients: we found that patients with no skin disease were most likely to be classified as Group A.We are the first to show that transcriptional signature of CM and NCM can be used to unbiasedly stratify SSc patients and correlate with disease activity outcome measures.

Many patients with rheumatoid arthritis (RA) experience sleep disturbances, commonly attributed to joint pain. Sleep disturbances could also influence pain. One mechanism may be through dysregulated pain processing, manifested by enhanced pain sensitivity. The present study was undertaken to examine the role of pain sensitization, measured by quantitative sensory testing (QST), as a mediator in the pathway of sleep disturbance leading to subsequent pain.We used longitudinal data from 221 patients with active RA who were followed for 12 weeks after initiating a disease-modifying antirheumatic drug. Baseline QST included pressure pain thresholds at articular (wrists, knees) and nonarticular (trapezius, thumbnails) sites, temporal summation (TS) at the wrist and forearm, and conditioned pain modulation (CPM). Baseline sleep disturbance and subsequent pain intensity were assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS). We evaluated correlations between sleep disturbance, QSTs, and subsequent pain intensity. Mediation analyses separately assessed each QST as a mediator, adjusting for baseline confounding factors.Sleep disturbance was correlated with all QST measures except wrist TS and CPM. Sleep disturbance significantly predicted subsequent pain (coefficient for a meaningful increase of 5 units in sleep disturbance = 0.32 (95% confidence interval 0.11, 0.50) in multiple regression. QST mediated 10-19% of this effect.Pain sensitization may be one mechanism through which sleep disturbance contributes to pain. The small magnitude of association indicates that unmeasured pathways may contribute to this relationship. Intervention studies are needed to establish causality and determine whether improving sleep can improve pain in patients with RA.

ObjectiveTo determine if the degree of baseline fibromyalgia (FM) symptoms in patients with rheumatoid arthritis (RA), as indicated by the Fibromyalgia Survey Questionnaire (FSQ) score, predicts RA disease activity after initiation or change of a disease-modifying antirheumatic drug (DMARD).MethodsOne hundred ninety-two participants with active RA were followed for 12 weeks after initiation or change of DMARD therapy. Participants completed the FSQ at the initial visit. The Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) was measured at baseline and follow-up to assess RA disease activity. We evaluated the association between baseline FSQ score and follow-up DAS28-CRP. As a secondary analysis, we examined the relationship between the 2 components of the FSQ, the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS), with follow-up DAS28-CRP. Multiple linear regression analyses were performed, adjusting for clinical and demographic variables.ResultsIn multiple linear regression models, FSQ score was independently associated with elevated DAS28-CRP scores 12 weeks after DMARD initiation (B = 0.04,P= 0.01). In secondary analyses, the WPI was significantly associated with increased follow-up DAS28-CRP scores (B = 0.08,P= 0.001), whereas the SSS was not (B = −0.03,P= 0.43).ConclusionHigher levels of FM symptoms weakly predicted worse disease activity after treatment. The primary factor that informed the FSQ’s prediction of disease activity was the spatial extent of pain, as measured by the WPI.

Objectives Over one-third of patients with RA exhibit evidence of fibromyalgianess, which is associated with higher rates of disability and inadequate responsiveness to RA treatment. Patients with RA often remain on glucocorticoids long-term, despite the known risk of dose-dependent morbidity. We undertook this study to examine the relationship between fibromyalgianess and glucocorticoid persistence among RA patients. Methods We followed participants with active RA on oral prednisone for ∼3 months after initiating a new DMARD. Fibromyalgianess was measured using the Fibromyalgia Survey Questionnaire (FSQ), previously shown to correlate with key FM features often superimposed upon RA. Severity of fibromyalgianess was stratified as follows: FSQ 10 high/very high. The association between baseline fibromyalgianess and glucocorticoid persistence, defined as prednisone use at 3-month follow-up visit after DMARD initiation, was assessed using multiple logistic regression adjusted for baseline demographics, RA duration, serostatus and inflammatory activity assessed using swollen joint count and CRP. Results Of the 97 participants on prednisone at baseline, 65% were still taking prednisone at follow-up. Fifty-seven percent of participants with low baseline fibromyalgianess had persistent glucocorticoid use, compared with 84% of participants with high or very high fibromyalgianess. After adjustment for non-inflammatory factors and inflammatory activity, participants with high/very high baseline fibromyalgianess were more likely to be taking prednisone at follow-up relative to those with low fibromyalgianess [odds ratio 4.99 (95% CI 1.20, 20.73)]. Conclusion High fibromyalgianess is associated with persistent glucocorticoid use, independent of inflammatory activity.

We investigated whether baseline sagittal-plane ankle, knee, and hip contribution to the total support moment (TSM) are each associated with baseline-to-2-year tibiofemoral and patellofemoral tissue damage worsening in adults with knee osteoarthritis. Ambulatory lower-limb kinetics were captured and computed. TSM is the sum of ankle, knee, and hip extensor moments at each instant during gait. Ankle, knee, and hip contributions to TSM were computed as joint moments divided by TSM, expressed as percentages. Participants underwent MRI of both knees at baseline and 2 years later. Logistic regression models assessed associations of baseline ankle contribution to TSM with baseline-to-2-year cartilage damage and bone marrow lesion worsening, adjusted for age, sex, BMI, gait speed, disease severity, and pain. We used similar analytic approaches for knee and hip contributions to TSM. Sample included 391 knees from 204 persons (age[SD]: 64[10] years; 76.5% women). Greater ankle contribution may be associated with increased odds of tibiofemoral cartilage damage worsening (OR = 2.38; 95% CI: 1.02-5.57) and decreased odds of patellofemoral bone marrow lesion worsening (OR = 0.14; 95% CI: 0.03-0.73). The ORs for greater knee contribution were in the protective range for tibiofemoral compartment and in the deleterious range for patellofemoral. Greater hip contribution may be associated with increased odds of tibiofemoral worsening (OR = 2.71; 95% CI: 1.17-6.30). Greater ankle contribution to TSM may be associated with baseline-to-2-year tibiofemoral worsening, but patellofemoral tissue preservation. Conversely, greater knee contribution may be associated with patellofemoral worsening, but tibiofemoral preservation. Preliminary findings illustrate potential challenges in developing biomechanical interventions beneficial to both tibiofemoral and patellofemoral compartments.

IntroductionWhile living donor (LD) kidney transplantation is the optimal treatment for patients with kidney failure, LDs assume a higher risk of future kidney failure themselves. LDs of African ancestry have an even greater risk of kidney failure post-donation than White LDs. Because evidence suggests that Apolipoprotein L1 (APOL1) risk variants contribute to this greater risk, transplant nephrologists are increasingly usingAPOL1genetic testing to evaluate LD candidates of African ancestry. However, nephrologists do not consistently perform genetic counselling with LD candidates aboutAPOL1due to a lack of knowledge and skill in counselling. Without proper counselling,APOL1testing will magnify LD candidates’ decisional conflict about donating, jeopardising their informed consent. Given cultural concerns about genetic testing among people of African ancestry, protecting LD candidates’ safety is essential to improve informed decisions about donating. Clinical ‘chatbots’, mobile apps that provide genetic information to patients, can improve informed treatment decisions. No chatbot onAPOL1is available and no nephrologist training programmes are available to provide culturally competent counselling to LDs aboutAPOL1. Given the shortage of genetic counsellors, increasing nephrologists’ genetic literacy is critical to integrating genetic testing into practice.Methods and analysisUsing a non-randomised, pre–post trial design in two transplant centres (Chicago, IL, and Washington, DC), we will evaluate the effectiveness of culturally competentAPOL1testing, chatbot and counselling on LD candidates’ decisional conflict about donating, preparedness for decision-making, willingness to donate and satisfaction with informed consent and longitudinally evaluate the implementation of this intervention into clinical practice using theReach,Effectiveness,Adoption,Implementation andMaintenance framework.Ethics and disseminationThis study will create a model forAPOL1testing of LDs of African ancestry, which can be implemented nationally via implementation science approaches.APOL1will serve as a model for integrating culturally competent genetic testing into transplant and other practices to improve informed consent. This study involves human participants and was approved by Northwestern University IRB (STU00214038). Participants gave informed consent to participate in the study before taking part.Trial registrationClinicalTrials.gov Identifier:NCT04910867. Registered 8 May 2021,https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000AWZ6&selectaction=Edit&uid=U0001PPF&ts=7&cx=-8jv7m2ClinicalTrials.gov Identifier:NCT04999436. Registered 5 November 2021,https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000AYWW&selectaction=Edit&uid=U0001PPF&ts=11&cx=9tny7v

A growing body of literature describes abdominal aesthetic goals to tailor surgical and nonsurgical treatment options to meet patient goals. The authors aimed to integrate layperson perceptions into the design of a novel professional aesthetic scale for the abdomen.An iterative process of expert consensus was used to choose five domains: abdominal muscle lines, abdominal shape, scar, skin, and umbilicus. A survey was developed to measure global and domain-specific aesthetic preferences on five abdomens. This was distributed through Amazon Mechanical Turk to 340 respondents. Principal component analysis was used to integrate survey data into weights for each of the scale's subquestions. Attending plastic surgeons then rated abdomens using the final scale, and reliability and validity were calculated.The final scale included 11 subquestions-hourglass shape, bulges, hernia, infraumbilical skin, supraumbilical skin, umbilicus shape, umbilicus medialization position, umbilicus height position, semilunar lines, central midline depression, and scar-within the five domains. Central midline depression held the highest weight (16.1 percent) when correlated with global aesthetic rating, followed by semilunar lines (15.8 percent) and infraumbilical skin (11.8 percent). The final scale demonstrated strong validity (Pearson r = 0.99) and was rated as easy to use by seven attending plastic surgeons.The final scale is the first published professional aesthetic scale for the abdomen that aims to integrate layperson opinion. This analysis and survey data provide insights into the importance of 11 components in overall aesthetic appeal of the abdomen.

Objective To determine the association between dysregulated central pain processing and treatment response in rheumatoid arthritis (RA). Methods One hundred eighty-two participants with active RA were followed up for 12 weeks after starting a disease-modifying antirheumatic drug (DMARD). To assess central pain processing, participants underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at the trapezius muscles, temporal summation, and conditioned pain modulation (CPM). QST measures were categorized as high central dysregulation versus low central dysregulation. The association between baseline central dysregulation and treatment response, as defined by the European League Against Rheumatism (EULAR) response criteria, was assessed using multiple logistic regression adjusted for demographic characteristics, RA-related variables, and psychosocial variables. Results A good EULAR response was achieved in fewer participants with high CPM dysregulation than participants with low CPM dysregulation (22.5% versus 40.3%; P = 0.01). A similar trend, though not significant, was noted when central dysregulation was assessed with PPT and temporal summation. The adjusted odds ratios (ORs) for the association between high central dysregulation and good EULAR response were 0.59 for PPTs (95% confidence interval [95% CI] 0.28-1.23), 0.60 for temporal summation (95% CI 0.27-1.34), and 0.40 for CPM (95% CI 0.19-0.83). In a model examining the combined effects of dysregulated temporal summation and CPM, dysregulation of both measures was associated with lower odds of achieving a good EULAR response (OR 0.23 [95% CI 0.07-0.73]). Conclusion Low CPM was significantly associated with lower odds of achieving a good EULAR response, suggesting that inefficient descending inhibitory mechanisms may be a potential treatment target for further study.

Background/PurposePatients with systemic sclerosis (SSc) display a complex clinical phenotype. There are numerous studies that relate transcriptional signatures from PBMC or whole skin of SSc patients to disease activity. However, analyses of whole tissue RNA-sequencing studies are subjected to changes in cellular composition that can drive gene expression signatures and a loss of the ability to detect biologically important transcriptional changes within minority cell populations. Here, we focused on circulating monocytes, which have been shown to exist as two central populations classical (CM) and non-classical (NCM).MethodsSSc patients were recruited from four different sites that form PRESS: Northwestern University, University of Texas, University of Michigan and University of Utah. Comprehensive clinical data was collected for all patients. We isolated CM and NCM from these patients and age, sex, and race-matched healthy volunteers were used as controls. RNA-seq was performed on CM and NCM populations as well as on isolated bulk macrophages from skin.ResultsWe first performed RNA-seq on CM, which are the predominant population in circulation. In order to capture the variability across the SSc cohort, we defined 1790 differentially expressed genes in each patient. We then used these genes to cluster patients into 3 subgroups: Groups A-C. Group A exhibited the strongest interferon signature and innate immune pathways. Group B patients expressed genes in the same pathways but was also enriched for response to cAMP and corticosteroids. Both Group B and Group C exhibited upregulation of genes associated with vasculature development and blood vessel formation. Group C uniquely upregulated TGFB pathways. Next, we performed RNA-seq on NCM isolated from the same patients. When NCM were clustered based on the same 1790 genes as CM, we found that Groups A and C were recapitulated, while Group B was less cohesive. Our analysis stratified SSc patients based on their transcriptional profiles in monocytes but was agnostic to their clinical presentation. We found that Group B and C patients exhibited significantly worsened lung function at the time of monocyte isolation than Group A patients. However, there were no significant differences in skin disease. We then isolated macrophages from skin biopsies of SSc patients and showed that the transcriptional profile of Group A and C in SSc patients was conserved. We also used gene expression data from another study on monocytes which stratified patients based on disease presentation. We found that Group A accurately distinguished dcSSc and ncSSc patients from controls, but not lcSSc.ConclusionWe are the first to show that transcriptomic analysis of classical and non-classical circulating monocytes can unbiasedly stratify SSc patients and correlate with disease activity outcome measures.

Clinical case reports circulate relevant information regarding disease presentation and describe treatment protocols, particularly for novel conditions. In the early months of the Covid-19 pandemic, case reports provided key insights into the pathophysiology and sequelae associated with Covid-19 infection and described treatment mechanisms and outcomes. However, case reports are often subject to selection bias due to their singular nature. To better understand how selection biases may have influenced Covid-19-releated case reports, we conducted a bibliometric analysis of Covid-19-releated case reports published in high impact journals from January 1 to June 1, 2020. Case reports were coded for patient sex, country of institutional affiliation, physiological system, and first and last author gender. Of 494 total case reports, 45% (n = 221) of patients were male, 30% (n = 146) were female, and 25% (n = 124) included both sexes. Ratios of male-only to female-only case reports varied by physiological system. The majority of case reports had male first (61%, n = 302) and last (70%, n = 340) authors. Case reports with male last authors were more likely to describe male patients [X2 (2, n = 465) = 6.6, p = 0.037], while case reports with female last authors were more likely to include patients of both sexes [OR = 1.918 (95% CI = 1.163–3.16)]. Despite a limited sample size, these data reflect emerging research on sex-differences in the physiological presentation and impact of Covid-19 and parallel large-scale trends in authorship patterns. Ultimately, this work highlights potential biases in the dissemination of clinical information via case reports and underscores the inextricable influences of sex and gender biases within biomedicine.

The practice of science outreach is more necessary than ever. However, a disconnect exists between the stated goals for science outreach and its actual impact. In order to examine one potential source of this disconnect, we undertook a survey-based study to explore whether barriers to participation (either intrinsic or extrinsic) in science outreach exist within the academic community. We received responses to our survey from 530 individuals, the vast majority of whom engage in some type of science outreach activity on an annual basis. Those who engage in outreach report doing so for both personal and altruistic reasons, and having high (yet varied) levels of comfort with performing outreach activities. Respondents also report the existence of several significant yet surmountable barriers to participation, including lack of time and funding. Our findings demonstrate that both levels of participation in, and attitudes toward, science outreach within the academic community are generally favorable, suggesting that the general ineffectiveness of science outreach is due to other causes. We place our findings within the context of the broader science outreach, science communication and public engagement literature. We make recommendations on how existing approaches and infrastructure can, and must, be changed in order to improve the practice.

BackgroundPatients with rheumatoid arthritis (RA) commonly demonstrate disordered pain processing, termed pain centralization. Heightened pain sensitivity and pain pathways associated with pain centralization are often assessed using quantitative sensory testing (QST), which is not routinely available and burdensome to patients. The self-administered fibromyalgia survey questionnaire (FSQ) has been proposed as a low-burden, surrogate measure of pain centralization. We examined the correlation between FSQ and QST as measures of pain centralization in a cohort of patients with active RA. MethodsParticipants in the multicenter Central Pain in Rheumatoid Arthritis (CPIRA) cohort underwent FSQ and QST evaluation at enrollment. QST measures included pressure pain threshold (PPT) at the thumb, trapezius, wrist and knee; temporal summation (TS) at the wrist and arm; and conditioned pain modulation (CPM). Partial Spearman correlation was assessed between FSQ and each QST measure, adjusted for age, sex, race, body mass index, serologic status, swollen joint count, C-reactive protein, pain catastrophizing, and study site. We performed sensitivity analyses including a) stratified analysis by sex and b) correlations between the two sub-components of the FSQ (widespread pain index [WPI], and symptom severity scale [SSS]) and QST measures.ResultsAmong 285 participants with high RA disease activity (mean baseline Clinical Disease Activity Index score 24.56), FSQ was weakly but statistically significantly correlated with PPT ( r = -0.21 to -0.31) and TS ( r = 0.13 to 0.15) at all sites in unadjusted analyses. After adjustment, statistically significant correlations persisted for PPT at all sites except the thumb, and for TS at the wrist Sensitivity analyses did not identify differences in association based on sex or with the components of the FSQ (WPI or SSS).ConclusionsFSQ and QST were correlated among participants with active RA, but the strength of association was modest. This may be due to the high level of RA disease activity of the cohort studied. Both QST and the FSQ are likely imperfect singular measures of pain centralization.

OBJECTIVE To examine the effects of a smartphone application (app) to monitor longitudinal electronic patient-reported outcomes (ePROs) on patient satisfaction and disease activity in patients with rheumatoid arthritis (RA). METHODS We conducted a 6-month randomized controlled trial of care coordination along with an app (intervention) versus care coordination alone (control) in 191 RA patients. Participants in the intervention group were prompted to provide information daily using ePROs. In both the intervention and control groups, a care coordinator contacted participants at 6 and 18 weeks to assess for flares. The main outcome measures were the global satisfaction score from the Treatment Satisfaction Questionnaire for Medication (TSQM), the score from the Perceived Efficacy in Patient-Physician Interactions (PEPPI) Questionnaire, and the Clinical Disease Activity Index (CDAI) score. RESULTS Groups were similar at baseline. The median TSQM score at 6 months was 83.3 in both groups, and the median PEPPI score at 6 months was 50 in both groups. The median CDAI score at 6 months was 8 in the intervention group versus 10 in the control group. No statistically significant group differences in the medians of TSQM, PEPPI, or CDAI scores at 6 months were detected. Of the 67 intervention participants who completed the exit survey, 90% rated their likelihood of recommending the app as ≥7 of 10. Of the 11 physicians who completed the exit survey, 73% agreed/strongly agreed that they wanted to continue offering the app to patients. CONCLUSION A mobile app designed to collect ePRO data on RA symptoms did not significantly improve patient satisfaction or disease activity compared to care coordination alone. However, both patients and physicians reported positive experiences with the app.

Objective Develop a model to predict gastrostomy tube (GT) for feeding at discharge in infants born < 30 weeks’ (w) gestational age (GA). Study design A single-center retrospective study at academic NICU. Total of 391 (78 GT, 313 non-GT) infants < 30 w GA admitted in 2015–2018 split into test (15–16) and validation (17–18) cohorts. Classification and regression tree analysis was used to identify predictive factors for GT. Results Several factors were associated with GT requirements. Four factors included in the model were postmenstrual age (PMA) at first oral feeding, birth GA, high-frequency ventilation exposure, necrotizing enterocolitis stage II/III. Area under the receiver operator characteristic curve was 0.944 in the test cohort, 0.815 in the validation cohort. Implementation plan based on the model was developed. Conclusions We developed a predictive model to risk-stratify infants born < 30 w GA for failing full oral feeding. We hope implementation at 38 w PMA will result in earlier placement of needed GT and discharge.

Obesity-related type 2 diabetes (DM) is a major public health concern. Adipose tissue metabolic dysfunction, including fibrosis, plays a central role in DM pathogenesis. Obesity is associated with changes in adipose tissue extracellular matrix (ECM), but the impact of these changes on adipose tissue mechanics and their role in metabolic disease is poorly defined. This study utilized atomic force microscopy (AFM) to quantify difference in elasticity between human DM and non-diabetic (NDM) visceral adipose tissue. The mean elastic modulus of DM adipose tissue was twice that of NDM adipose tissue (11.50 kPa vs. 4.48 kPa) to a 95% confidence level, with significant variability in elasticity of DM compared to NDM adipose tissue. Histologic and chemical measures of fibrosis revealed increased hydroxyproline content in DM adipose tissue, but no difference in Sirius Red staining between DM and NDM tissues. These findings support the hypothesis that fibrosis, evidenced by increased elastic modulus, is enhanced in DM adipose tissue, and suggest that measures of tissue mechanics may better resolve disease-specific differences in adipose tissue fibrosis compared with histologic measures. These data demonstrate the power of AFM nanoindentation to probe tissue mechanics, and delineate the impact of metabolic disease on the mechanical properties of adipose tissue.

Background The Centers for Disease Control and Prevention advises that patients with moderate-to-severe asthma belong to a high-risk group that is susceptible to severe COVID-19. However, the association between asthma and COVID-19 has not been well-established. Objective The primary objective was to determine the prevalence of asthma among COVID-19 patients in a major U.S. health system. We assessed the clinical characteristics and comorbidities in asthmatic and non-asthmatic COVID-19 patients. We also determined the risk of hospitalization associated with asthma and/or inhaled corticosteroid use. Methods Medical records of patients with COVID-19 were searched by a computer algorithm (March 1–April 15, 2020), and chart review was used to validate the diagnosis of asthma and medications prescribed for asthma. All patients were PCR-confirmed COVID-19. Demographics and clinical features were characterized. Regression models were used to assess the associations between asthma and corticosteroid use and the risk of COVID-19-related hospitalization. Results Of 1,526 patients identified with COVID-19, 220 (14%) were classified as having asthma. Asthma was not associated with an increased risk of hospitalization (RR of 0.96 [95%CI: 0.77-1.19]) after adjusting for age, sex, gender, and comorbidities. The ongoing use of ICS did not increase the risk of hospitalization in a similar adjusted model (RR of 1.39 [95%CI: 0.90-2.15]). Conclusions Despite a substantial prevalence of asthma in our COVID-19 cohort, asthma was not associated with an increased risk of hospitalization. Similarly, the use of ICS with or without systemic corticosteroids was not associated with COVID-19-related hospitalization., This retrospective study found an asthma prevalence of 14% in a general COVID-19 cohort. A diagnosis of asthma or the use of inhaled corticosteroids was not associated with an increased risk of COVID-19-related hospitalization.