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OBJECTIVE To assess the relationship between measures of disease assessment in patients with large vessel vasculitis. METHODS Patients with giant cell arteritis (GCA) or Takayasu arteritis (TAK) were recruited into a prospective, observational cohort. Assessments within the following outcomes were independently recorded: 1) patient-reported outcomes (Multidimensional Fatigue Inventory, patient global assessment of disease activity [PtGA], Short Form 36 health survey [SF-36], Brief Illness Perception Questionnaire), 2) physician global assessment of disease activity (PhGA), 3) laboratory outcomes (C-reactive protein [CRP] level, erythrocyte sedimentation rate [ESR]), and 4) imaging outcomes (PETVAS, a qualitative score of vascular 18 F-fluorodeoxyglucose-positron emission tomography activity). RESULTS Analyses were performed on 112 patients (GCA = 56, TAK = 56), over 296 visits, with a median follow-up of 6 months. Correlation network analysis revealed assessment measures clustered independently by type of outcome. PhGA was centrally linked to all other outcome types, but correlations were modest (ρ = 0.12-0.32; P < 0.05). PETVAS, CRP level, and PtGA were independently associated with clinically active disease. All 4 patient-reported outcomes strongly correlated with each other (ρ = 0.35-0.60; P < 0.0001). Patient-reported outcomes were not correlated with PETVAS, and only PtGA correlated with CRP level (ρ = 0.16; P < 0.01). Patients whose clinical assessment changed from active disease to remission (n = 29) had a corresponding significant decrease in ESR, CRP level, and PETVAS at the remission visit. Patients whose clinical assessment changed from remission to active disease (n = 11) had a corresponding significant increase in CRP level and PtGA at the active visit. CONCLUSION Measures of disease assessment in large vessel vasculitis consist of independent, yet complementary, outcomes, supporting the need to develop composite outcome measures or a standard set of measures covering multiple types of outcomes.

OBJECTIVES: To determine the impact of imaging acquisition time on interpretation of disease activity on (18)F-fluorodeoxyglucose positron emission tomography (PET) in large-vessel vasculitis (LVV) and assess the relationship between clinical features and image acquisition time. METHODS: Patients with giant cell arteritis (GCA) and Takayasu’s arteritis (TAK) were recruited into a prospective, observational cohort. After a single injection of FDG, all patients underwent two sequential PET scans at one and two-hour time points. Images were interpreted for active vasculitis by subjective assessment, qualitative assessment, and semi-quantitative assessment. Agreement was assessed by percent agreement, Cohen’s kappa, and McNemar’s test. Multivariable logistic regression identified associations between PET activity and clinical variables. RESULTS: 79 patients (GCA=44, TAK=35) contributed 168 paired one and two-hour PET studies. A total of 94 out of 168 scans (56%) were interpreted as active at the one-hour time point, and 129 scans (77%) were interpreted as active at the two-hour time point (p

Objective.To assess patient-reported burden of disease in pediatric patients with relapsing polychondritis (RP) and to compare those findings to adult patients.Methods.A survey based on known clinical symptoms of RP was developed and administered to patients with a pediatric diagnosis of RP. Adult patients completed a similar survey.Results.Twenty-one pediatric patients, or their parents, completed surveys. Median age at symptom onset was 6 years (interquartile range 1.8–12). Prior to diagnosis, most pediatric patients went to the emergency room (ER; 61.9%), saw > 3 physicians (57.1%), and took > 1 year to be diagnosed (61.9%). Pediatric patients were often diagnosed with asthma (42.9%), ear infections (42.9%), or sinusitis (33.3%) prior to diagnosis of RP. Symptoms prior to diagnosis included ear pain/redness (85.7%), joint pain/swelling (61.9%), and airway symptoms (38.1%). Four pediatric patients (19%) reported tracheomalacia requiring tracheostomy. Pediatric patients frequently missed school because of their disease (71.4%). Surveys from 290 adult patients were compared to pediatric patients. Pediatric patients were significantly more likely to undergo biopsy (42.9% vs 17.4%; p < 0.01) and be treated with biologics (42.9% vs 19%; p = 0.02). Adults were significantly more likely to be female (87.8% vs 28.6%; p < 0.01) and to report airway symptoms (77.9% vs 47.6%; p = 0.01). Prevalence of disease complications was not significantly different between adult and pediatric patients.Conclusions.The burden of disease in pediatric patients with RP includes missed school, diagnostic delay, ER visits, and multisystem disease, with resultant damage to cartilaginous structures. Differences in airway involvement and treatment approaches may exist between pediatric and adult patients.

Background: Coronavirus disease 2019 is a pandemic with no specific therapeutic agents or vaccination. Small published case series on critically ill adults suggest improvements in clinical status with minimal adverse events when patients receive coronavirus disease 2019 convalescent plasma, but data on critically ill pediatric patients are lacking. We report a series of four critically ill pediatric patients with acute respiratory failure who received coronavirus disease 2019 convalescent plasma as a treatment strategy for severe disease. Case Summary: Patients ranged in age from 5 to 16 years old. All patients received coronavirus disease 2019 convalescent plasma within the first 26 hours of hospitalization. Additional disease modifying agents were also used. All patients made a full recovery and were discharged home off of oxygen support. No adverse events occurred from the coronavirus disease 2019 convalescent plasma transfusions. Conclusion: Coronavirus disease 2019 convalescent plasma is a feasible therapy for critically ill pediatric patients infected with severe acute respiratory syndrome coronavirus 2. Well-designed clinical trials are necessary to determine overall safety and efficacy of coronavirus disease 2019 convalescent plasma and additional treatment modalities in pediatric patients.

Objective Relapsing polychondritis (RP) is a systemic disease. Failure to recognize RP can lead to diagnostic delay and further complications, including death. This study was undertaken to identify clinical patterns in a prospective cohort of patients with RP. Methods Patient subgroups were identified using latent class analysis based on 8 clinical variables: saddle-nose deformity, subglottic stenosis, tracheomalacia, bronchomalacia, ear chondritis, tenosynovitis/synovitis, inflammatory eye disease, and audiovestibular disease. Model selection was based on Akaike's information criterion. Results Seventy-three patients were included in this study. Patients were classified into 1 of 3 subgroups: type 1 RP (14%), type 2 RP (29%), and type 3 RP (58%). Type 1 RP was characterized by ear chondritis (100%), tracheomalacia (100%), saddle-nose deformity (90%), and subglottic stenosis (80%). These patients had the shortest median time to diagnosis (1 year), highest disease activity, and greatest frequency of admission to the intensive care unit and tracheostomy. Type 2 RP was characterized by tracheomalacia (100%) and bronchomalacia (52%), but no saddle-nose deformity or subglottic stenosis. These patients had the longest median time to diagnosis (10 years) and highest percentage of work disability. Type 3 RP was characterized by tenosynovitis/synovitis (60%) and ear chondritis (55%). There were no significant differences in sex, race, or treatment strategies between the 3 subgroups. Conclusion Our findings indicate that there are 3 subgroups of patients with RP, with differences in time to diagnosis, clinical and radiologic characteristics, and disease-related complications. Recognizing a broader spectrum of clinical patterns in RP, beyond cartilaginous involvement of the ear and upper airway, may facilitate more timely diagnosis.

Limited evidence is available to guide treatment of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A hyperinflammatory state mediated by interleukin-6 (IL-6) has been proposed as a driver of severe disease. Use of the IL-6 receptor inhibitor tocilizumab for severe COVID-19 was first reported in China, where a case series described marked improvements in inflammatory markers, fever, oxygen requirement, and outcomes following its administration. Here, we provide the first description of a tocilizumab-treated cohort of patients with COVID-19 in the United States. We describe 11 patients from a single academic medical center, nine (82%) of whom were critically ill requiring mechanical ventilation in an intensive care unit at the time of tocilizumab administration. C-reactive protein levels decreased in all patients following treatment (median 211.6 pre- vs. 19.7 mg/L 5 days post-tocilizumab [p=0.001]). When IL-6 levels were obtained before and after therapy, wide variation was seen in baseline levels; post-dose IL-6 concentrations were consistently increased. In contrast to prior reports, we did not observe significant clinical improvement in temperature or oxygen requirements in most patients. Two patients were discharged (18%), five remained in critical condition in the intensive care unit (46%), one was weaned off the ventilator to room air (9%), and three died (27%). Our findings suggest that tocilizumab should be used with caution in severe and critically ill patients and highlight the need for data from randomized controlled trials to determine its efficacy in the treatment of COVID-19.

ObjectiveTo assess the validity and clinical utility of the Brief Illness Perception Questionnaire (BIPQ) to measure illness perceptions in multiple forms of vasculitis.MethodsPatients with giant cell arteritis (GCA), Takayasu arteritis (TA), antineutrophil cytoplasmic antibody–associated vasculitis (AAV), and relapsing polychondritis (RP) were recruited into a prospective, observational cohort. Patients independently completed the BIPQ, Multidimensional Fatigue Inventory (MFI), Medical Outcomes Study 36-item Short Form survey (SF-36), and a patient global assessment (PtGA) at successive study visits. Physicians concurrently completed a physician global assessment (PGA) form. Illness perceptions, as assessed by the BIPQ, were compared to responses from the full-length Revised Illness Perception Questionnaire (IPQ-R) and to other clinical outcome measures.ResultsThere were 196 patients (GCA = 47, TA = 47, RP = 56, AAV = 46) evaluated over 454 visits. Illness perception scores in each domain were comparable between the BIPQ and IPQ-R (3.28 vs 3.47, P = 0.22). Illness perceptions differed by type of vasculitis, with the highest perceived psychological burden of disease in RP. The BIPQ was significantly associated with all other patient-reported outcome measures (rho = |0.50–0.70|, P < 0.0001), but did not correlate with PGA (rho = 0.13, P = 0.13). A change in the BIPQ composite score of ≥ 7 over successive visits was associated with concomitant change in the PtGA. Change in the MFI and BIPQ scores significantly correlated over time (rho = 0.38, P = 0.0008).ConclusionThe BIPQ is an accurate and valid assessment tool to measure and monitor illness perceptions in patients with vasculitis. Use of the BIPQ as an outcome measure in clinical trials may provide complementary information to physician-based assessments.

The interleukin-6 receptor antagonist tocilizumab became widely used early in the coronavirus disease 2019 (COVID-19) pandemic based on small observational studies that suggested clinical benefit in COVID-19 patients with a hyperinflammatory state. To inform our local treatment algorithms in the absence of randomized clinical trial results, we performed a rapid analysis of the first 11 hospitalized COVID-19 patients treated with tocilizumab at our academic medical center. We report their early clinical outcomes and describe the process by which we assembled a team of diverse trainees and stakeholders to extract, analyze, and disseminate data during a time of clinical uncertainty.

Background and aims Organoids provide a powerful system to study epithelia in vitro. Recently, this approach was applied successfully to the biliary tree, a series of ductular tissues responsible for the drainage of bile and pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (extrahepatic bile ducts; EHBDs) or inside the liver (intrahepatic bile ducts; IHBDs). These organoids share many characteristics, including expression of cholangiocyte markers such as keratin (KRT) 19. However, the relationship between these organoids and their tissues of origin, and to each other, is largely unknown. Approach and results Organoids were derived from human gallbladder, common bile duct, pancreatic duct, and IHBDs using culture conditions promoting WNT signaling. The resulting IHBD and EHBD organoids expressed stem/progenitor markers leucine-rich repeat-containing G-protein-coupled receptor 5/prominin 1 and ductal markers KRT19/KRT7. However, RNA sequencing revealed that organoids conserve only a limited number of regional-specific markers corresponding to their location of origin. Of particular interest, down-regulation of biliary markers and up-regulation of cell-cycle genes were observed in organoids. IHBD and EHBD organoids diverged in their response to WNT signaling, and only IHBDs were able to express a low level of hepatocyte markers under differentiation conditions. Conclusions Taken together, our results demonstrate that differences exist not only between extrahepatic biliary organoids and their tissue of origin, but also between IHBD and EHBD organoids. This information may help to understand the tissue specificity of cholangiopathies and also to identify targets for therapeutic development.

ObjectiveTo compare the presence of head, neck and upper extremity symptoms in patients with Takayasu’s (TAK) and giant cell arteritis (GCA) and their association with vascular inflammation assessed by18F-fluorodeoxyglucose positron emission tomography (FDG-PET) or arterial damage assessed by magnetic resonance angiography (MRA).MethodsPatients with TAK and GCA underwent clinical and imaging assessments within 24 hours, blinded to each other. Vascular inflammation was defined as arterial FDG-PET uptake greater than liver by visual assessment. Arterial damage was defined as stenosis, occlusion, or aneurysm by MRA. Clinically reported symptoms were compared with corresponding imaging findings using generalised mixed model regression. Cranial symptoms were studied in association with burden of arterial disease in the neck using ordinal regression.ResultsParticipants with TAK (n=56) and GCA (n=54) contributed data from 270 visits. Carotidynia was reported only in patients with TAK (21%) and was associated with vascular inflammation (pConclusionThe distribution of symptoms and association with imaging abnormalities differs in patients with TAK and GCA. These findings may help clinicians predict associated FDG-PET and MRA findings based on a specific clinical symptom.Clinical trial registration numberNCT02257866.

18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can detect vascular inflammation in large-vessel vasculitis (LVV). Clinical factors that influence distribution of FDG into the arterial wall and other tissues have not been characterized in LVV. Understanding these factors will inform analytic strategies to quantify vascular PET activity. Patients with LVV (n = 69) underwent 141 paired FDG-PET imaging studies at one and two hours per a delayed image acquisition protocol. Arterial uptake was quantified as standardized uptake values (SUVMax). SUVMean values were obtained for background tissues (blood pool, liver, spleen). Target-to-background ratios (TBRs) were calculated for each background tissue. Mixed model multivariable linear regression was used to identify time-dependent associations between FDG uptake and selected clinical features. Clinical factors associated with FDG distribution differed in a tissue- and time-dependent manner. Age, body mass index, and C-reactive protein were significantly associated with arterial FDG uptake at both time points. Clearance factors (e.g. glomerular filtration rate) were significantly associated with FDG uptake in background tissues at one hour but were weakly or not associated at two hours. TBRs using liver or blood pool at two hours were most strongly associated with vasculitis-related factors. These findings inform standardization of FDG-PET protocols and analytic approaches in LVV.

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids $\textit{in vivo}$ and demonstrate that ECOs self-organize into bile duct–like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded $\textit{in vitro}$.

This study examined the influence of psychopathy and intelligence on malingering in a simulated malingering design. We hypothesized that participants high in both traits would be more adept at evading detection on performance validity tests (PVTs). College students (N = 92) were first administered the Wechsler Test of Adult Reading, a reading measure that estimates intelligence, and the Psychopathic Personality Inventory-Short Form under standard conditions. They were then asked to imagine as if they had suffered a concussion a year ago and were instructed to fake or exaggerate symptoms in a believable fashion to improve their settlement as part of a lawsuit. Participants were subsequently administered a brief neuropsychological battery that included the Word Memory Test, Rey 15-Item Test with Recognition, Finger-Tapping Test, and Digit Span from the Wechsler Adult Intelligence Scale-Fourth Edition. Moderated multiple regressions with hierarchical entry were conducted. Intelligence, psychopathy, and the interaction of intelligence and psychopathy were not related to performance on any of the PVTs. In other words, participants who scored higher on intelligence and psychopathy did not perform differently on these measures compared with other participants. Though a null finding, implications of this study are discussed in terms of the broader research and clinical literature on malingering.

Mudancas no perfil de acidos graxos tem sido associadas a varios processos patofisiologicos. Dados obtidos por cromatografia gasosa-espectrometria de massas (GC-MS) usando monitoramento seletivo de ions foram empregados para revelarem, apos analise por analise de componentes principais (PCA), um conjunto relevante de ions para quantificacao e caracterizacao de acidos graxos. Este protocolo foi aplicado com sucesso na analise de acidos graxos presentes em diversas fracoes lipidicas de sangue, permitindo a quantificacao de diversos acidos graxos e revelando seus numeros de insaturacoes. Adicionalmente, a presenca de contaminantes, artefatos e co-eluicoes no cromatograma tambem foram reveladas sem analises adicionais. Por fim, acidos graxos presentes em triacilglicerideos, fosfolipidios e esteres de colesterol presentes em plasma e membrana de eritrocitos foram determinados com exatidao adequada, repetibilidade e baixos limites de deteccao e de quantificacao. Changes in fatty acid profiles have been associated with several pathophysiological processes. Gas chromatography-mass spectrometry (GC-MS) data monitoring of selected ions was used with principal components analysis (PCA), revealing a set of relevant ions for quantification and characterization of fatty acids. This protocol was successfully applied to the analyses of fatty acids in different human blood lipids, allowing the quantification of several fatty acids and revealing their unsaturation numbers. Moreover the presences of contaminants, artifacts and co-eluitions in the chromatogram were also revealed without any additional analyses. Thus, fatty acid constituents of triglycerides, phospholipids and esters of cholesterol present in plasma and erythrocyte membranes were accurately determined, with repeatability, low limits of determination and of quantification.

The current study was conducted to determine (a) the demographic and injury characteristics of individuals who did not receive treatment for mild brain injury and (b) the reasons these individuals do not receive or seek treatment. In a large sample of undergraduate students initially surveyed via an on-line questionnaire (n = 1,853), 35% of those who responded to a subsequent survey acknowledged that they had experienced at least one mild traumatic brain injury (TBI) for which they were not treated. Compared with those who were treated for each TBI, those who were untreated were more likely to be men and were less likely to report persisting symptoms 3 months after the injury. There were no differences in demographics or injury characteristics (e.g., length of time unconscious) between groups. Of those with an untreated TBI, the most common reasons for not seeking treatment were that the symptoms resolved quickly and that they were neither bothersome nor disruptive. Findings are discussed in terms of research on recovery from mild TBI.