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 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 in vitro.

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.

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.

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 18F‐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.

We describe early outcomes in 11 COVID-19 patients treated with the IL-6 receptor inhibitor tocilizumab. While C-reactive protein decreased, neither clinical improvement nor reduced temperature or oxygen requirements was observed in most patients. Our findings contrast with prior reports and raise questions about tocilizumab use in severe COVID-19.

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<0.01). Associations between clinical variables and PET activity categories (dual inactive, delayed active, dual active) were evaluated. Using multivariable nominal regression, clinically active disease was significantly more common in patients in the delayed active group (Odds Ratio 1.94, 95%CI 1.13 -3.53; p=0.02) and the dual active group (Odds Ratio 1.71, 95%CI 1.06 -2.93; p=0.04) compared to the dual inactive group.

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.

ObjectiveRelapsing 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.MethodsPatient 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.ResultsSeventy‐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.ConclusionOur 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.