SUMMARYMutations in the human Notch ligand jagged 1 (JAG1) result in a multi-system disorder called Alagille syndrome (AGS). AGS is chiefly characterized by a paucity of intrahepatic bile ducts (IHBD), but also includes cardiac, ocular, skeletal, craniofacial and renal defects. The disease penetration and severity of the affected organs can vary significantly and the molecular basis for this broad spectrum of pathology is unclear. Here, we report that Jag1 inactivation in the portal vein mesenchyme (PVM), but not in the endothelium of mice, leads to the hepatic defects associated with AGS. Loss of Jag1 expression in SM22a-positive cells of the PVM leads to defective bile duct development beyond the initial formation of the ductal plate. Cytokeratin 19-positive cells are detected surrounding the portal vein, yet they are unable to form biliary tubes, revealing an instructive role of the vasculature in liver development. These findings uncover the cellular basis for the defining feature of AGS, identify mesenchymal Jag1-dependent and -independent stages of duct development, and provide mechanistic information for the role of Jag1 in IHBD formation.

Diabetes is a risk factor for developing severe COVID-19, but the pathogenesis remains unclear. We investigated if the association of diabetes and COVID-19 severity may be mediated by inflammation. We also hypothesized that this increased risk may extend to prediabetes. Hospitalized patients in Singapore with COVID-19 were subdivided into three groups in a retrospective cohort: normoglycemia (HbA1c: ≤5.6%), prediabetes (HbA1c: 5.7%-6.4%) and diabetes (HbA1c: ≥6.5%). The primary outcome of severe COVID-19 was defined by respiratory rate ≥30, SpO2 ≤93% or intensive care unit admission. The association between clinical factors on severe COVID-19 outcome was analyzed by cox regression. Adjusted mediation analysis of C-reactive protein (CRP) on the relationship between diabetes and severe COVID-19 was performed. Of 1042 hospitalized patients, mean age 39 ± 11 years, 13% had diabetes, 9% prediabetes and 78% normoglycemia. Severe COVID-19 occurred in 4.9% of subjects. Compared to normoglycemia, diabetes was significantly associated with severe COVID-19 on both univariate (hazard ratio [HR]: 9.94; 95% confidence interval [CI]: 5.54-17.84; p < .001) and multivariate analysis (HR: 3.99; 95% CI: 1.92-8.31; p < .001), while prediabetes was not a risk factor (HR: 0.94; 95% CI: 0.22-4.03; p = .929). CRP, a biomarker of inflammation, mediated 32.7% of the total association between diabetes and severe COVID-19 outcome. In conclusion, CRP is a partial mediator of the association between diabetes and severe COVID-19 infection, confirming that inflammation is important in the pathogenesis of severe COVID-19 in diabetes.

Background:The vasoconstricting thromboxane A 2 prostanoid receptor (TP) is physically coupled to the MaxiK channel ␣-subunit, down-regulating its activity, but the role of the MaxiK ␤1-subunit is unknown. Results: The MaxiK ␤1-subunit can interact with TP independently of the MaxiK ␣-subunit and counteracts activated TPinduced current inhibition, and its ablation increases TP vasoconstricting potency. Conclusion: The ␤1-subunit modifies TP actions. Significance: This is the first demonstration that the MaxiK ␤1-subunit associates with a vasoconstricting receptor.

Summary Thyroid storm with multi-organ failure limits the use of conventional treatment. A 44-year-old male presented with thyroid storm and experienced cardiovascular collapse after beta-blocker administration, with resultant fulminant multi-organ failure requiring inotropic support, mechanical ventilation, extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy. Hepatic and renal failure precluded the use of conventional thyroid storm treatment and early plasma exchange was instituted. The patient underwent emergency thyroidectomy after four effective exchanges, with subsequent rapid reversal of multi-organ failure. The challenges of institution of plasma exchanges with ongoing ECMO support, dialysis and timing of thyroidectomy are discussed. This case highlights the important role of early therapeutic plasma exchange (TPE) as an effective salvage therapy for lowering circulating hormones and stabilization of patients in preparation for emergency thyroidectomy in patients with thyroid storm and fulminant multi-organ failure. Learning points: Administration of beta-blockers in thyroid storm presenting with congestive cardiac failure may precipitate cardiovascular collapse due to inhibition of thyroid-induced hyperadrenergic compensation which maintains cardiac output. TPE can be an effective bridging therapy to emergency total thyroidectomy when conventional thyroid storm treatment is contraindicated. End-organ support using ECMO and CRRT can be combined with TPE effectively in the management of critically ill cases of thyroid storm. The effectiveness of plasma exchange in lowering thyroid hormones appears to wane after 44–48 h of therapy in this case, highlighting the importance early thyroidectomy.

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