Misfolding of secretory proteins in the endoplasmic reticulum (ER) features in many human diseases. In α 1 -antitrypsin deficiency, the pathogenic Z variant aberrantly assembles into polymers in the hepatocyte ER, leading to cirrhosis. We show that α 1 -antitrypsin polymers undergo a liquid:solid phase transition, forming a protein matrix that retards mobility of ER proteins by size-dependent molecular filtration. The Z-α 1 -antitrypsin phase transition is promoted during ER stress by an ATF6-mediated unfolded protein response. Furthermore, the ER chaperone calreticulin promotes Z-α 1 -antitrypsin solidification and increases protein matrix stiffness. Single-particle tracking reveals that solidification initiates in cells with normal ER morphology, previously assumed to represent a healthy pool. We show that Z-α 1 -antitrypsin–induced hypersensitivity to ER stress can be explained by immobilization of ER chaperones within the polymer matrix. This previously unidentified mechanism of ER dysfunction provides a template for understanding a diverse group of related proteinopathies and identifies ER chaperones as potential therapeutic targets.

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Objectives: Sophisticated scores have been proposed for prognostication of mortality due to SARS-CoV-2 but perform inconsistently. We conducted these meta-analyses to uncover why and to pragmatically seek a single dependable biomarker for mortality. Design: We searched the PubMed database for the keywords SARS-CoV-2 with biomarker name and mortality. All studies published from 01st December 2019 to 30th June 2021 were surveyed. To aggregate the data, the meta library in R was used to report overall mean values and 95% confidence intervals. We fitted a random effects model to obtain pooled AUCs and associated 95% confidence intervals for the European/North American, Asian, and overall datasets. Setting and Participants: Data was collected from 131 studies on SARS-CoV-2 PCR-positive general hospital adult admissions (n=76,169 patients in total). Main Outcome Measures: We planned a comparison of pooled area under curves (AUCs) from Receiver Operator Characteristic curves plotted for admission D-dimer, CRP, urea, troponin and interleukin-6 levels. Main Results: Biomarker effectiveness varies significantly in different regions of the world. Admission CRP levels are a good prognostic marker for mortality due to SARS-CoV-2 in Asian countries, with a pooled area under curve (AUC) of 0.83 (95% CI 0.80-0.85), but only an average predictor of mortality in Europe/North America, with a pooled AUC of 0.67 (95% CI 0.63-0.71, P<0.0001). We observed the same pattern for D-dimer and IL-6. This variability explains why the proposed prognostic scores did not perform evenly. Notably, urea and troponin had pooled AUCs ≥ 0.78 regardless of location, implying that end-organ damage at presentation is a key prognostic factor. These differences might be due to age, genetic backgrounds, or different modes of death (younger patients in Asia dying of cytokine storm while older patients die of multi-organ failure). Conclusions: Biomarker effectiveness for prognosticating SARS-CoV-2 mortality varies significantly by geographical location. We propose that biomarkers and by extension prognostic scores need to be tailored for specific populations. This also implies that validation of commonly used prognostic scores for other conditions should occur before they are used in different populations.

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Aim: Pulmonary arterial hypertension (PAH) covers a range of life-limiting illnesses characterised by increased pulmonary arterial pressures leading to right heart failure and death, if untreated. 15-25% of patients have a genetic mutation, the most common affecting bone morphogenetic protein receptor type 2 (BMPR2). The aim was to profile inflammatory cytokines in BMPR2-mutation positive and PAH patients without mutations and analyse their influence on survival. Methods and Results: Levels of cytokines and growth factors were measured in plasma samples from BMPR2-mutation positive patients (BMPR2mut, n=54), patients without any driving mutations (n=54), and healthy controls (n=56) recruited from the United Kingdom cohort. BMPR2-mutation positive patients and patients without mutations had high levels of interleukin-6, interleukin-8, tumour necrosis factor-alpha, and vascular endothelial growth factor-A compared to controls. Only BMPR2-mutation carrying patients had higher G-CSF levels compared to controls. VEGF-A levels were substantially higher in patients without mutations compared to the BMPR2mut group. Only interleukin-6 was a significant discriminator for mortality in the BMPR2mut cohort (cumulative survival with interleukin-6>1.6pg/ml at 3 years was 65% compared to 96% with interleukin-6<1.6pg/ml, P=0.0013). N-Terminal pro-B-Type natriuretic peptide levels did not discriminate for survival in our BMPR2mut cohort (cumulative survival for patients with an NT-proBNP>130ng/ml at 3 years was 76% compared to 84% for patients with an NT-proBNP<130ng/ml, P=0.37). NT-proBNP outperformed interleukin-6 in PAH without driving mutations. Conclusions: BMPR2-mutation positive and PAH patients without mutations have different inflammatory profiles. In our BMPR2-mutation positive cohort IL-6 was the strongest prognostic biomarker and NT-proBNP failed to discriminate for survival. This is the first instance of genotype directly affecting clinical care in pulmonary vascular disease.