Model-guided combinatorial optimization of complex synthetic gene networks

Constructing gene circuits that satisfy quantitative performance criteria has been a long‐standing challenge in synthetic biology. Here, we show a strategy for optimizing a complex three‐gene circuit, a novel proportional miRNA biosensor, using predictive modeling to initiate a search in the phase space of sensor genetic composition. We generate a library of sensor circuits using diverse genetic building blocks in order to access favorable parameter combinations and uncover specific genetic compositions with greatly improved dynamic range. The combination of high‐throughput screening data and the data obtained from detailed mechanistic interrogation of a small number of sensors was used to validate the model. The validated model facilitated further experimentation, including biosensor reprogramming and biosensor integration into larger networks, enabling in principle arbitrary logic with miRNA inputs using normal form circuits. The study reveals how model‐guided generation of genetic diversity followed by screening and model validation can be successfully applied to optimize performance of complex gene networks without extensive prior knowledge.ISSN:1744-429

Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial.

Dear Editor, We read with great interest the recent article by Kamboj et al., in which they described the risk of developing moderate to severe Coronavirus Disease 2019 (COVID-19) in patients with hematological malignancies receiving tixagevimab-cilgavimab (T-C) during a period in which the dominant circulating variants of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) were resistant to T-C.1 The authors highlight the ongoing need to urgently address the mAb treatment gap, particularly for immunocompromised patients. The unmet need is further highlighted by the DisCoVeRy Phase 3, adaptive, multicentre European, randomized, double-blind, superiority trial that evaluated the efficacy and safety of intravenous T-C in SARS-CoV-2 antigenic positive patients (i.e those with a high SARS-CoV-2 viral load) hospitalized with COVID-19 and followed-up to day 90. [...

Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial

International audienc

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

International audienceAbstract Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 )