Machine learning for determining lateral flow device results for testing of SARS-CoV-2 infection in asymptomatic populations

Rapid antigen tests, in the form of lateral flow devices (LFD) allow testing of a large population for SARS-CoV-2. To reduce the variability seen in device interpretation, we show the design and testing of an AI algorithm based on machine learning. The machine learning (ML) algorithm is trained on a combination of artificially hybridised LFDs and LFD data linked to RT-qPCR result. Participants are recruited from assisted test sites (ATS) and health care workers undertaking self-testing and images analysed using the ML algorithm. A panel of trained clinicians are used to resolve discrepancies. In total, 115,316 images are returned. In the ATS sub study, sensitivity increased from 92.08% to 97.6% and specificity from 99.85% to 99.99%. In the self-read sub-study, sensitivity increased from 16.00% to 100%, and specificity from 99.15% to 99.40%. An ML-based classifier of LFD results outperforms human reads in asymptomatic testing sites and self-reading

Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation

In mammals, ∼100 deubiquitinases act on ∼20,000 intracellular ubiquitination sites. Deubiquitinases are commonly regarded as constitutively active, with limited regulatory and targeting capacity. The BRCA1-A and BRISC complexes serve in DNA double-strand break repair and immune signaling and contain the lysine-63 linkage-specific BRCC36 subunit that is functionalized by scaffold subunits ABRAXAS and ABRO1, respectively. The molecular basis underlying BRCA1-A and BRISC function is currently unknown. Here we show that in the BRCA1-A complex structure, ABRAXAS integrates the DNA repair protein RAP80 and provides a high-affinity binding site that sequesters the tumor suppressor BRCA1 away from the break site. In the BRISC structure, ABRO1 binds SHMT2α, a metabolic enzyme enabling cancer growth in hypoxic environments, which we find prevents BRCC36 from binding and cleaving ubiquitin chains. Our work explains modularity in the BRCC36 DUB family, with different adaptor subunits conferring diversified targeting and regulatory functions.ISSN:1097-2765ISSN:1097-416

Passions and Actions : Deleuze's Cinematographic Cogito.

When writing about cinema does Deleuze have a conception of cinema spectatorship? In New Philosophy for New Media, Mark Hansen argues that Deleuze does have a conception of cinema spectatorship but that the subjectivity central to that spectatorship is weak and impoverished. This article argues against Hansen's reductive interpretation of Deleuze. In doing so, it relies on the three syntheses of time developed in Difference and Repetition alongside an elaboration of Deleuze's notion of a ‘cinematographic Cogito’. In this way, the article offers a way of understanding the processes of cinema spectatorship from a Deleuzian perspective

Effect of Repeated Glucagon Doses on Hepatic Glycogen in Type 1 Diabetes: Implications for a Bihormonal Closed-Loop System

OBJECTIVE To evaluate subjects with type 1 diabetes for hepatic glycogen depletion after repeated doses of glucagon, simulating delivery in a bihormonal closed-loop system. RESEARCH DESIGN AND METHODS Eleven adult subjects with type 1 diabetes participated. Subjects underwent estimation of hepatic glycogen using 13C MRS. MRS was performed at the following four time points: fasting and after a meal at baseline, and fasting and after a meal after eight doses of subcutaneously administered glucagon at a dose of 2 µg/kg, for a total mean dose of 1,126 µg over 16 h. The primary and secondary end points were, respectively, estimated hepatic glycogen by MRS and incremental area under the glucose curve for a 90-min interval after glucagon administration. RESULTS In the eight subjects with complete data sets, estimated glycogen stores were similar at baseline and after repeated glucagon doses. In the fasting state, glycogen averaged 21 ± 3 g/L before glucagon administration and 25 ± 4 g/L after glucagon administration (mean ± SEM) (P = NS). In the fed state, glycogen averaged 40 ± 2 g/L before glucagon administration and 34 ± 4 g/L after glucagon administration (P = NS). With the use of an insulin action model, the rise in glucose after the last dose of glucagon was comparable to the rise after the first dose, as measured by the 90-min incremental area under the glucose curve. CONCLUSIONS In adult subjects with well-controlled type 1 diabetes (mean A1C 7.2%), glycogen stores and the hyperglycemic response to glucagon administration are maintained even after receiving multiple doses of glucagon. This finding supports the safety of repeated glucagon delivery in the setting of a bihormonal closed-loop system

Generation of a Protective T-Cell Response Following Coronavirus Infection of the Central Nervous System Is Not Dependent on IL-12/23 Signaling

The functional role of IL-12 and IL-23 in host defense and disease following viral infection of the CNS was determined. Instillation of mouse hepatitis virus (MHV, a positive-strand RNA virus) into the CNS of mice results in acute encephalitis followed by a chronic immune-mediated demyelinating disease. Antibody-mediated blocking of either IL-23 (anti-IL-23p19) or IL-12 and IL-23 (anti-IL-12/23p40) signaling did not mute T-cell trafficking into the CNS or antiviral effector responses and mice were able to control viral replication within the brain. Therapeutic administration of either anti-IL-23p19 or anti-IL-12/23p40 to mice with viral-induced demyelination did not attenuate T-cell or macrophage infiltration into the CNS nor improve clinical disease or diminish white matter damage. In contrast, treatment of mice with anti-IL-12/23p40 or anti-IL-23p19 resulted in inhibition of the autoimmune model of demyelination, experimental autoimmune encephalomyelitis (EAE). These data indicate that (1) IL-12 and IL-23 signaling are dispensable in generating a protective T-cell response following CNS infection with MHV, and (2) IL-12 and IL-23 do not contribute to demyelination in a model independent of autoimmune T-cell–mediated pathology. Therefore, therapeutic targeting of IL-12 and/or IL-23 for the treatment of autoimmune diseases may offer unique advantages by reducing disease severity without muting protective responses following viral infection