COVID-19: combining antiviral and anti-inflammatory treatments

Both coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are characterised by an overexuberant inflammatory response and, for SARS, viral load is not correlated with the worsening of symptoms. In our previous Correspondence to The Lancet, we described how BenevolentAI's proprietary artificial intelligence (AI)-derived knowledge graph, queried by a suite of algorithms, enabled identification of a target and a potential therapeutic against SARS coronavirus 2 (SARS-CoV-2; the causative organism in COVID-19). We identified a group of approved drugs that could inhibit clathrin-mediated endocytosis and thereby inhibit viral infection of cells (appendix). The drug targets are members of the numb-associated kinase (NAK) family—including AAK1 and GAK—the inhibition of which has been shown to reduce viral infection in vitro. Baricitinib was identified as a NAK inhibitor, with a particularly high affinity for AAK1, a pivotal regulator of clathrin-mediated endocytosis. We suggested that this drug could be of use in countering SARS-CoV-2 infections, subject to appropriate clinical testing. To take this work further in a short timescale, a necessity when dealing with a new human pathogen, we re-examined the affinity and selectivity of all the approved drugs in our knowledge graph to identify those with both antiviral and anti-inflammatory properties. Such drugs are predicted to be of particular importance in the treatment of severe cases of COVID-19, when the host inflammatory response becomes a major cause of lung damage and subsequent mortality. Comparison of the properties of the three best candidates are shown in the table. Baricitinib, fedratinib, and ruxolitinib are potent and selective JAK inhibitors approved for indications such as rheumatoid arthritis and myelofibrosis. All three are powerful anti-inflammatories that, as JAK–STAT signalling inhibitors, are likely to be effective against the consequences of the elevated levels of cytokines (including interferon-γ) typically observed in people with COVID-19·2 Although the three candidates have similar JAK inhibitor potencies, a high affinity for AAK1 suggests baricitinib is the best of the group, especially given its once-daily oral dosing and acceptable side-effect profile.The most significant side-effect seen over 4214 patient-years in the clinical trial programmes used for European Medicines Agency registration was a small increase in upper respiratory tract infections (similar to that observed with methotrexate), but the incidence of serious infections (eg, herpes zoster) over 52 weeks' dosing was small (3·2 per 100 patient-years), and similar to placebo.7 Use of this agent in patients with COVID-19 over 7–14 days, for example, suggests side-effects would be trivial.</p

Drawing as reflective practice

This exhibition, organised as part of the wider international aspects of the Drawing Group, comprised 8 individuals engaged with a discourse on drawing as a means of critique and as a vehicle for reflective practice.The exhibition was curated by Drew Plunkett (Glasgow School of Art). The catalogue ISBN 978 1 905527 20 5, with an accompanying introduction by Plunkett, includes statements from all participants. The exhibition has subsequently been shown at the Glasgow School of Art (2006), the College of Fine Arts, NSW University (2007) and been the subject of a public seminar at The Collection, Lincoln (2006). Bingham’s six drawings (example scale 21 x 38cms) resulted from a reappraisal of works originally concerned with the creation of new profiles for redundant objects. These new drawings assimilate previous peripheral and fleeting references as potential for the development a more substantive presence. Reflective practice in this instance was a process of analysis, a means to edit and to critically focus on emergent themes, making significant the incidental reference, and engaging with drawing as a means of introspective enquiry. The latter was subsequently further explored in a paper ‘Drawing over the page (checking the health of the patient)’ presented at the Drawing Board symposium (July 06) ISBN 1860502091 at Lincoln. Participation in the wider, national debate resulted in an opportunity to chair and report on proceedings of a discussion group at Networking in Drawing Research, a one day forum at Wimbledon College of Art (2007) held in partnership with the Drawing Research Network. Proceedings published in ‘Drawing: The Network’ ISBN 978 1 906203 05 4.</p

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

Given the scale and rapid spread of the 2019 novel coronavirus (2019-nCoV) acute respiratory disease, there is an immediate need for medicines that can help before a vaccine can be produced. Results of rapid sequencing of 2019-nCoV, coupled with molecular modelling based on the genomes of related virus proteins,1 have suggested a few compounds that are likely to be effective, including the anti-HIV lopinavir plus ritonavir combination...</p

Exercise Prevents Weight Gain and Alters the Gut Microbiota in a Mouse Model of High Fat Diet-Induced Obesity

<div><p>Background</p><p>Diet-induced obesity (DIO) is a significant health concern which has been linked to structural and functional changes in the gut microbiota. Exercise (Ex) is effective in preventing obesity, but whether Ex alters the gut microbiota during development with high fat (HF) feeding is unknown.</p><p>Objective</p><p>Determine the effects of voluntary Ex on the gastrointestinal microbiota in LF-fed mice and in HF-DIO.</p><p>Methods</p><p>Male C57BL/6 littermates (5 weeks) were distributed equally into 4 groups: low fat (LF) sedentary (Sed) LF/Sed, LF/Ex, HF/Sed and HF/Ex. Mice were individually housed and LF/Ex and HF/Ex cages were equipped with a wheel and odometer to record Ex. Fecal samples were collected at baseline, 6 weeks and 12 weeks and used for bacterial DNA isolation. DNA was subjected both to quantitative PCR using primers specific to the 16S rRNA encoding genes for Bacteroidetes and Firmicutes and to sequencing for lower taxonomic identification using the Illumina MiSeq platform. Data were analyzed using a one or two-way ANOVA or Pearson correlation.</p><p>Results</p><p>HF diet resulted in significantly greater body weight and adiposity as well as decreased glucose tolerance that were prevented by voluntary Ex (p<0.05). Visualization of Unifrac distance data with principal coordinates analysis indicated clustering by both diet and Ex at week 12. Sequencing demonstrated Ex-induced changes in the percentage of major bacterial phyla at 12 weeks. A correlation between total Ex distance and the ΔCt Bacteroidetes: ΔCt Firmicutes ratio from qPCR demonstrated a significant inverse correlation (r² = 0.35, p = 0.043).</p><p>Conclusion</p><p>Ex induces a unique shift in the gut microbiota that is different from dietary effects. Microbiota changes may play a role in Ex prevention of HF-DIO.</p></div

ΔCt Bacteroidetes: ΔCt Firmicutes Ratio Correlates with Exercise Distance.

<p>There was a significant, but modest inverse relationship between the ΔCt Bacteroidetes: ΔCt Firmicutes ratio and the distance recorded for the combined LF/Ex and HF/Ex mice. Data analyzed by Pearson product-moment correlation coefficient with an alpha level of p<0.05. n = 6 all groups.</p

Beta Diversity is Elevated by HF Diet and Exercise.

<p>Significant differences indicated as follows: “*” p<0.05 for diet effect, “†” p<0.05 activity effect and “‡” p<0.05 diet and activity interaction. n = 6 mice/group.</p

Clustering of Samples Based on Litter, Diet and Activity.

<p>Principal coordinate analysis (PCA) was performed based on the weighted UniFrac distance matrix generated from sequencing fecal 16S rRNA gene in samples from mice at week 0 and 12 of the diet and activity protocol. A. Clustering demonstrated by litter at week 0. B. No clustering demonstrated by litter at week 12. C. No clustering demonstrated by diet and activity at week 0. D. Clustering demonstrated by diet and activity at week 12. The top panels show the PCA keyed by litter (6 liters, 1–6, of 4 mice each) and the bottom panels show the PCA keyed by diet and activity group. The X-axis represents the primary coordinate, the Y-axis represents the secondary coordinate. Axis numbering represents the relative distance between samples based on the weighted UniFrac distance matrix.</p

Body and fat weight, exercise distance, food intake, heart and muscle weight and gut transit.

<p>Data represent mean ± SEM. For the low fat/exercise group, one mouse died prior to harvesting tissues. Statistically significant diet effect indicated by * and activity effect by ^† based on a two-way ANOVA with a Sidak post hoc test.</p

Diet and Activity Altered Families within the Bacteroidetes, Actinobacteria and Proteobacteria Phyla.

<p>Family level taxonomic groups were identified from sequencing 16S rDNA at week 12 of the diet and activity protocol. A. Within the phylum Bacteroidetes, the class Bacteroidia had one family that was altered by diet and activity: <i>S24-7</i>. B. Within the Actinobacteria phylum and class, one family was altered by diet and activity: <i>Bifidobacteriaceae</i>. C. Within the Proteobacteria phylum, the class Deltaproteobacteria had one family that demonstrated a trend toward an effect of diet and activity: <i>Desulfovibrionaceae</i>. Data were analyzed by 2-way ANOVA with a Sidak post hoc test. Significant differences indicated as follows: “*” p<0.05 for diet effect, “†” p<0.05 activity effect and “‡” p<0.05 diet and activity interaction. n = 6 mice/group.</p

Diet and Activity Altered the Relative Level of Bacteroidetes and Firmicutes.

<p>A. The fold change in Bacteroidetes and Firmicutes was determined from the 2^−ΔΔCt values calculated from the ΔCt values generated by quantitative polymerase chain reaction (qPCR) using primers specific to each phyla (one-way ANOVA). B. Criterion validity of qPCR was examined by correlating the ΔCt-Bacteroidetes: ΔCt-Firmicutes ratio with the %-Bacteroidetes: %- Firmicutes ratios from sequencing. Data was analyzed by Pearson product-moment correlation coefficient and alpha level of p<0.05.</p