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Rationale of using the dual chemokine receptor CCR2/CCR5 inhibitor cenicriviroc for the treatment of COVID-19
Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created a global pandemic infecting over 230 million people and costing millions of lives. Therapies to attenuate severe disease are desperately needed. Cenicriviroc (CVC), a C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) antagonist, an agent previously studied in advanced clinical trials for patients with HIV or nonalcoholic steatohepatitis (NASH), may have the potential to reduce respiratory and cardiovascular organ failures related to COVID-19. Inhibiting the CCR2 and CCR5 pathways could attenuate or prevent inflammation or fibrosis in both early and late stages of the disease and improve outcomes of COVID-19. Clinical trials using CVC either in addition to standard of care (SoC; e.g., dexamethasone) or in combination with other investigational agents in patients with COVID-19 are currently ongoing. These trials intend to leverage the anti-inflammatory actions of CVC for ameliorating the clinical course of COVID-19 and prevent complications. This article reviews the literature surrounding the CCR2 and CCR5 pathways, their proposed role in COVID-19, and the potential role of CVC to improve outcomes.
Journal Article
The real-time infection hospitalisation and fatality risk across the COVID-19 pandemic in England
The COVID-19 pandemic led to 231,841 deaths and 940,243 hospitalisations in England, by the end of March 2023. This paper calculates the real-time infection hospitalisation risk (IHR) and infection fatality risk (IFR) using the Office for National Statistics Coronavirus Infection Survey (ONS CIS) and the Real-time Assessment of Community Transmission Survey between November 2020 to March 2023. The IHR and the IFR in England peaked in January 2021 at 3.39% (95% Credible Intervals (CrI): 2.79, 3.97) and 0.97% (95% CrI: 0.62, 1.36), respectively. After this time, there was a rapid decline in the severity from infection, with the lowest estimated IHR of 0.32% (95% CrI: 0.27, 0.39) in December 2022 and IFR of 0.06% (95% CrI: 0.04, 0.08) in April 2022. We found infection severity to vary more markedly between regions early in the pandemic however, the absolute heterogeneity has since reduced. The risk from infection of SARS-CoV-2 has changed substantially throughout the COVID-19 pandemic with a decline of 86.03% (80.86, 89.35) and 89.67% (80.18, 93.93) in the IHR and IFR, respectively, since early 2021. From April 2022 until March 2023, the end of the ONS CIS study, we found fluctuating patterns in the severity of infection with the resumption of more normative mixing, resurgent epidemic waves, patterns of waning immunity, and emerging variants that have shown signs of convergent evolution.
The severity of SARS-CoV-2 infection varied over the course of the pandemic due to factors such as changes in variant characteristics and population immunity from previous infection or vaccination. Here, the authors estimate infection hospitalisation and infection fatality rates in England over time from the start of the pandemic until March 2023.
Journal Article
Animation
With an introduction by John Lasseter-- and very little else in the way of words-- this second book in The Artist Series lavishly showcases the most brilliant animation created by such luminaries as Ub Iwerks, Norm Ferguson, Ben Sharpsteen, Hamilton Luske, Dick Huemer, Grim Natwick, Art Babbitt, Fred Moore, Bill Tytla, Frank Thomas, Ollie Johnston, Milt Kahl, Marc Davis, John Lounsbery, Ward Kimball, Eric Larson, Les Clark, Wolfgang Reitherman, John Sibley, Bill Justice, Clyde Geronimi, Ted Berman, Glen Keane, Andreas Deja, Eric Goldberg, Mark Henn and Tony Bancroft. The artwork-- much of which has never before been published-- offers the opportunity to marvel at the those magical lines of pencil that brought life to so many unforgettable Disney characters. Animation represents a rare opportunity to enjoy a glimpse into the truly spectacular trove of treasures from the Walt Disney Animation Research Library.
Book
Using a geographic information system to enhance patient access to point-of-care diagnostics in a limited-resource setting
Background
Rapid and accurate diagnosis drives evidence-based care in health. Point-of-care testing (POCT) aids diagnosis by bringing advanced technologies closer to patients. Health small-world networks are constrained by natural connectivity in the interactions between geography of resources and social forces. Using a geographic information system (GIS) we can understand how populations utilize their health networks, visualize their inefficiencies, and compare alternatives.
Methods
This project focuses on cardiac care resource in rural Isaan, Thailand. A health care access analysis was created using ArcGIS Network Analyst 10.1 from data representing aggregated population, roads, health resource facilities, and diagnostic technologies. The analysis quantified cardiac health care access and identified ways to improve it using both widespread and resource-limited strategies.
Results
Results indicated that having diagnostic technologies closer to populations streamlines critical care paths. GIS allowed us to compare the effectiveness of the implementation strategies and put into perspective the benefits of adopting rapid POCT within health networks.
Conclusions
Geospatial analyses derive high impact by improving alternative diagnostic placement strategies in limited-resource settings and by revealing deficiencies in health care access pathways. Additionally, the GIS provides a platform for comparing relative costs, assessing benefits, and improving outcomes. This approach can be implemented effectively by health ministries seeking to enhance cardiac care despite limited resources.
Journal Article
Bayesian spatial modelling of localised SARS-CoV-2 transmission through mobility networks across England
In the early phases of growth, resurgent epidemic waves of SARS-CoV-2 incidence have been characterised by localised outbreaks. Therefore, understanding the geographic dispersion of emerging variants at the start of an outbreak is key for situational public health awareness. Using telecoms data, we derived mobility networks describing the movement patterns between local authorities in England, which we have used to inform the spatial structure of a Bayesian BYM2 model. Surge testing interventions can result in spatio-temporal sampling bias, and we account for this by extending the BYM2 model to include a random effect for each timepoint in a given area. Simulated-scenario modelling and real-world analyses of each variant that became dominant in England were conducted using our BYM2 model at local authority level in England. Simulated datasets were created using a stochastic metapopulation model, with the transmission rates between different areas parameterised using telecoms mobility data. Different scenarios were constructed to reproduce real-world spatial dispersion patterns that could prove challenging to inference, and we used these scenarios to understand the performance characteristics of the BYM2 model. The model performed better than unadjusted test positivity in all the simulation-scenarios, and in particular when sample sizes were small, or data was missing for geographical areas. Through the analyses of emerging variant transmission across England, we found a reduction in the early growth phase geographic clustering of later dominant variants as England became more interconnected from early 2022 and public health interventions were reduced. We have also shown the recent increased geographic spread and dominance of variants with similar mutations in the receptor binding domain, which may be indicative of convergent evolution of SARS-CoV-2 variants.
Journal Article
A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma
Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB.
Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056).
DFMO doses of 500-1500 mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway.
Clinicaltrials.gov NCT#01059071.
Journal Article
Motion sickness and sense of presence in a virtual reality environment developed for manual wheelchair users, with three different approaches
Visually Induced Motion Sickness (VIMS) is a bothersome and sometimes unsafe experience, frequently experienced in Virtual Reality (VR) environments. In this study, the effect of up to four training sessions to decrease VIMS in the VR environment to a minimal level was tested and verified through explicit declarations of all 14 healthy participants that were recruited in this study. Additionally, the Motion Sickness Assessment Questionnaire (MSAQ) was used at the end of each training session to measure responses to different aspects of VIMS. Total, gastrointestinal, and central motion sickness were shown to decrease significantly by the last training session, compared to the first one. After acclimatizing to motion sickness, participants’ sense of presence and the level of their motion sickness in the VR environment were assessed while actuating three novel and sophisticated VR systems. They performed up to four trials of the Illinois agility test in the VR systems and the real world, then completed MSAQ and Igroup Presence Questionnaire (IPQ) at the end of each session. Following acclimatization, the three VR systems generated relatively little motion sickness and high virtual presence scores, with no statistically meaningful difference among them for either MSAQ or IPQ. Also, it was shown that presence has a significant negative correlation with VIMS.
Journal Article
Design and Rationale of a Phase 2 Study of NeurOtoxin (Botulinum Toxin Type A) for the PreVention of Post-Operative Atrial Fibrillation – The NOVA Study
: Post-operative AF (POAF) is the most common complication following cardiac surgery, occurring in 30% to 60% of patients undergoing bypass and/or valve surgery. POAF is associated with longer intensive care unit/hospital stays, increased healthcare utilization, and increased morbidity and mortality. Injection of botulinum toxin type A into the epicardial fat pads resulted in reduction of AF in animal models, and in two clinical studies of cardiac surgery patients, without new safety observations.
: The objective of NOVA is to assess the use of AGN-151607 (botulinum toxin type A) for prevention of POAF in cardiac surgery patients. This randomized, multi-site, placebo-controlled trial will study one-time injections of AGN-151607 125 U (25 U / fat pad) and 250 U (50 U / fat pad) or placebo during cardiac surgery in ∼330 participants. Primary endpoint: % of patients with continuous AF ≥ 30 s. Secondary endpoints include several measures of AF frequency, duration, and burden. Additional endpoints include clinically important tachycardia during AF, time to AF termination, and healthcare utilization. Primary and secondary efficacy endpoints will be assessed using continuous ECG monitoring for 30 days following surgery. All patients will be followed for up to 1 year for safety.
: The NOVA Study will test the hypothesis that injections of AGN-151607 will reduce the incidence of POAF and associated resource utilization. If demonstrated to be safe and effective, the availability of a one-time therapy for the prevention of POAF would represent an important treatment option for patients undergoing cardiac surgery.
Journal Article