Modelling the impact of antibody-dependent enhancement on disease severity of Zika virus and dengue virus sequential and co-infection

Human infections with viruses of the genus Flavivirus, including dengue virus (DENV) and Zika virus (ZIKV), are of increasing global importance. Owing to antibody-dependent enhancement (ADE), secondary infection with one Flavivirus following primary infection with another Flavivirus can result in a significantly larger peak viral load with a much higher risk of severe disease. Although several mathematical models have been developed to quantify the virus dynamics in the primary and secondary infections of DENV, little progress has been made regarding secondary infection of DENV after a primary infection of ZIKV, or DENV-ZIKV co-infection. Here, we address this critical gap by developing compartmental models of virus dynamics. We first fitted the models to published data on dengue viral loads of the primary and secondary infections with the observation that the primary infection reaches its peak much more gradually than the secondary infection. We then quantitatively show that ADE is the key factor determining a sharp increase/decrease of viral load near the peak time in the secondary infection. In comparison, our simulations of DENV and ZIKV co-infection (simultaneous rather than sequential) show that ADE has very limited influence on the peak DENV viral load. This indicates pre-existing immunity to ZIKV is the determinant of a high level of ADE effect. Our numerical simulations show that (i) in the absence of ADE effect, a subsequent co-infection is beneficial to the second virus; and (ii) if ADE is feasible, then a subsequent co-infection can induce greater damage to the host with a higher peak viral load and a much earlier peak time for the second virus, and for the second peak for the first virus.Fil: Tang, Biao. University of York; Reino Unido. University of Toronto; CanadáFil: Xiao, Yanni. Xi'an Jiaotong University; ChinaFil: Sander, Beate. University of Toronto; CanadáFil: Kulkarni, Manisha A.. University of Ottawa; CanadáFil: Wu, Jianhong. University of York; Reino UnidoFil: Miretti, Marcos Mateo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Posadas | Universidad Nacional de Misiones. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Posadas; Argentin

Structural imaging biomarkers of sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy is a major cause of premature death in people with epilepsy. We aimed to assess whether structural changes potentially attributable to sudden death pathogenesis were present on magnetic resonance imaging in people who subsequently died of sudden unexpected death in epilepsy. In a retrospective, voxel-based analysis of T1 volume scans, we compared grey matter volumes in 12 cases of sudden unexpected death in epilepsy (two definite, 10 probable; eight males), acquired 2 years [median, interquartile range (IQR) 2.8] before death [median (IQR) age at scanning 33.5 (22) years], with 34 people at high risk [age 30.5 (12); 19 males], 19 at low risk [age 30 (7.5); 12 males] of sudden death, and 15 healthy controls [age 37 (16); seven males]. At-risk subjects were defined based on risk factors of sudden unexpected death in epilepsy identified in a recent combined risk factor analysis. We identified increased grey matter volume in the right anterior hippocampus/amygdala and parahippocampus in sudden death cases and people at high risk, when compared to those at low risk and controls. Compared to controls, posterior thalamic grey matter volume, an area mediating oxygen regulation, was reduced in cases of sudden unexpected death in epilepsy and subjects at high risk. The extent of reduction correlated with disease duration in all subjects with epilepsy. Increased amygdalo-hippocampal grey matter volume with right-sided changes is consistent with histo-pathological findings reported in sudden infant death syndrome. We speculate that the right-sided predominance reflects asymmetric central influences on autonomic outflow, contributing to cardiac arrhythmia. Pulvinar damage may impair hypoxia regulation. The imaging findings in sudden unexpected death in epilepsy and people at high risk may be useful as a biomarker for risk-stratification in future studies

Assessing ZIKV transmission dynamics and mitigation strategies : a multidisciplinary approach

The project took place in three Latin American countries that have different epidemiological and ecological settings of Zika virus transmission: Colombia, Argentina and Ecuador; with the objective of characterizing the ecological transmission dynamics of Zika virus (ZIKV) and designing integrated intervention approaches. The report provides country-specific information regarding project implementation. The multi-country regression analysis identified several factors associated with an increased density of adult female Aedes mosquitoes, which represent important risk factors for arboviral disease transmission that can be considered in the design of disease prevention and control strategies. The report includes analysis and outputs from the project

Reactive strategies for containing developing outbreaks of pandemic influenza

Abstract Background In 2009 and the early part of 2010, the northern hemisphere had to cope with the first waves of the new influenza A (H1N1) pandemic. Despite high-profile vaccination campaigns in many countries, delays in administration of vaccination programs were common, and high vaccination coverage levels were not achieved. This experience suggests the need to explore the epidemiological and economic effectiveness of additional, reactive strategies for combating pandemic influenza. Methods We use a stochastic model of pandemic influenza to investigate realistic strategies that can be used in reaction to developing outbreaks. The model is calibrated to documented illness attack rates and basic reproductive number (R0) estimates, and constructed to represent a typical mid-sized North American city. Results Our model predicts an average illness attack rate of 34.1% in the absence of intervention, with total costs associated with morbidity and mortality of US$81 million for such a city. Attack rates and economic costs can be reduced to 5.4$37 million, respectively, when low-coverage reactive vaccination and limited antiviral use are combined with practical, minimally disruptive social distancing strategies, including short-term, as-needed closure of individual schools, even when vaccine supply-chain-related delays occur. Results improve with increasing vaccination coverage and higher vaccine efficacy. Conclusions Such combination strategies can be substantially more effective than vaccination alone from epidemiological and economic standpoints, and warrant strong consideration by public health authorities when reacting to future outbreaks of pandemic influenza

A cost comparison of electronic and hybrid data collection systems in Ontario during pandemic and seasonal influenza vaccination campaigns

<p>Abstract</p> <p>Background</p> <p>During the pandemic (H1N1) 2009 influenza vaccination campaign, health regions in Canada collected client-level immunization data using fully electronic or hybrid systems, with the latter comprising both electronic and paper-based elements. The objective of our evaluation was to compare projected five-year costs associated with implementing these systems in Ontario public health units (PHUs) during pandemic and seasonal influenza vaccination campaigns.</p> <p>Methods</p> <p>Six PHUs provided equipment and staffing costs during the pandemic (H1N1) 2009 influenza vaccination campaign and staffing algorithms for seasonal campaigns. We standardized resources to population sizes 100,000, 500,000 and 1,000,000, assuming equipment lifetime of five years and public health vaccine administration rates of 18% and 2.5% for H1N1 and seasonal campaigns, respectively. Two scenarios were considered: Year 1 pandemic and Year 1 seasonal campaigns, each followed by four regular influenza seasons. Costs were discounted at 5%.</p> <p>Results</p> <p>Assuming a Year 1 pandemic, the five-year costs per capita for the electronic system decrease as PHU population size increases, becoming increasingly less costly than hybrid systems ($4.33 vs.$4.34 [100,000], $4.17 vs.$4.34 [500,000], $4.12 vs.$4.34 [1,000, 000]). The same trend is observed for the scenario reflecting five seasonal campaigns, with the electronic system being less expensive per capita than the hybrid system for all population sizes ($1.93 vs.$1.95 [100,000], $1.91 vs.$1.94 [500,000], $1.87 vs.$1.94 [1,000, 000]). Sensitivity analyses identified factors related to nurse hours as affecting the direction and magnitude of the results.</p> <p>Conclusions</p> <p>Five-year cost projections for electronic systems were comparable or less expensive than for hybrid systems, at all PHU population sizes. An intangible benefit of the electronic system is having data rapidly available for reporting.</p

Arbovirus vectors of epidemiological concern in the Americas: A scoping review of entomological studies on Zika, dengue and chikungunya virus vectors

Background Three arthropod-borne viruses (arboviruses) causing human disease have been the focus of a large number of studies in the Americas since 2013 due to their global spread and epidemiological impacts: Zika, dengue, and chikungunya viruses. A large proportion of infections by these viruses are asymptomatic. However, all three viruses are associated with moderate to severe health consequences in a small proportion of cases. Two mosquito species, Aedes aegypti and Aedes albopictus, are among the world´s most prominent arboviral vectors, and are known vectors for all three viruses in the Americas. Objectives This review summarizes the state of the entomological literature surrounding the mosquito vectors of Zika, dengue and chikungunya viruses and factors affecting virus transmission. The rationale of the review was to identify and characterize entomological studies that have been conducted in the Americas since the introduction of chikungunya virus in 2013, encompassing a period of arbovirus co-circulation, and guide future research based on identified knowledge gaps. Methods The preliminary search for this review was conducted on PubMed (National Library of Health, Bethesda, MD, United States). The search included the terms ´zika´ OR ´dengue´ OR ´chikungunya´ AND ´vector´ OR ´Aedes aegypti´ OR ´Aedes albopictus´. The search was conducted on March 1st of 2018, and included all studies since January 1st of 2013. Results A total of 96 studies were included in the scoping review after initial screening and subsequent exclusion of out-of-scope studies, secondary data publications, and studies unavailable in English language. Key findings We observed a steady increase in number of publications, from 2013 to 2018, with half of all studies published from January 2017 to March 2018. Interestingly, information on Zika virus vector species composition was abundant, but sparse on Zika virus transmission dynamics. Few studies examined natural infection rates of Zika virus, vertical transmission, or co-infection with other viruses. This is in contrast to the wealth of research available on natural infection and co-infection for dengue and chikungunya viruses, although vertical transmission research was sparse for all three viruses.Fil: Jones, Reilly. University of Toronto; CanadáFil: Kulkarni, Manisha A.. University of Ottawa; CanadáFil: Davidson, Thomas M.V.. University of Toronto; CanadáFil: Sander, Beate. Public Health Ontario; CanadáFil: González, Camila. Universidad de Los Andes; VenezuelaFil: Wu, Jianhong. York University ; CanadáFil: Miretti, Marcos Mateo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Posadas | Universidad Nacional de Misiones. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Posadas; ArgentinaFil: Espinel, Mauricio. Universidad Laica Elroy Alfaro de Manabí; EcuadorFil: Cevallos Viteri, Varsovia Enid. Instituto Nacional de Salud Pública; EcuadorFil: Cevallos, Varsovia. Instituto Nacional de Salud Pública; EcuadorFil: Talbot, Benoit. University of Ottawa; Canad

Do Health Technology Assessment organisations consider manufacturers' costs in relation to drug price? A study of reimbursement reports

Introduction Drug reimbursement decisions are often made based on a price set by the manufacturer. In some cases, this price leads to public and scientific debates about whether its level can be justified in relation to its costs, including those related to research and development (R&D) and manufacturing. Such considerations could enter the decision process in collectively financed health care systems. This paper investigates whether manufacturers’ costs in relation to drug prices, or profit margins, are explicitly mentioned and considered by health technology assessment (HTA) organisations. Method An analysis of reimbursement reports for cancer drugs was performed. All relevant Dutch HTA-reports, published between 2017 and 2019, were selected and matched with HTA-reports from three other jurisdictions (England, Canada, Australia). Information was extracted. Additionally, reimbursement reports for three cases of expensive non-oncolytic orphan drugs prominent in pricing debates in the Netherlands were investigated in depth to examine consideration of profit margins. Results A total of 66 HTA-reports concerning 15 cancer drugs were included. None of these reports contained information on manufacturer’s costs or profit margins. Some reports contained general considerations of the HTA organisation which related prices to manufacturers’ costs: six contained a statement on the lack of price setting transparency, one mentioned recouping R&D costs as a potential argument to justify a high price. For the case studies, 21 HTA-reports were selected. One contained a cost-based price justification provided by the manufacturer. None of the other reports contained information on manufacturer’s costs or profit margins. Six reports contained a discussion about lack of transparency. Reports from two jurisdictions contained invitations to justify high prices by demonstrating high costs. Conclusion Despite the attention given to manufacturers’ costs in relation to price in public debates and in the literature, this issue does not seem to get explicit systematic consideration in the reimbursement reports of expensive drugs

Dupilumab but not cyclosporine treatment shifts the microbiome toward a healthy skin flora in patients with moderate‐to‐severe atopic dermatitis

Background: Atopic dermatitis (AD) patients display an altered skin microbiome which may not only be an indicator but also a driver of inflammation. We aimed to investigate associations among AD patients' skin microbiome, clinical data, and response to systemic therapy in patients of the TREATgermany registry. Methods: Skin swabs of 157 patients were profiled with 16S rRNA gene amplicon sequencing before and after 3 months of treatment with dupilumab or cyclosporine. For comparison, 16s microbiome data from 258 population-based healthy controls were used. Disease severity was assessed using established instruments such as the Eczema Area and Severity Index (EASI). Results: We confirmed the previously shown correlation of Staphylococcus aureus abundance and bacterial alpha diversity with AD severity as measured by EASI. Therapy with Dupilumab shifted the bacterial community toward the pattern seen in healthy controls. The relative abundance of Staphylococci and in particular S. aureus significantly decreased on both lesional and non-lesional skin, whereas the abundance of Staphylococcus hominis increased. These changes were largely independent from the degree of clinical improvement and were not observed for cyclosporine. Conclusions: Systemic treatment with dupilumab but not cyclosporine tends to restore a healthy skin microbiome largely independent of the clinical response indicating potential effects of IL-4RA blockade on the microbiome

Variability in transmissibility of the 2009 H1N1 pandemic in Canadian communities

Abstract Background The prevalence and severity of the 2009 H1N1 pandemic appeared to vary significantly across populations and geographic regions. We sought to investigate the variability in transmissibility of H1N1 pandemic in different health regions (including urban centres and remote, isolated communities) in the province of Manitoba, Canada. Methods The Richards model was used to fit to the daily number of laboratory-confirmed cases and estimate transmissibility (referred to as the basic reproduction number, R0), doubling times, and turning points of outbreaks in both spring and fall waves of the H1N1 pandemic in several health regions. Results We observed considerable variation in R0 estimates ranging from 1.55 to 2.24, with confidence intervals ranging from 1.45 to 2.88, for an average generation time of 2.9 days, and shorter doubling times in some remote and isolated communities compared to urban centres, suggesting a more rapid spread of disease in these communities during the first wave. For the second wave, R e , the effective reproduction number, is estimated to be lower for remote and isolated communities; however, outbreaks appear to have been driven by somewhat higher transmissibility in urban centres. Conclusions There was considerable geographic variation in transmissibility of the 2009 pandemic outbreaks. While highlighting the importance of estimating R0 for informing health responses, the findings indicate that projecting the transmissibility for large-scale epidemics may not faithfully characterize the early spread of disease in remote and isolated communities