scholarly journals Dengue antigenic relationships predict evolutionary dynamics

2018 ◽  
Author(s):  
Sidney Bell ◽  
Leah Katzelnick ◽  
Trevor Bedford
Keyword(s):  
Population Dynamics ◽  
Dengue Virus ◽  
Real World ◽  
Genetic Divergence ◽  
Vaccine Design ◽  
Antigenic Diversity ◽  
Antigenic Evolution ◽  
Nuanced Understanding ◽  
The Impact ◽  
Antigenic Heterogeneity

AbstractDengue virus (DENV) exists as four genetically distinct serotypes, each of which is historically assumed to be antigenically uniform. However, recent analyses suggest that antigenic heterogeneity may exist within each serotype, but its source, extent and impact remain unclear. Here, we construct a sequence-based model to directly map antigenic change to underlying genetic divergence. We identify 49 specific substitutions and four colinear substitution clusters that contribute to dengue antigenic diversity. We report moderate antigenic diversity within each serotype, resulting in variation in genotype-specific patterns of heterotypic cross-neutralization. We also quantify the impact of this antigenic heterogeneity on real-world DENV population dynamics. We find that antigenic fitness mediates fluctuations in DENV clade frequencies, although this appears to be primarily explained by coarser serotype-level antigenic differences. These results provide a more nuanced understanding of dengue antigenic evolution, with important ramifications for vaccine design and epidemic preparedness.Author SummaryDengue virus (DENV), the causative agent of dengue hemorrhagic fever, exists as four genetically distinct serotypes, DENV1 to DENV4. These serotypes are antigenically distinct: symptomatic reinfection with a homotypic virus is very rare, while reinfection with a heterotypic virus is sometimes associated with severe disease. Until recently, it has been assumed that viruses within each serotype are antigenically uniform. However, specific genotypes within each serotype have been anecdotally associated with varying severity of patient outcomes and epidemic magnitude. One hypothesis is that each serotype contains overlooked, meaningful antigenic diversity. While antigenic cartography conducted on neutralization titers suggests that heterogeneity may exist within each serotype, its source, extent and impact is unclear. Here, we analyze a previously published titer dataset to quantify and characterize the extent of DENV intraserotype antigenic diversity. We map antigenic changes to specific mutations inE, the dengue envelope protein, and interpolate across the alignment to estimate the antigenic distance between pairs of viruses based on their genetic differences. We identify 49 specific substitutions and four colinear substitution clusters that contribute to dengue antigenic evolution. We find that DENV antigenic divergence is tightly coupled to DENV genetic divergence, and is likely a gradual, ongoing process. We report modest but significant antigenic diversity within each serotype of DENV, which may have important ramifications for vaccine design. To understand the impact of this antigenic heterogeneity on real-world DENV population dynamics, we also quantify the extent to which population immunity—accumulated through recent circulation of antigenically similar genotypes—determines the success and decline of DENV clades in a hyperendemic population. We find that antigenic fitness is a key determinant of DENV population turnover, although this appears to be driven by coarser serotype-level antigenic differences. By leveraging both molecular data and real-world population dynamics, these results provide a more nuanced understanding of dengue antigenic evolution, with important ramifications for improving vaccine design and epidemic preparedness.

scholarly journals Dengue genetic divergence generates within-serotype antigenic variation, but serotypes dominate evolutionary dynamics

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Sidney M Bell ◽  
Leah Katzelnick ◽  
Trevor Bedford
Keyword(s):  
Genetic Divergence ◽  
Evolutionary Dynamics ◽  
Antigenic Variation ◽  
Antigenic Evolution ◽  
Cross Neutralization ◽  
Nuanced Understanding ◽  
The Impact ◽  
The Relationship ◽  
Antigenic Relationships ◽  
Antigenic Heterogeneity

Dengue virus (DENV) exists as four genetically distinct serotypes, each of which is historically assumed to be antigenically uniform. Recent analyses suggest that antigenic heterogeneity may exist within each serotype, but its source, extent and impact remain unclear. Here, we construct a sequence-based model to directly map antigenic change to underlying genetic divergence. We identify 49 specific substitutions and four colinear substitution clusters that robustly predict dengue antigenic relationships. We report moderate antigenic diversity within each serotype, resulting in genotype-specific patterns of heterotypic cross-neutralization. We also quantify the impact of antigenic variation on real-world DENV population dynamics, and find that serotype-level antigenic fitness is a dominant driver of dengue clade turnover. These results provide a more nuanced understanding of the relationship between dengue genetic and antigenic evolution, and quantify the effect of antigenic fitness on dengue evolutionary dynamics.

Long-term population dynamics of the red deer and European roe deer at the protected and not-protected areas in Mountain Crimea

2017 ◽  
Vol 7 (4) ◽  
pp. 65-72
Author(s):  
V. N. Shmagol' ◽  
V. L. Yarysh ◽  
S. P. Ivanov ◽  
V. I. Maltsev
Keyword(s):  
Population Dynamics ◽  
Protected Areas ◽  
Red Deer ◽  
Nature Reserve ◽  
Roe Deer ◽  
Precipitation Amount ◽  
Annual Precipitation ◽  
Population Number ◽  
The Impact

<p>The long-term population dynamics of the red deer (<em>Cervus elaphus</em> L.) and European roe deer (<em>Capreolus</em> <em>capreolus</em> L.) at the mountain and forest zone of Crimea during 1980-2017 is presented. Fluctuations in numbers of both species are cyclical and partly synchronous. Period of oscillations in the population of red deer is about 25 years, the average duration of the oscillation period of number of roe deer is 12.3 years. During the fluctuations in the number the increasing and fall in population number of the red deer had been as 26-47 %, and roe deer – as 22-34 %. Basing on the dada obtained we have assumed that together with large-scale cycles of fluctuations in population number of both red deer and roe deer the short cycles of fluctuations in the number of these species with period from 3.5 to 7.5 years take place. Significant differences of the parameters of cyclical fluctuations in the number of roe deer at some sites of the Mountainous Crimea: breaches of synchronicity, as well as significant differences in the duration of cycles are revealed. The greatest deviations from the average values of parameters of long-term dynamics of the number of roe deer in Crimea are noted for groups of this species at two protected areas. At the Crimean Nature Reserve the cycle time of fluctuations of the numbers of roe deer was 18 years. At the Karadag Nature Reserve since 1976 we can see an exponential growth in number of roe deer that is continued up to the present time. By 2016 the number of roe deer reached 750 individuals at a density of 437 animals per 1 thousand ha. Peculiarity of dynamics of number of roe deer at some sites proves the existence in the mountain forest of Crimea several relatively isolated groups of deer. We assumed that "island" location of the Crimean populations of red deer and European roe deer, their relatively little number and influence of permanent extreme factors of both natural and anthropogenic origination have contributed to a mechanism of survival of these populations. The elements of such a mechanism include the following features of long-term dynamics of the population: the reduction in the period of cyclic population fluctuations, while maintaining their amplitude and the appearance of additional small cycles, providing more flexible response of the population to the impact of both negative and positive environmental factors. From the totality of the weather conditions for the Crimean population of roe deer the recurring periods of increases and downs in the annual precipitation amount may have relevance. There was a trend of increase in the roe deer population during periods of increasing annual precipitation.</p>

1607-P: Real-World Evidence of the Impact of Obesity on Residual Teeth in the Japanese Population

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1607-P
Author(s):  
MAYU HAYASHI ◽  
KATSUTARO MORINO ◽  
KAYO HARADA ◽  
MIKI ISHIKAWA ◽  
ITSUKO MIYAZAWA ◽  
...  
Keyword(s):  
Real World ◽  
Japanese Population ◽  
Real World Evidence ◽  
The Impact

scholarly journals POS1121 DEMOGRAPHICS, COMORBIDITIES, AND RENAL FUNCTION OF UNCONTROLLED GOUT PATIENTS WHO RECEIVED PEGLOTICASE: FINDING FROM A LARGE US CLAIMS DATABASE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 839.2-840
Author(s):  
C. Vesel ◽  
A. Morton ◽  
M. Francis-Sedlak ◽  
B. Lamoreaux
Keyword(s):  
Kidney Function ◽  
Real World ◽  
Randomized Clinical Trials ◽  
Small Subset ◽  
Phase 3 ◽  
Claims Database ◽  
Medical Diagnoses ◽  
Ckd Stage ◽  
Before And After ◽  
The Impact

Background:NHANES data indicate that approximately 9.2 million Americans have gout,1 with a small subset having uncontrolled disease.2 Pegloticase is a PEGylated recombinant uricase enzyme indicated for treating uncontrolled gout that markedly reduces serum uric acid levels (sUA)3 and resolves tophi in treatment responders.4 Despite pegloticase availability in the US for many years, real world demographics of pegloticase users in the treatment of uncontrolled gout have not been previously reported in a population-based cohort.Objectives:This study utilized a large US claims database to examine demographics and co-morbidities of uncontrolled gout patients treated with pegloticase. Kidney function before and after pegloticase treatment and concomitant therapy with immunomodulators were also examined.Methods:The TriNetX Diamond database includes de-identified data from 4.3 million US patients with gout (as of September 2019), including demographics, medical diagnoses, laboratory values, procedures (e.g. infusions, surgeries), and pharmacy data. Patients who had received ≥1 pegloticase infusion were included in these analyses. The number of infusions was evaluated for a subgroup of patients who were in the database ≥3 months before and ≥2 years after the first pegloticase infusion (i.e. first infusion prior to September 2017) to ensure only complete courses of therapy were captured. In this subpopulation, kidney function before and after pegloticase therapy was examined, along with the presence of immunomodulation prescriptions (methotrexate, mycophenolate mofetil, azathioprine, leflunomide) within 60 days prior to and 14 days after the first pegloticase infusion.Results:1494 patients treated with pegloticase were identified. Patients were 63.1 ± 14.0 years of age (range: 23–91), mostly male (82%), and white (76%). Mean sUA prior to pegloticase was 8.7 ± 2.4 mg/dL (n=50), indicating uncontrolled gout in the identified population. The most commonly reported comorbidities were chronic kidney disease (CKD, 48%), essential hypertension (71%), type 2 diabetes (39%), and cardiovascular disease (38%), similar to pegloticase pivotal Phase 3 trial populations. In patients with pre-therapy kidney function measures (n=134), pre-treatment eGFR averaged 61.2 ± 25.7 ml/min/1.73 m2, with 44% having Stage 3-5 CKD. In patients with complete therapy course capture and pre- and post-therapy eGFR measures (n=48), kidney function remained stable (change in eGFR: -2.9 ± 18.2 ml/min/1.73 m2) and CKD stage remained the same or improved in 81% of patients. In 791 patients with complete treatment course capture, patients had received 8.7 ± 13.8 infusions (median: 3, IQR: 2-10). Of these, 189 (24%) patients received only 1 pegloticase infusion and 173 (22%) received ≥12 infusions. As the data cut-off for this analysis pre-dated emerging data on the use of immunomodulation as co-therapy, only 19 of 791 (2%) patients received immunomodulation co-therapy with pegloticase.Conclusion:This relatively large group of patients with uncontrolled gout treated with pegloticase had similar patient characteristics of those studied in the phase 3 randomized clinical trials. Patients with uncontrolled gout are significantly burdened with systemic co-morbid diseases. The majority of patients had stable or improved kidney function following pegloticase treatment. As these results reflect patients initiating treatment prior to 2018, before co-treatment with immunomodulation was introduced, this cohort only included a small percentage of patients who were co-treated with an immunomodulator. Future studies using more current datasets are needed to evaluate real world outcomes in patients treated with pegloticase/immunomodulator co-therapy and to evaluate the impact of systemic co-morbid diseases.References:[1]Chen-Xu M, et al. Arthritis Rheumatol 2019 71:991-999.[2]Fels E, Sundy JS. Curr Opin Rheumatol 2008;20:198-202.[3]Sundy J, et al. JAMA 2011;306:711-720.[4]Mandell BF, et al. Arthritis Res Ther 2018;20:286.Disclosure of Interests:Claudia Vesel Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Allan Morton Speakers bureau: Sanofi, Amgen, and Horizon, Megan Francis-Sedlak Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Brian LaMoreaux Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc.

PP469 From Theory To Practice: Which Value Framework Is Applied For Onco-Hematology Therapies In Italy? A 5-year Retrospective Analysis

2020 ◽  
Vol 36 (S1) ◽  
pp. 37-37
Author(s):  
Americo Cicchetti ◽  
Rossella Di Bidino ◽  
Entela Xoxi ◽  
Irene Luccarini ◽  
Alessia Brigido
Keyword(s):  
Real World ◽  
Ad Hoc ◽  
Grey Literature ◽  
National Level ◽  
Pharmaceutical Products ◽  
European Medicines Agency ◽  
The Real ◽  
R Process ◽  
The One ◽  
The Impact

IntroductionDifferent value frameworks (VFs) have been proposed in order to translate available evidence on risk-benefit profiles of new treatments into Pricing & Reimbursement (P&R) decisions. However limited evidence is available on the impact of their implementation. It's relevant to distinguish among VFs proposed by scientific societies and providers, which usually are applicable to all treatments, and VFs elaborated by regulatory agencies and health technology assessment (HTA), which focused on specific therapeutic areas. Such heterogeneity in VFs has significant implications in terms of value dimension considered and criteria adopted to define or support a price decision.MethodsA literature research was conducted to identify already proposed or adopted VF for onco-hematology treatments. Both scientific and grey literature were investigated. Then, an ad hoc data collection was conducted for multiple myeloma; breast, prostate and urothelial cancer; and Non Small Cell Lung Cancer (NSCLC) therapies. Pharmaceutical products authorized by European Medicines Agency from January 2014 till December 2019 were identified. Primary sources of data were European Public Assessment Reports and P&R decision taken by the Italian Medicines Agency (AIFA) till September 2019.ResultsThe analysis allowed to define a taxonomy to distinguish categories of VF relevant to onco-hematological treatments. We identified the “real-world” VF that emerged given past P&R decisions taken at the Italian level. Data was collected both for clinical and economical outcomes/indicators, as well as decisions taken on innovativeness of therapies. Relevant differences emerge between the real world value framework and the one that should be applied given the normative framework of the Italian Health System.ConclusionsThe value framework that emerged from the analysis addressed issues of specific aspects of onco-hematological treatments which emerged during an ad hoc analysis conducted on treatment authorized in the last 5 years. The perspective adopted to elaborate the VF was the one of an HTA agency responsible for P&R decisions at a national level. Furthermore, comparing a real-world value framework with the one based on the general criteria defined by the national legislation, our analysis allowed identification of the most critical point of the current national P&R process in terms ofsustainability of current and future therapies as advance therapies and agnostic-tumor therapies.

scholarly journals Is the use of two versus one long-acting bronchodilator by patients with COPD associated with a higher risk of acute coronary syndrome in real-world clinical practice?

2021 ◽  
Vol 8 (1) ◽  
pp. e000840
Author(s):  
Lianne Parkin ◽  
Sheila Williams ◽  
David Barson ◽  
Katrina Sharples ◽  
Simon Horsburgh ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Clinical Practice ◽  
Real World ◽  
Chronic Obstructive ◽  
Treatment Intensification ◽  
Cardiovascular Comorbidity ◽  
Coronary Syndrome ◽  
Long Acting ◽  
The Impact

BackgroundCardiovascular comorbidity is common among patients with chronic obstructive pulmonary disease (COPD) and there is concern that long-acting bronchodilators (long-acting muscarinic antagonists (LAMAs) and long-acting beta2 agonists (LABAs)) may further increase the risk of acute coronary events. Information about the impact of treatment intensification on acute coronary syndrome (ACS) risk in real-world settings is limited. We undertook a nationwide nested case–control study to estimate the risk of ACS in users of both a LAMA and a LABA relative to users of a LAMA.MethodsWe used routinely collected national health and pharmaceutical dispensing data to establish a cohort of patients aged >45 years who initiated long-acting bronchodilator therapy for COPD between 1 February 2006 and 30 December 2013. Fatal and non-fatal ACS events during follow-up were identified using hospital discharge and mortality records. For each case we used risk set sampling to randomly select up to 10 controls, matched by date of birth, sex, date of cohort entry (first LAMA and/or LABA dispensing), and COPD severity.ResultsFrom the cohort (n=83 417), we identified 5399 ACS cases during 281 292 person-years of follow-up. Compared with current use of LAMA therapy, current use of LAMA and LABA dual therapy was associated with a higher risk of ACS (OR 1.28 (95% CI 1.13 to 1.44)). The OR in an analysis restricted to fatal cases was 1.46 (95% CI 1.12 to 1.91).ConclusionIn real-world clinical practice, use of two versus one long-acting bronchodilator by people with COPD is associated with a higher risk of ACS.

scholarly journals Design of a companion bioinformatic tool to detect the emergence and geographical distribution of SARS-CoV-2 Spike protein genetic variants

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Alice Massacci ◽  
Eleonora Sperandio ◽  
Lorenzo D’Ambrosio ◽  
Mariano Maffei ◽  
Fabio Palombo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Consensus Sequence ◽  
Cell Epitope ◽  
Vaccine Design ◽  
Binding Domain ◽  
Spike Protein ◽  
Antibody Activity ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
The Impact

Abstract Background Tracking the genetic variability of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is a crucial challenge. Mainly to identify target sequences in order to generate robust vaccines and neutralizing monoclonal antibodies, but also to track viral genetic temporal and geographic evolution and to mine for variants associated with reduced or increased disease severity. Several online tools and bioinformatic phylogenetic analyses have been released, but the main interest lies in the Spike protein, which is the pivotal element of current vaccine design, and in the Receptor Binding Domain, that accounts for most of the neutralizing the antibody activity. Methods Here, we present an open-source bioinformatic protocol, and a web portal focused on SARS-CoV-2 single mutations and minimal consensus sequence building as a companion vaccine design tool. Furthermore, we provide immunogenomic analyses to understand the impact of the most frequent RBD variations. Results Results on the whole GISAID sequence dataset at the time of the writing (October 2020) reveals an emerging mutation, S477N, located on the central part of the Spike protein Receptor Binding Domain, the Receptor Binding Motif. Immunogenomic analyses revealed some variation in mutated epitope MHC compatibility, T-cell recognition, and B-cell epitope probability for most frequent human HLAs. Conclusions This work provides a framework able to track down SARS-CoV-2 genomic variability.

Population dynamics driven by truncated stable processes with Markovian switching

2021 ◽  
Vol 58 (2) ◽  
pp. 505-522
Author(s):  
Zhenzhong Zhang ◽  
Jinying Tong ◽  
Qingting Meng ◽  
You Liang
Keyword(s):  
Population Dynamics ◽  
Sufficient Conditions ◽  
Necessary And Sufficient Conditions ◽  
Markovian Switching ◽  
Stable Processes ◽  
Necessary And Sufficient ◽  
The Impact

AbstractWe focus on the population dynamics driven by two classes of truncated $\alpha$-stable processes with Markovian switching. Almost necessary and sufficient conditions for the ergodicity of the proposed models are provided. Also, these results illustrate the impact on ergodicity and extinct conditions as the parameter $\alpha$ tends to 2.

scholarly journals Parasitism of Aedes albopictus by Ascogregarina taiwanensis lowers its competitive ability against Aedes triseriatus

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Emma Stump ◽  
Lauren M. Childs ◽  
Melody Walker
Keyword(s):  
Population Dynamics ◽  
Competitive Advantage ◽  
Aedes Albopictus ◽  
Abiotic Factors ◽  
Mosquito Species ◽  
Disease Spread ◽  
Aedes Triseriatus ◽  
La Crosse Virus ◽  
The Impact ◽  
Ascogregarina Taiwanensis

Abstract Background Mosquitoes are vectors for diseases such as dengue, malaria and La Crosse virus that significantly impact the human population. When multiple mosquito species are present, the competition between species may alter population dynamics as well as disease spread. Two mosquito species, Aedes albopictus and Aedes triseriatus, both inhabit areas where La Crosse virus is found. Infection of Aedes albopictus by the parasite Ascogregarina taiwanensis and Aedes triseriatus by the parasite Ascogregarina barretti can decrease a mosquito’s fitness, respectively. In particular, the decrease in fitness of Aedes albopictus occurs through the impact of Ascogregarina taiwanensis on female fecundity, larval development rate, and larval mortality and may impact its initial competitive advantage over Aedes triseriatus during invasion. Methods We examine the effects of parasitism of gregarine parasites on Aedes albopictus and triseriatus population dynamics and competition with a focus on when Aedes albopictus is new to an area. We build a compartmental model including competition between Aedes albopictus and triseriatus while under parasitism of the gregarine parasites. Using parameters based on the literature, we simulate the dynamics and analyze the equilibrium population proportion of the two species. We consider the presence of both parasites and potential dilution effects. Results We show that increased levels of parasitism in Aedes albopictus will decrease the initial competitive advantage of the species over Aedes triseriatus and increase the survivorship of Aedes triseriatus. We find Aedes albopictus is better able to invade when there is more extreme parasitism of Aedes triseriatus. Furthermore, although the transient dynamics differ, dilution of the parasite density through uptake by both species does not alter the equilibrium population sizes of either species. Conclusions Mosquito population dynamics are affected by many factors, such as abiotic factors (e.g. temperature and humidity) and competition between mosquito species. This is especially true when multiple mosquito species are vying to live in the same area. Knowledge of how population dynamics are affected by gregarine parasites among competing species can inform future mosquito control efforts and help prevent the spread of vector-borne disease.

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