How Can Viral Dynamics Models Inform Endpoint Measures in Clinical Trials of Therapies for Acute Viral Infections?

Acute viral infections pose many practical challenges for the accurate assessment of the impact of novel therapies on viral growth and decay. Using the example of influenza A, we illustrate how the measurement of infection-related quantities that determine the dynamics of viral load within the human host, can inform investigators on the course and severity of infection and the efficacy of a novel treatment. We estimated the values of key infection-related quantities that determine the course of natural infection from viral load data, using Markov Chain Monte Carlo methods. The data were placebo group viral load measurements collected during volunteer challenge studies, conducted by Roche, as part of the oseltamivir trials. We calculated the values of the quantities for each patient and the correlations between the quantities, symptom severity and body temperature. The greatest variation among individuals occurred in the viral load peak and area under the viral load curve. Total symptom severity correlated positively with the basic reproductive number. The most sensitive endpoint for therapeutic trials with the goal to cure patients is the duration of infection. We suggest laboratory experiments to obtain more precise estimates of virological quantities that can supplement clinical endpoint measurements

Fear of covid-19 for individuals and family members: Indications from the national cross-sectional study of the epicovid19 web-based survey

The study analyzed the association of the fear of contagion for oneself and for family members (FMs) during the first wave of the COVID-19 pandemic, with demographic and socioeconomic status (SES) and health factors. The study was performed within the EPICOVID19 web-based Italian survey, involving adults from April–June 2020. Out of 207,341 respondents, 95.9% completed the questionnaire (60% women with an average age of 47.3 vs. 48.9 years among men). The association between fear and demographic and SES characteristics, contacts with COVID-19 cases, nasopharyngeal swab, self-perceived health, flu vaccination, chronic diseases and specific symptoms was analyzed by logistic regression model; odds ratios adjusted for sex, age, education and occupation were calculated (aORs). Fear for FMs prevailed over fear for oneself and was higher among women than men. Fear for oneself decreased with higher levels of education and in those who perceived good health. Among those vaccinated for the flu, 40.8% responded they had feelings of fear for themselves vs. 34.2% of the not vaccinated. Fear increased when diseases were declared and it was higher when associated with symptoms such as chest pain, olfactory/taste disorders, heart palpitations (aORs > 1.5), lung or kidney diseases, hypertension, depression and/or anxiety. Trends in fear by region showed the highest percentage of positive responses in the southern regions. The knowledge gained from these results should be used to produce tailored messages and shared public health decisions

Random Planar Lattices and Integrated SuperBrownian Excursion

In this paper, a surprising connection is described between a specific brand of random lattices, namely planar quadrangulations, and Aldous' Integrated SuperBrownian Excursion (ISE). As a consequence, the radius r_n of a random quadrangulation with n faces is shown to converge, up to scaling, to the width r=R-L of the support of the one-dimensional ISE. More generally the distribution of distances to a random vertex in a random quadrangulation is described in its scaled limit by the random measure ISE shifted to set the minimum of its support in zero. The first combinatorial ingredient is an encoding of quadrangulations by trees embedded in the positive half-line, reminiscent of Cori and Vauquelin's well labelled trees. The second step relates these trees to embedded (discrete) trees in the sense of Aldous, via the conjugation of tree principle, an analogue for trees of Vervaat's construction of the Brownian excursion from the bridge. From probability theory, we need a new result of independent interest: the weak convergence of the encoding of a random embedded plane tree by two contour walks to the Brownian snake description of ISE. Our results suggest the existence of a Continuum Random Map describing in term of ISE the scaled limit of the dynamical triangulations considered in two-dimensional pure quantum gravity.Comment: 44 pages, 22 figures. Slides and extended abstract version are available at http://www.loria.fr/~schaeffe/Pub/Diameter/ and http://www.iecn.u-nancy.fr/~chassain

New morphological and molecular evidence confirm the presence of the Norwegian skate Dipturus nidarosiensis (Storm, 1881) in the Mediterranean Sea and extend its distribution to the western basin

The present study confirms the presence of the Norwegian skate Dipturus nidarosiensis (Storm, 1881) in the Mediterranean Sea, by means of morphological traits and molecular markers providing the first record of this species in the Alboran Sea. Cannas et al. (2010) reported D. nidarosiensis for the first time in the Mediterranean from specimens captured in the central western basin, but Ebert & Stehmann (2013) and Stehmann et al. (2015) considered these records "likely refer to the smaller morphotype, Dipturus sp.", a species not yet described. Eight specimens of the Dipturus genus (Rajiformes: Rajidae) were caught off the Alboran Island (western Mediterranean) in 2012, 2013 and 2016, between 620 and 819 m depth. These specimens showed morphometric diagnostic features corresponding to those of Norwegian skates from the Northeast Atlantic and the central western Mediterranean Sea. Moreover, the Alboran individuals were genetically compared to Northeast Atlantic specimens available in GenBank by means of two mitochondrial DNA fragments: cytochrome c oxidase subunit I (COI) and cytochrome b (Cytb). Analyses showed that the Northeast Atlantic Norwegian skate specimens and the Alboran Sea ones were genetically similar and shared haplotypes, corroborating the identification of the Alboran individuals as Dipturus nidarosiensis. However, they were different from other Dipturus species distributed throughout the Northeast Atlantic and the Mediterranean Sea. Our results confirm the occurrence of this deep-sea large skate species in the Mediterranean, although the IUCN Red List of Threatened Species does not consider it possible (Stehmann et al., 2015)Versión del edito

Severe Aortic Stenosis and Myocardial Function: Diagnostic and Prognostic Usefulness of Ultrasonic Integrated Backscatter Analysis

Background— The aim of this study was to assess the myocardial reflectivity pattern in severe aortic valve stenosis through the use of integrated backscatter (IBS) analysis. Patients with aortic stenosis (AS) were carefully selected in the Department of Cardiology. Methods and Results— Thirty-five subjects (AS: valve orifice ≤1 cm2; 12 female; mean age, 71.8±6.2 years) and 25 healthy subjects were studied. All subjects of the study had conventional 2D-Doppler echocardiography and IBS. Backscatter signal was sampled at the septum and posterior wall levels. Patients with AS were divided into 2 groups: 16 patients with initial signs of congestive heart failure and a depressed left ventricular systolic function (DSF) (ejection fraction [EF] range, 35% to 50%) and 19 asymptomatic patients with normal left ventricular systolic function (NSF) (EF >50%). Myocardial echo intensity (pericardium related) was significantly higher at the septum and posterior wall levels in DSF than in NSF and in control subjects. IBS variation, as an expression of variation of the signal, appeared to be significantly lower in AS with DSF than in NSF and in control subjects, at both the septum and posterior wall levels. Patients with DSF underwent aortic valve replacement, and, during surgical intervention, a septal myocardial biopsy was made for evaluation of myocardium/fibrosis ratio. Abnormally increased echo intensity was detected in left ventricular pressure overload by severe aortic stenosis and correlated with increase of myocardial collagen content (operating biopsy). Conclusions— One year after aortic valve replacement, we observed a significant reduction of left ventricular mass, and, only if pericardial indexed IBS value (reduction of interstitial fibrosis) decreased, it was possible to observe an improvement of EF and of IBS variation

Genetic evidence for the association between COVID-19 epidemic severity and timing of non-pharmaceutical interventions

Unprecedented public health interventions including travel restrictions and national lockdowns have been implemented to stem the COVID-19 epidemic, but the effectiveness of non- pharmaceutical interventions is still debated. We carried out a phylogenetic analysis of more than 29,000 publicly available whole genome SARS-CoV-2 sequences from 57 locations to estimate the time that the epidemic originated in different places. These estimates were examined in relation to the dates of the most stringent interventions in each location as well as to the number of cumulative COVID-19 deaths and phylodynamic estimates of epidemic size. Here we report that the time elapsed between epidemic origin and maximum intervention is associated with different measures of epidemic severity and explains 11% of the variance in reported deaths one month after the most stringent intervention. Locations where strong non-pharmaceutical interventions were implemented earlier experienced 30 much less severe COVID-19 morbidity and mortality during the period of study

Assessment of epidemic projections using recent HIV survey data in South Africa: a validation analysis of ten mathematical models of HIV epidemiology in the antiretroviral therapy era

Background Mathematical models are widely used to simulate the eff ects of interventions to control HIV and to project future epidemiological trends and resource needs. We aimed to validate past model projections against data from a large household survey done in South Africa in 2012. Methods We compared ten model projections of HIV prevalence, HIV incidence, and antiretroviral therapy (ART) coverage for South Africa with estimates from national household survey data from 2012. Model projections for 2012 were made before the publication of the 2012 household survey. We compared adult (age 15–49 years) HIV prevalence in 2012, the change in prevalence between 2008 and 2012, and prevalence, incidence, and ART coverage by sex and by age groups between model projections and the 2012 household survey. Findings All models projected lower prevalence estimates for 2012 than the survey estimate (18·8%), with eight models’ central projections being below the survey 95% CI (17·5–20·3). Eight models projected that HIV prevalence would remain unchanged (n=5) or decline (n=3) between 2008 and 2012, whereas prevalence estimates from the household surveys increased from 16·9% in 2008 to 18·8% in 2012 (diff erence 1·9, 95% CI –0·1 to 3·9). Model projections accurately predicted the 1·6 percentage point prevalence decline (95% CI –0·3 to 3·5) in young adults aged 15–24 years, and the 2·2 percentage point (0·5 to 3·9) increase in those aged 50 years and older. Models accurately represented the number of adults on ART in 2012; six of ten models were within the survey 95% CI of 1·54–2·12 million. However, the diff erential ART coverage between women and men was not fully captured; all model projections of the sex ratio of women to men on ART were lower than the survey estimate of 2·22 (95% CI 1·73–2·71). Interpretation Projections for overall declines in HIV epidemics during the ART era might have been optimistic. Future treatment and HIV prevention needs might be greater than previously forecasted. Additional data about service provision for HIV care could help inform more accurate projections