The pitfalls of inferring virus-virus interactions from co-detection prevalence data: application to influenza and SARS-CoV-2

There is growing experimental evidence that many respiratory viruses—including influenza and SARS-CoV-2—can interact, such that their epidemiological dynamics may not be independent. To assess these interactions, standard statistical tests of independence suggest that the prevalence ratio—defined as the ratio of co-infection prevalence to the product of single-infection prevalences—should equal unity for non-interacting pathogens. As a result, earlier epidemiological studies aimed to estimate the prevalence ratio from co-detection prevalence data, under the assumption that deviations from unity implied interaction. To examine the validity of this assumption, we designed a simulation study that built on a broadly applicable epidemiological model of co-circulation of two emerging or seasonal respiratory viruses. By focusing on the pair influenza–SARS-CoV-2, we first demonstrate that the prevalence ratio systematically underestimates the strength of interaction, and can even misclassify antagonistic or synergistic interactions that persist after clearance of infection. In a global sensitivity analysis, we further identify properties of viral infection—such as a high reproduction number or a short infectious period—that blur the interaction inferred from the prevalence ratio. Altogether, our results suggest that ecological or epidemiological studies based on co-detection prevalence data provide a poor guide to assess interactions among respiratory viruses

Estimating the impact of influenza on the epidemiological dynamics of SARS-CoV-2

As in past pandemics, co-circulating pathogens may play a role in the epidemiology of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In particular, experimental evidence indicates that influenza infection can up-regulate the expression of ACE2—the receptor of SARS-CoV-2 in human cells—and facilitate SARS-CoV-2 infection. Here we hypothesized that influenza impacted the epidemiology of SARS-CoV-2 during the early 2020 epidemic of COVID-19 in Europe. To test this hypothesis, we developed a population-based model of SARS-CoV-2 transmission and of COVID-19 mortality, which simultaneously incorporated the impact of non-pharmaceutical control measures and of influenza on the epidemiological dynamics of SARS-CoV-2. Using statistical inference methods based on iterated filtering, we confronted this model with mortality incidence data in four European countries (Belgium, Italy, Norway, and Spain) to systematically test a range of assumptions about the impact of influenza. We found consistent evidence for a 1.8–3.4-fold (uncertainty range across countries: 1.1 to 5.0) average population-level increase in SARS-CoV-2 transmission associated with influenza during the period of co-circulation. These estimates remained robust to a variety of alternative assumptions regarding the epidemiological traits of SARS-CoV-2 and the modeled impact of control measures. Although further confirmatory evidence is required, our results suggest that influenza could facilitate the spread and hamper effective control of SARS-CoV-2. More generally, they highlight the possible role of co-circulating pathogens in the epidemiology of COVID-19

Deletion of the Zinc Transporter Lipoprotein AdcAII Causes Hyperencapsulation of Streptococcus pneumoniae Associated with Distinct Alleles of the Type I Restriction-Modification System.

The capsule is the dominant Streptococcus pneumoniae virulence factor, yet how variation in capsule thickness is regulated is poorly understood. Here, we describe an unexpected relationship between mutation of adcAII, which encodes a zinc uptake lipoprotein, and capsule thickness. Partial deletion of adcAII in three of five capsular serotypes frequently resulted in a mucoid phenotype that biochemical analysis and electron microscopy of the D39 adcAII mutants confirmed was caused by markedly increased capsule thickness. Compared to D39, the hyperencapsulated ΔadcAII mutant strain was more resistant to complement-mediated neutrophil killing and was hypervirulent in mouse models of invasive infection. Transcriptome analysis of D39 and the ΔadcAII mutant identified major differences in transcription of the Sp_0505-0508 locus, which encodes an SpnD39III (ST5556II) type I restriction-modification system and allelic variation of which correlates with capsule thickness. A PCR assay demonstrated close linkage of the SpnD39IIIC and F alleles with the hyperencapsulated ΔadcAII strains. However, transformation of ΔadcAII with fixed SpnD39III alleles associated with normal capsule thickness did not revert the hyperencapsulated phenotype. Half of hyperencapsulated ΔadcAII strains contained the same single nucleotide polymorphism in the capsule locus gene cps2E, which is required for the initiation of capsule synthesis. These results provide further evidence for the importance of the SpnD39III (ST5556II) type I restriction-modification system for modulating capsule thickness and identified an unexpected linkage between capsule thickness and mutation of ΔadcAII Further investigation will be needed to characterize how mutation of adcAII affects SpnD39III (ST5556II) allele dominance and results in the hyperencapsulated phenotype.IMPORTANCE The Streptococcus pneumoniae capsule affects multiple interactions with the host including contributing to colonization and immune evasion. During infection, the capsule thickness varies, but the mechanisms regulating this are poorly understood. We have identified an unsuspected relationship between mutation of adcAII, a gene that encodes a zinc uptake lipoprotein, and capsule thickness. Mutation of adcAII resulted in a striking hyperencapsulated phenotype, increased resistance to complement-mediated neutrophil killing, and increased S. pneumoniae virulence in mouse models of infection. Transcriptome and PCR analysis linked the hyperencapsulated phenotype of the ΔadcAII strain to specific alleles of the SpnD39III (ST5556II) type I restriction-modification system, a system which has previously been shown to affect capsule thickness. Our data provide further evidence for the importance of the SpnD39III (ST5556II) type I restriction-modification system for modulating capsule thickness and identify an unexpected link between capsule thickness and ΔadcAII, further investigation of which could further characterize mechanisms of capsule regulation

Seasonality of urinary tract infections in the United Kingdom in different age groups: longitudinal analysis of The Health Improvement Network (THIN)

Evidence regarding the seasonality of urinary tract infection (UTI) consultations in primary care is conflicting and methodologically poor. To our knowledge, this is the first study to determine whether this seasonality exists in the UK, identify the peak months and describe seasonality by age. The monthly number of UTI consultations (N = 992 803) and nitrofurantoin and trimethoprim prescriptions (N = 1 719 416) during 2008-2015 was extracted from The Health Improvement Network (THIN), a large nationally representative UK dataset of electronic patient records. Negative binomial regression models were fitted to these data to investigate seasonal fluctuations by age group (14-17, 18-24, 25-45, 46-69, 70-84, 85+) and by sex, accounting for a change in the rate of UTI over the study period. A September to November peak in UTI consultation incidence was observed for ages 14-69. This seasonality progressively faded in older age groups and no seasonality was found in individuals aged 85+, in whom UTIs were most common. UTIs were rare in males but followed a similar seasonal pattern than in females. We show strong evidence of an autumnal seasonality for UTIs in individuals under 70 years of age and a lack of seasonality in the very old. These findings should provide helpful information when interpreting surveillance reports and the results of interventions against UTI

Georges Scott (1873-1943). Itinéraire du dernier peintre militaire français

Born in Paris in 1873, Georges Scott began his career as an illustrator at the age of 18 in collaboration with L'Illustration for almost fifty years. Nevertheless, the notoriety of this patriotic artist resulted above all at the time from his artistic commitment to the French Army: with his sketches, drawings, watercolours, oils on canvas in small and large format, he occupied for more than forty years the at the forefront of "military painting". But his circle of influence is not limited to the military sphere since he obtains to carry out official portraits of heads of state or great figures living in Europe in the first third of the 20th century. Feeling that he no longer understood the world in which he lived, Georges Scott died in 1943 in the greatest isolation. If the artist bequeaths an abundant work to posterity, the place he occupies today in the reference dictionaries or in the works of art history remains anecdotal, even non-existent. This research is not only part of a monographic perspective, but it attempts to demonstrate the mechanics of the artist's rise to fame in a complex political, international and social context, from the 1914-1918 war to the defeat of 1940, period of the golden age for the artist. If the military sphere is of particular interest in the immediate environment of the artist, the political and diplomatic world also remains a field of investigation to be privileged. The singular commissions that Scott receives from the heads of state of foreign powers during his career suggest that he enjoys political support and a powerful international network allowing him access to this world. By studying in detail the life and work of Georges Scott, we will make up for the lack of an academic monograph on the painter and we will answer the premonitory question and the hypothesis that Georges Scott is undoubtedly the last military painter. FrenchNé à Paris en 1873, Georges Scott débute à l'âge de 18 ans une carrière d'illustrateur en collaboration avec L'Illustration durant près de cinquante ans. Néanmoins, la notoriété de cet artiste patriote résulte avant tout à l'époque de son engagement artistique envers l'Armée française : avec ses croquis, dessins, aquarelles, huiles sur toile de petit et grand format, il occupe pendant plus de quarante ans le devant de la scène de la « peinture militaire ». Mais son cercle d'influence ne se résume pas à la sphère militaire puisqu'il obtient de réaliser des portraits officiels de chefs d'État ou de grands personnages vivant dans l'Europe du premier tiers du XXe siècle. Ayant le sentiment de ne plus comprendre le monde dans lequel il vit, Georges Scott s'éteint en 1943 dans le plus grand isolement. Si l'artiste lègue une œuvre abondante à la postérité, la place qu'il occupe aujourd'hui dans les dictionnaires de référence ou dans les ouvrages d'histoire de l'art reste anecdotique, voire inexistante. Cette recherche ne s'inscrit pas seulement dans une perspective monographique, mais elle tente de démontrer la mécanique ascensionnelle de la célébrité de l'artiste dans un contexte politique, international et social complexe, de la guerre 1914-1918 à la défaite de 1940, période de l'âge d'or pour l'artiste.Si la sphère militaire revêt un intérêt tout particulier dans l'environnement immédiat de l'artiste, le monde politique et diplomatique reste également un champ d'investigation à privilégier. Les commandes singulières que reçoit Scott de la part des chefs d'État des puissances étrangères au cours de sa carrière laissent à penser qu'il bénéficie de soutien politique et d'un puissant réseau international lui permettant d'accéder à ce monde. En étudiant dans le détail la vie et l'œuvre de Georges Scott, nous comblerons l'absence d'une monographie universitaire sur le peintre et nous répondrons à la question prémonitoire et l'hypothèse selon laquelle Georges Scott est sans doute le dernier peintre militaire français