Trade-off between local transmission and long-range dispersal drives infectious disease outbreak size in spatially structured populations

by Elisa Benincà, Thomas Hagenaars, Gert Jan Boender, Jan van de Kassteele, Michiel van Boven

Transmission of infectious diseases between immobile hosts (e.g., plants, farms) is strongly dependent on the spatial distribution of hosts and the distance-dependent probability of transmission. As the interplay between these factors is poorly understood, we use spatial process and transmission modelling to investigate how epidemic size is shaped by host clustering and spatial range of transmission. We find that for a given degree of clustering and individual-level infectivity, the probability that an epidemic occurs after an introduction is generally higher if transmission is predominantly local. However, local transmission also impedes transfer of the infection to new clusters. A consequence is that the total number of infections is maximal if the range of transmission is intermediate. In highly clustered populations, the infection dynamics is strongly determined by the probability of transmission between clusters of hosts, whereby local clusters act as multiplier of infection. We show that in such populations, a metapopulation model sometimes provides a good approximation of the total epidemic size, using probabilities of local extinction, the final size of infections in local clusters, and probabilities of cluster-to-cluster transmission. As a real-world example we analyse the case of avian influenza transmission between poultry farms in the Netherlands.

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Winter is coming: Pathogen emergence in seasonal environments

by Philippe Carmona, Sylvain Gandon

Many infectious diseases exhibit seasonal dynamics driven by periodic fluctuations of the environment. Predicting the risk of pathogen emergence at different points in time is key for the development of effective public health strategies. Here we study the impact of seasonality on the probability of emergence of directly transmitted pathogens under different epidemiological scenarios. We show that when the period of the fluctuation is large relative to the duration of the infection, the probability of emergence varies dramatically with the time at which the pathogen is introduced in the host population. In particular, we identify a new effect of seasonality (the winter is coming effect) where the probability of emergence is vanishingly small even though pathogen transmission is high. We use this theoretical framework to compare the impact of different preventive control strategies on the average probability of emergence. We show that, when pathogen eradication is not attainable, the optimal strategy is to act intensively in a narrow time interval. Interestingly, the optimal control strategy is not always the strategy minimizing R0, the basic reproduction ratio of the pathogen. This theoretical framework is extended to study the probability of emergence of vector borne diseases in seasonal environments and we show how it can be used to improve risk maps of Zika virus emergence.

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Associations of substance use, psychosis, and mortality among people living in precarious housing or homelessness: A longitudinal, community-based study in Vancouver, Canada

by Andrea A. Jones, Kristina M. Gicas, Sam Seyedin, Taylor S. Willi, Olga Leonova, Fidel Vila-Rodriguez, Ric M. Procyshyn, Geoffrey N. Smith, Toby A. Schmitt, A. Talia Vertinsky, Tari Buchanan, Alex Rauscher, Donna J. Lang, G. William MacEwan, Viviane D. Lima, Julio S. G. Montaner, William J. Panenka, Alasdair M. Barr, Allen E. Thornton, William G. Honer

Background

The “trimorbidity” of substance use disorder and mental and physical illness is associated with living in precarious housing or homelessness. The extent to which substance use increases risk of psychosis and both contribute to mortality needs investigation in longitudinal studies.

Methods and findings

A community-based sample of 437 adults (330 men, mean [SD] age 40.6 [11.2] years) living in Vancouver, Canada, completed baseline assessments between November 2008 and October 2015. Follow-up was monthly for a median 6.3 years (interquartile range 3.1–8.6). Use of tobacco, alcohol, cannabis, cocaine, methamphetamine, and opioids was assessed by interview and urine drug screen; severity of psychosis was also assessed. Mortality (up to November 15, 2018) was assessed from coroner’s reports and hospital records. Using data from monthly visits (mean 9.8, SD 3.6) over the first year after study entry, mixed-effects logistic regression analysis examined relationships between risk factors and psychotic features. A past history of psychotic disorder was common (60.9%). Nonprescribed substance use included tobacco (89.0%), alcohol (77.5%), cocaine (73.2%), cannabis (72.8%), opioids (51.0%), and methamphetamine (46.5%). During the same year, 79.3% of participants reported psychotic features at least once. Greater risk was associated with number of days using methamphetamine (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.05–1.24, p = 0.001), alcohol (aOR 1.09, 95% CI 1.01–1.18, p = 0.04), and cannabis (aOR 1.08, 95% CI 1.02–1.14, p = 0.008), adjusted for demographic factors and history of past psychotic disorder. Greater exposure to concurrent month trauma was associated with increased odds of psychosis (adjusted model aOR 1.54, 95% CI 1.19–2.00, p = 0.001). There was no evidence for interactions or reverse associations between psychotic features and time-varying risk factors. During 2,481 total person years of observation, 79 participants died (18.1%). Causes of death were physical illness (40.5%), accidental overdose (35.4%), trauma (5.1%), suicide (1.3%), and unknown (17.7%). A multivariable Cox proportional hazard model indicated baseline alcohol dependence (adjusted hazard ratio [aHR] 1.83, 95% CI 1.09–3.07, p = 0.02), and evidence of hepatic fibrosis (aHR 1.81, 95% CI 1.08–3.03, p = 0.02) were risk factors for mortality. Among those under age 55 years, a history of a psychotic disorder was a risk factor for mortality (aHR 2.38, 95% CI 1.03–5.51, p = 0.04, adjusted for alcohol dependence at baseline, human immunodeficiency virus [HIV], and hepatic fibrosis). The primary study limitation concerns generalizability: conclusions from a community-based, diagnostically heterogeneous sample may not apply to specific diagnostic groups in a clinical setting. Because one-third of participants grew up in foster care or were adopted, useful family history information was not obtainable.

Conclusions

In this study, we found methamphetamine, alcohol, and cannabis use were associated with higher risk for psychotic features, as were a past history of psychotic disorder, and experiencing traumatic events. We found that alcohol dependence, hepatic fibrosis, and, only among participants

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Healthy behaviors at age 50 years and frailty at older ages in a 20-year follow-up of the UK Whitehall II cohort: A longitudinal study

by Andres Gil-Salcedo, Aline Dugravot, Aurore Fayosse, Julien Dumurgier, Kim Bouillon, Alexis Schnitzler, Mika Kivimäki, Archana Singh-Manoux, Séverine Sabia

Background

Frailty is associated with increased risk of various health conditions, disability, and death. Health behaviors are thought to be a potential target for frailty prevention, but the evidence from previous studies is based on older populations with short follow-ups, making results susceptible to reverse causation bias. We examined the associations of healthy behaviors at age 50, singly and in combination, as well as 10-year change in the number of healthy behaviors over midlife with future risk of frailty.

Methods and findings

In this prospective cohort study of 6,357 (29.2% women; 91.7% white) participants from the British Whitehall II cohort, healthy behaviors—nonsmoking, moderate alcohol consumption, ≥2.5 hours per week of moderate to vigorous physical activity, and consumption of fruits or vegetables at least twice a day—were measured at age 50, and change in behaviors was measured between 1985 (mean age = 44.4) and 1997 (mean age = 54.8). Fried’s frailty phenotype was assessed in clinical examinations in 2002, 2007, 2012, and 2015. Participants were classified as frail if they had ≥3 of the following criteria: slow walking speed, low grip strength, weight loss, exhaustion, and low physical activity. An illness–death model accounting for both competing risk of death and interval censoring was used to examine the association between healthy behaviors and risk of frailty. Over an average follow-up of 20.4 years (standard deviation, 5.9), 445 participants developed frailty. Each healthy behavior at age 50 was associated with lower risk of incident frailty: hazard ratio (HR) after adjustment for other health behaviors and baseline characteristics 0.56 (95% confidence interval [CI] 0.44–0.71; p p p 0.001) for ≥2.5 hours of physical activity per week, and 0.76 (95% CI 0.59–0.98; p = 0.03) for consumption of fruits or vegetables at least twice a day. A greater number of healthy behaviors was associated with reduced risk of frailty, with the HR for each additional healthy behavior being 0.69 (95% CI 0.62–0.76; p 0.001) and the HR for having all versus no healthy behaviors at age 50 being 0.28 (95% CI 0.15–0.52; p 0.001). Among participants with no or 1 healthy behavior in 1985, those who increased the number of healthy behaviors by 1997 were at a lower risk of frailty (mean follow-up = 16 years) compared with those with no such increase: the HR was 0.64 (95% CI 0.44–0.94; p = 0.02) for change to 2 healthy behaviors and 0.57 (95% CI 0.38–0.87; p 0.001) for change to 3–4 healthy behaviors in 1997. The primary limitation of this study is potential selection bias during the follow-up due to missing data on frailty components.

Conclusions

Our findings suggest that healthy behaviors at age 50, as well as improvements in behaviors over midlife, are associated with a lower risk of frailty later in life. Their benefit accumulates so that risk of frailty decreases with greater number of healthy behaviors. These results suggest that healthy behaviors in midlife are a good target for frailty prevention.

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Campylobacter jejuni motility integrates specialized cell shape, flagellar filament, and motor, to coordinate action of its opposed flagella

by Eli J. Cohen, Daisuke Nakane, Yoshiki Kabata, David R. Hendrixson, Takayuki Nishizaka, Morgan Beeby

Campylobacter jejuni rotates a flagellum at each pole to swim through the viscous mucosa of its hosts’ gastrointestinal tracts. Despite their importance for host colonization, however, how C. jejuni coordinates rotation of these two opposing flagella is unclear. As well as their polar placement, C. jejuni’s flagella deviate from the norm of Enterobacteriaceae in other ways: their flagellar motors produce much higher torque and their flagellar filament is made of two different zones of two different flagellins. To understand how C. jejuni’s opposed motors coordinate, and what contribution these factors play in C. jejuni motility, we developed strains with flagella that could be fluorescently labeled, and observed them by high-speed video microscopy. We found that C. jejuni coordinates its dual flagella by wrapping the leading filament around the cell body during swimming in high-viscosity media and that its differentiated flagellar filament and helical body have evolved to facilitate this wrapped-mode swimming.

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Dynamic rotation of the protruding domain enhances the infectivity of norovirus

by Chihong Song, Reiko Takai-Todaka, Motohiro Miki, Kei Haga, Akira Fujimoto, Ryoka Ishiyama, Kazuki Oikawa, Masaru Yokoyama, Naoyuki Miyazaki, Kenji Iwasaki, Kosuke Murakami, Kazuhiko Katayama, Kazuyoshi Murata

Norovirus is the major cause of epidemic nonbacterial gastroenteritis worldwide. Lack of structural information on infection and replication mechanisms hampers the development of effective vaccines and remedies. Here, using cryo-electron microscopy, we show that the capsid structure of murine noroviruses changes in response to aqueous conditions. By twisting the flexible hinge connecting two domains, the protruding (P) domain reversibly rises off the shell (S) domain in solutions of higher pH, but rests on the S domain in solutions of lower pH. Metal ions help to stabilize the resting conformation in this process. Furthermore, in the resting conformation, the cellular receptor CD300lf is readily accessible, and thus infection efficiency is significantly enhanced. Two similar P domain conformations were also found simultaneously in the human norovirus GII.3 capsid, although the mechanism of the conformational change is not yet clear. These results provide new insights into the mechanisms of non-enveloped norovirus transmission that invades host cells, replicates, and sometimes escapes the hosts immune system, through dramatic environmental changes in the gastrointestinal tract.

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Repression of tick microRNA-133 induces organic anion transporting polypeptide expression critical for Anaplasma phagocytophilum survival in the vector and transmission to the vertebrate host

by Ellango Ramasamy, Vikas Taank, John F Anderson, Hameeda Sultana, Girish Neelakanta

The microRNAs (miRNAs) are important regulators of gene expression. In this study, we provide evidence for the first time to show that rickettsial pathogen Anaplasma phagocytophilum infection results in the down-regulation of tick microRNA-133 (miR-133), to induce Ixodes scapularis organic anion transporting polypeptide (isoatp4056) gene expression critical for this bacterial survival in the vector and for its transmission to the vertebrate host. Transfection studies with recombinant constructs containing transcriptional fusions confirmed binding of miR-133 to isoatp4056 mRNA. Treatment with miR-133 inhibitor resulted in increased bacterial burden and isoatp4056 expression in ticks and tick cells. In contrast, treatment with miR-133 mimic or pre-mir-133 resulted in dramatic reduction in isoatp4056 expression and bacterial burden in ticks and tick cells. Moreover, treatment of ticks with pre-mir-133 affected vector-mediated A. phagocytophilum infection of murine host. These results provide novel insights to understand impact of modulation of tick miRNAs on pathogen colonization in the vector and their transmission to infect the vertebrate host.

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Brassinosteroids regulate root meristem development by mediating BIN2-UPB1 module in Arabidopsis

by Taotao Li, Wei Lei, Ruiyuan He, Xiaoya Tang, Jifu Han, Lijuan Zou, Yanhai Yin, Honghui Lin, Dawei Zhang

Plant steroid hormones brassinosteroids (BRs) regulate plant growth and development at many levels. While negative regulatory factors that inhibit development and are counteracted by BRs exist in the root meristem, these factors have not been characterized. The functions of UPB1 transcription factor in BR-regulated root growth have not been established, although its role in regulating root are well documented. Here, we found that BIN2 interacts with and phosphorylates the UPB1 transcription factor consequently promoting UPB1 stability and transcriptional activity. Genetic analysis revealed that UPB1 deficiency could partially recover the short-root phenotype of BR-deficient mutants. Expression of a mutated UPB1S37AS41A protein lacking a conserved BIN2 phosphorylation sites can rescue shorter root phenotype of bin2-1 mutant. In addition, UPB1 was repressed by BES1 at the transcriptional level. The paclobutrazol-resistant protein family (PRE2/3) interacts with UPB1 and inhibits its transcriptional activity to promote root meristem development, and BIN2-mediated phosphorylation of UPB1 suppresses its interaction with PRE2/3, and subsequently impairing root meristem development. Taken together, our data elucidate a molecular mechanism by which BR promotes root growth via inhibiting BIN2-UPB1 module.

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