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bioRxiv2017

Ceasing the use of the highest priority critically important antimicrobials does not adversely affect production, health or welfare parameters in dairy cows

Due to scientific, public and political concern regarding antimicrobial resistance (AMR), several EU countries have already taken steps to reduce antimicrobial (AM) usage in production animal medicine, particularly that of the highest priority critically important AMs (HP-CIAs). While veterinarians are aware of issues surrounding AMR, barriers to change such as concerns of reduced animal health, welfare or production may inhibit AM prescribing changes.\n\nFarmers from seven dairy farms in South West England engaged in changing AM use through an active process of education and herd health planning meetings. Prescribing data was collected from veterinary sales records; production and health data were accessed via milk recording and farm-recorded data.\n\nThis study demonstrates that cattle health and welfare - as measured by production parameters, fertility, udder health, mobility data and culling rates - can be maintained and even improved alongside a complete cessation in the use of HP-CIAs as well as an overall reduction of AM use on dairy farms.\n\nThis study also identified a need to consider different metrics when analysing AM use data, including dose-based metrics as well as those of total quantities to allow better representation of the direction and magnitude of changes in AM use.

epidemiology↗

bioRxiv2017

Preliminary results of models to predict areas in the Americas with increased likelihood of Zika virus transmission in 2017.

Numerous Zika virus vaccines are being developed. However, identifying sites to evaluate the efficacy of a Zika virus vaccine is challenging due to the general decrease in Zika virus activity. We compare results from three different modeling approaches to estimate areas that may have increased relative risk of Zika virus transmission during 2017. The analysis focused on eight priority countries (i.e., Brazil, Colombia, Costa Rica, Dominican Republic, Ecuador, Mexico, Panama, and Peru). The models projected low incidence rates during 2017 for all locations in the priority countries but identified several subnational areas that may have increased relative risk of Zika virus transmission in 2017. Given the projected low incidence of disease, the total number of participants, number of study sites, or duration of study follow-up may need to be increased to meet the efficacy study endpoints.

epidemiology↗

bioRxiv2017

Food environments and obesity: cannot see the fat for the restaurants?

We recently showed that across the mainland USA there is no association between the density of fast food and full service restaurants and the prevalence of obesity. In a recent editorial it was suggested there are 4 problems with our analysis. The suggested problems were the area of analysis may not reflect adequately the exposure to different outlets, using the absolute numbers of restaurants rather than their ratio, using a global model which assumes the same relationship across all sites and finally the potential for residual confounding. In this short note we address all four of these issues and provide some new analysis of the impact of the ratio of restaurant types on obesity prevalence showing there is only a very weak association (r2 = 0.006). We conclude that none of the supposed weaknesses in our original analysis are valid.

epidemiology↗

bioRxiv2017

The Microbiomes of Pancreatic Tissue in Pancreatic Cancer and Non-Cancer Subjects

ObjectiveTo determine whether bacteria are present in the pancreas of pancreatic cancer and non-cancer subjects and examine whether bacterial profiles vary by site and disease phenotype.\n\nDesign77 patients requiring surgery for pancreatic diseases, or diseases of the foregut, at the Rhode Island Hospital (RIH) were recruited into this study between 2014 and 2016. In addition, 36 whole pancreas were obtained from the National Disease Research Interchange (NDRI) from subjects who were of similar age as the RIH patients and had not died of cancer. The primary exposure of interest was the measurement of the relative abundance of bacterial taxa in all tissue specimens using 16S rRNA gene sequencing.\n\nResultsNumber of bacterial reads per sample varied substantially across sample type and patients, but all demonstrated the presence of diverse gastrointestinal bacteria, including bacterial taxa typically identified in the oral cavity. Bacterial profiles were noted to be more similar within individuals across sites in the pancreas, than between individuals by site, suggesting that the pancreas as a whole has its own microbiome. Comparing the mean relative abundance of bacterial taxa in pancreatic cancer patients to those without cancer revealed differences in bacterial taxa previously linked to periodontal disease, including Porphyromonas.\n\nConclusionsBacterial taxa known to inhabit the oral cavity, as well as the intestine, were identified in pancreatic tissue of cancer and non-cancer subjects. Whether any of these bacteria play a causal role in pancreatic carcinogenesis, or are simply opportunistic in nature, needs to be further examined.

epidemiology↗

bioRxiv2017

fingertipsR: an R package for accessing population health information in England

Fingertips is a major public repository of population and public health indicators for England, built and maintained by Public Health England (PHE). The indicators are arranged in thematic or topical profiles covering a wide range of health issues including:\n\nO_LIbroad Health Profiles\nC_LIO_LIspecific topics such as liver disease and end of life\nC_LIO_LIrisk factors including alcohol, smoking, physical activity\nC_LIO_LIpopulation healthcare health services data for general practices, cancer, mental health\nC_LIO_LIhealth protection data on general health protection, TB, antimicrobial resistance\nC_LIO_LIlifecourse profiles for younger and older people\nC_LIO_LImortality and morbidity.\nC_LI\n\nFingertips makes data available for more than 1,500 indicators spread across more than 70 profiles. The data can be accessed from https://fingertips.phe.org.uk where the data are visualised in variety of ways including heatmaps, choropleth maps, line charts for trends, \"spine\" charts (graphs which compare multiple indicators for a single geographic area), scatter plots and so on. Data can be obtained as downloads or figures which can be exported or cut and paste into reports and slides.\n\nA recent addition to the Fingertips platform was an Automated Programming Interface (API) to enable developers to re-use the data. To facilitate access to Fingertips data we have designed an R package - fingertipsR - enabling rapid and easy access to the data by analysts and data scientists. The package is available from the Comprehensive R Archive Network (CRAN).\n\nThis paper describes the fingertipsR package which provides tools accessing a wide range of public health data for England from the Fingertips website using its API.

epidemiology↗

bioRxiv2017

Sociodemographic patterning in the oral microbiome of a diverse sample of New Yorkers

11.1 PurposeVariations in the oral microbiome are potentially implicated in social inequalities in oral disease, cancers, and metabolic disease. We describe sociodemographic variation of oral microbiomes in a diverse sample.\n\n1.2 MethodsWe performed 16S rRNA sequencing on mouthwash specimens in a subsample (n=282) of the 2013-14 population-based New York City Health and Nutrition Examination Study (NYC-HANES). We examined differential abundance of 216 operational taxonomic units (OTUs), and alpha and beta diversity by age, sex, income, education, nativity, and race/ethnicity. For comparison, we also examined differential abundance by diet, smoking status, and oral health behaviors.\n\n1.3 Results69 OTUs were differentially abundant by any sociodemographic variable (false discovery rate < 0.01), including 27 by race/ethnicity, 21 by family income, 19 by education, three by sex. We also found 49 differentially abundant by smoking status, 23 by diet, 12 by oral health behaviors. Genera differing for multiple sociodemographic characteristics included Lactobacillus, Prevotella, Porphyromonas, Fusobacterium.\n\n1.4 ConclusionsWe identified oral microbiome variation consistent with health inequalities, with more taxa differing by race/ethnicity than diet, and more by SES variables than oral health behaviors. Investigation is warranted into possible mediating effects of the oral microbiome in social disparities in oral, metabolic and cancers.\n\nHighlightsO_LIMost microbiome studies to date have had minimal sociodemographic variability, limiting what is known about associations of social factors and the microbiome.\nC_LIO_LIWe examined the oral microbiome in a population-based sample of New Yorkers with wide sociodemographic variation.\nC_LIO_LINumerous taxa were differentially abundant by race/ethnicity, income, education, marital status, and nativity.\nC_LIO_LIFrequently differentially abundant taxa include Porphyromonas, Fusobacterium, Streptococcus, and Prevotella, which are associated with oral and systemic disease.\nC_LIO_LIMediation of health disparities by microbial factors may represent an important intervention site to reduce health disparities, and should be explored in prospective studies.\nC_LI

epidemiology↗

bioRxiv2017

Association of a biomarker-based frailty index with telomere length in older US adults: Findings from NHANES 1999-2002

ObjectivesTo study the link between frailty and cellular senescence, we examine the association of leukocyte telomere length (LTL) with a recently introduced measure of subclinical frailty that is based entirely on laboratory test biomarkers (FI-LAB).\n\nMethodsThis study was conducted on a random sample of 1890 Americans aged 60+. Multiple Linear Regression was used to examine the relationship between FI-LAB and LTL.\n\nResultsA statistically significant association was found between FI-LAB and LTL after adjusting for multiple covariates, indicating that higher FI-LAB scores are associated with shorter telomeres.\n\nDiscussionOur study results establish a link between subclinical frailty (FI-LAB) and cellular aging, which may help elucidate the pathophysiological mechanisms giving rise to frailty.

epidemiology↗

bioRxiv2017

Competing effects of indirect protection and clustering on the power of cluster-randomized controlled vaccine trials

Power considerations for trials evaluating vaccines against infectious diseases are complicated by indirect protective effects of vaccination. While cluster-randomized trials (cRCTs) are less statistically efficient than individually randomized trials (iRCT), a cRCTs ability to measure direct and indirect vaccine effects may mitigate the loss of efficiency due to clustering. Within cRCTs, the number and size of clusters affects three determinants of power: the effect size being measured, disease incidence, and intra-cluster correlation. We simulate trials conducted in a collection of small communities to assess how indirect protection and clustering affect the power of cRCTs and iRCTs during an emerging epidemic. Across diverse parameters, we find that within the same trial population, cRCTs are never more powerful than iRCTs, although the difference can be small. We also identify two effects that attenuate the loss of cRCT power traditionally associated with increased cluster size. First, if enrollment of fewer, larger clusters is performed to achieve higher vaccine coverage within vaccinated communities, this increases the effect to be measured and, consequently, power. Second, the greater rate of imported transmission in larger communities may increase the attack rate and similarly mitigate loss of power relative to a trial in many, smaller communities.

epidemiology↗

bioRxiv2017

Quantification of anti-parasite and anti-disease immunity to malaria as a function of age and exposure

Malaria immunity is complex and multi-faceted, and fundamental gaps remain in our understanding of how it develops. Here, we use detailed clinical and entomological data from three parallel cohort studies conducted across the malaria transmission spectrum in Uganda to quantify the development of immunity against symptomatic Plasmodium falciparum as a function of age and transmission intensity. We focus on: anti-parasite immunity (i.e; ability to control parasite densities) and anti-disease immunity (i.e; ability to tolerate higher parasite densities without fever). Our findings suggest a strong effect of age on both types of immunity, that remains significant after adjusting for cumulative exposure. They also show a non-linear effect of transmission intensity, where children experiencing the lowest transmission appear to develop immunity faster than those experiencing higher transmission. These findings illustrate how anti-parasite and anti-disease immunity develop in parallel, reducing the probability of experiencing symptomatic malaria upon each subsequent P. falciparum infection.

epidemiology↗

bioRxiv2017

Spillover effects of a combined water, sanitation, and handwashing intervention in rural Bangladesh: a randomized controlled trial

BackgroundWater, sanitation, and handwashing (WSH) interventions may confer indirect benefits (\"spillovers\") on neighbors of recipients by interrupting pathogen transmission. We measured geographically local spillovers in WASH Benefits, a cluster-randomized trial in rural Bangladesh, by comparing outcomes among neighbors of intervention vs. control participants.\n\nMethodsWASH Benefits had randomly allocated geographically-defined clusters to a compound-level intervention (chlorinated drinking water, upgraded sanitation, and handwashing promotion) or control and followed children for two years. We enrolled neighboring children age-matched to trial participants that would have been eligible for WASH Benefits had they been conceived slightly earlier or later. After 28 months of intervention, we quantified fecal indicator bacteria in toy rinse and drinking water samples, measured soil-transmitted helminth infections, and recorded caregiver-reported diarrhea and respiratory illness. Neither fieldworkers nor participants were masked. Analysis was intention-to-treat.\n\nResultsWe enrolled neighbors of WASH Benefits participants in 90 control (N=900) and 90 intervention clusters (N=899). Neighbors characteristics were balanced across arms. The prevalence of any detectable E. coli in tubewell samples was lower for neighbors of intervention vs. control (prevalence ratio=0.83; 0.73, 0.95). There was no difference in E. coli and coliform prevalence between arms for other environmental samples. Disease prevalence was similar in neighbors of intervention vs. control participants: Ascaris (prevalence difference [PD]=0.00; -0.07, 0.08), hookworm (PD=0.01; -0.01, 0.04), Trichuris (PD=0.02; -0.02, 0.05), diarrhea (PD=0.00; -0.02,0.03), respiratory illness (PD=-0.01; -0.04, 0.03).\n\nConclusionsWe found spillover effects of a compound-level combined WSH intervention for tubewell water contamination but not for child health outcomes.\n\nKey MessagesO_LIWater, sanitation, and handwashing (WSH) interventions may confer indirect benefits (\"spillovers\") on neighbors of recipients by interrupting pathogen transmission, reducing environmental contamination, or spurring the adoption of health behaviors.\nC_LIO_LIWe conducted a randomized trial in rural Bangladesh to measure whether neighbors of a compound-level WSH intervention improved hygiene behaviors and had lower prevalence environmental contamination, soil-transmitted helminth infection, diarrhea, and respiratory illness among children under 5 years after two years of intervention.\nC_LIO_LIWe did not find evidence of intervention adoption or improved hygiene behavior among neighbors of a WSH intervention delivered for 2 years.\nC_LIO_LIThe WSH intervention reduced fecal contamination of neighbors tubewell water but did not lead to spillovers for other proximal measures of contamination in the domestic environment or for child health outcomes. For proximal spillover effects to translate to distal spillover effects, improvements in neighbors health behaviors may have been necessary.\nC_LI

epidemiology↗

bioRxiv2017

The Asian tiger mosquito, Aedes albopictus (Skuse, 1894), a vector of dengue, chikungunya and zika, reaches Portugal

The mosquito Aedes albopictus is here reported for the first time in Portugal, from the south of the country, at least 240km west of the nearest known observation in Spain. A population of more than fifty specimens was spotted within a suburban garden over seven days of survey. As an important vector of Human affecting zoonoses such as dengue, chikungunya and yellow-fever, the presence of this mosquito in Portugal now enhances the outbreak chances for such diseases.

epidemiology↗

bioRxiv2017

Quantifying Seasonal and Diel Variation in Anopheline and Culex Human Biting Rates in Southern Ecuador

BackgroundQuantifying mosquito biting rates for specific locations enables estimation of mosquito-borne disease risk, and can inform intervention efforts. Measuring biting itself is fraught with ethical concerns, so the landing rate of mosquitoes on humans is often used as a proxy measure. Southern coastal Ecuador was historically endemic for malaria (P. falciparum and P. vivax), although successful control efforts in the 2000s eliminated autochthonous transmission (since 2011). This study presents an analysis of data collected during the elimination period.\n\nMethodsWe examined human landing catch (HLC) data for three mosquito taxa: 2 malaria vectors, Anopheles albimanus and Anopheles punctimacula, and grouped Culex spp. These data were collected by the National Vector Control Service of the Ministry of Health over a 5-year time span (2007 - 2012) in five cities in southern coastal Ecuador, at multiple households, in all months of the year, during dusk-dawn (18:00-6:00) hours, often at both indoor and outdoor locations. Hurdle models were used to determine if biting activity was fundamentally different for the three taxa, and to identify spatial and temporal factors influencing bite rate. Due to the many different approaches to studying and quantifying bite rates in the literature, we also created a glossary of terms, to facilitate comparative studies in the future.\n\nResultsBiting trends varied significantly with species and time. All taxa exhibited exophagic feeding behavior, and outdoor locations increased both the odds and incidence of bites across taxa. An. albimanus was most frequently observed biting, with an average of 4.7 bites per hour. The highest and lowest respective months for significant biting activity were March and July for An. albimanus, July and August for An. punctimacula, and February and July for Culex spp.\n\nConclusionsFine-scale spatial and temporal differences exist in biting patterns among mosquito taxa in southern coastal Ecuador. This analysis provides detailed information for targeting vector control and household level behavioral interventions. These data were collected as part of routine vector surveillance conducted by the Ministry of Health, but such data have not been collected since. Reinstating such surveillance measures would provide important information to aid in preventing malaria re-emergence.

epidemiology↗

bioRxiv2017

The impact of surveillance and control on highly pathogenic avian influenza outbreaks in poultry in Dhaka division, Bangladesh

In Bangladesh, the poultry industry is an economically and socially important sector, but it is persistently threatened by the effects of H5N1 highly pathogenic avian influenza. Thus, identifying the optimal control policy in response to an emerging disease outbreak is a key challenge for policy-makers. To inform this aim, a common approach is to carry out simulation studies comparing plausible strategies, while accounting for known capacity restrictions. In this study we perform simulations of a previously developed H5N1 influenza transmission model framework, fitted to two separate historical outbreaks, to assess specific control objectives related to the burden or duration of H5N1 outbreaks among poultry farms in the Dhaka division of Bangladesh. In particular, we explore the optimal implementation of ring culling, ring vaccination and active surveillance measures when presuming disease transmission predominately occurs from premises-to-premises, versus a setting requiring the inclusion of external factors. Additionally, we determine the sensitivity of the management actions under consideration to differing levels of capacity constraints and outbreaks with disparate transmission dynamics. While we find that reactive culling and vaccination policies should pay close attention to these factors to ensure intervention targeting is optimised, across multiple settings the top performing control action amongst those under consideration were targeted proactive surveillance schemes. Our findings may advise the type of control measure, plus its intensity, that could potentially be applied in the event of a developing outbreak of H5N1 amongst originally H5N1 virus-free commercially-reared poultry in the Dhaka division of Bangladesh.

epidemiology↗

bioRxiv2017

Insights into Hepatitis C Transmission in Young Persons who Inject Drugs: Results From a Dynamic Modeling Approach Informed by State-Level Public Health Surveillance Data

Rising use of heroin and prescription opioids are major contributors to increases in Hepatitis C Virus (HCV) incidence in US young adults since the late 1990s. How best to interrupt transmission and decrease HCV prevalence in young persons who inject drugs (PWID) is uncertain, but modeling studies in older populations support interventions that increase HCV treatment among all PWID. We developed a transmission model of young (aged 15-30 years) PWID, which we fit to state-level US HCV surveillance data, and simulated the potential impact of primary (reducing injection initiation), secondary (increasing cessation, reducing injection partners, or reducing injection drug use relapse), and tertiary (HCV treatment) interventions on incident and prevalent HCV cases. Interventions with primary prevention initiatives (reducing injection initiation) yielded concurrent reductions to HCV incidence and prevalence. Treatment of former PWID led to prevalence reductions but did not reduce incidence. Treatment of current and former PWID without other interventions led to incidence reductions in scenarios with high injection initiation rates, high syringe sharing, and low relapse rates after injection cessation. While these results are specific to Michigan, our approach could be applied in other states conducting HCV surveillance to identify local-level intervention opportunities.

epidemiology↗

bioRxiv2018

Identifying Critical Points of Trajectories of Depressive Symptoms From Childhood to Young Adulthood: Evidence of Sex Differences from the Avon Longitudinal Study of Parents and Children (ALSPAC)

Depression is a common mental illness associated with increased substance misuse and risk of suicide. Potential risk factors for depression include sex and depressive symptoms in early life, however the mechanisms responsible are not yet understood. Research has focused on late childhood and adolescence as this developmental period may be a modifiable risk factor that prevents or reduces depression at a later stage. It is also important to establish at what ages the level of depression is changing as this will help identify critical points to intervene with treatment. We used multilevel growth-curve models to explore adolescent trajectories of depressive symptoms in the Avon Longitudinal Study of Parents and Children, a UK based pregnancy cohort. Using data from 9301 individuals, trajectories of depressive symptoms were constructed for males and females between 10.6 and 22.8 years old. We calculated the age of peak velocity for depressive symptoms (the age at which depressive symptoms increases most rapidly) and the age of maximum depressive symptoms. Adjusted results suggested that being female was associated with a steeper trajectory compared to being male (per 1 year increase in relation to depressive symptoms: 0.128, SE = 0.035, [95% CI: 0.059, 0.198]; p <0.001). We found evidence suggesting that females had an earlier age of peak velocity of depressive symptoms (females 13.7 years old, SE = 0.321, [95% CI: 12.9, 14.4] and males 16.4 years old, SE = 0.096, [95% CI: 16.2, 16.6]; p <0.001), but weak evidence of an earlier age of maximum depressive symptoms (p = 0.125). Possible mechanisms that underlie this sex difference include the roles of pubertal development and timing. Using multilevel growth curve models to estimate the age of peak velocity and maximum depressive symptoms for different population subgroups may provide useful knowledge for treating and preventing later depression.

epidemiology↗

bioRxiv2017

The GENIUS Approach to Robust Mendelian Randomization Inference

Mendelian randomization (MR) is a popular instrumental variable (IV) approach, in which one or several genetic markers serve as IVs that can be leveraged to recover under certain conditions, valid inferences about a given exposure-outcome causal association subject to unmeasured confounding. A key IV identification condition known as the exclusion restriction states that the IV has no direct effect on the outcome that is not mediated by the exposure in view. In MR studies, such an assumption requires an unrealistic level of knowledge and understanding of the mechanism by which the genetic markers causally affect the outcome, particularly when a large number of genetic variants are considered as IVs. As a result, possible violation of the exclusion restriction can seldom be ruled out in such MR studies, and if present, such violation can invalidate IVbased inferences even if unbeknownst to the analyst, confounding is either negligible or absent. To address this concern, we introduce a new class of IV estimators which are robust to violation of the exclusion restriction under a large collection of data generating mechanisms consistent with parametric models commonly assumed in the MR literature. Our approach which we have named \"MR G-Estimation under No Interaction with Unmeasured Selection\" (MR GENIUS) may in fact be viewed as a modification to Robins G-estimation approach that is robust to both additive unmeasured confounding and violation of the exclusion restriction assumption. We also establish that estimation with MR GENIUS may also be viewed as a robust generalization of the well-known Lewbel estimator for a triangular system of structural equations with endogeneity. Specifically, we show that unlike Lewbel estimation, MR GENIUS is under fairly weak conditions also robust to unmeasured confounding of the effects of the genetic IVs on both the exposure and the outcome, another possible violation of a key IV Identification condition. Furthermore, while Lewbel estimation involves specification of linear models both for the outcome and the exposure, MR GENIUS generally does not require specification of a structural model for the direct effect of invalid IVs on the outcome, therefore allowing the latter model to be unrestricted. Finally, unlike Lewbel estimation, MR GENIUS is shown to equally apply for binary, discrete or continuous exposure and outcome variables and can be used under prospective sampling, or retrospective sampling such as in a case-control study, as well as for right censored time-to-event outcomes under an additive hazards model.

epidemiology↗

bioRxiv2017

Interactions between immunotoxicants and parasite stress: implications for host health

Many organisms face a wide variety of biotic and abiotic stressors which reduce individual survival, interacting synergistically to further reduce fitness. Here we studied the effects of two such synergistically interacting stressors; immunotoxicant exposure and parasite infection. We model the dynamics of a within-host infection and the associated immune response of an individual. We consider both the indirect sub-lethal effects on immunosuppression and the direct effects on health and mortality of individuals exposed to toxicants. We demonstrate that sub-lethal exposure to toxicants can promote infection through the suppression of the immune system. This happens through the depletion of the immune response which causes rapid proliferation in parasite load. In addition, high toxicant exposure can alter cellular regulation and cause the breakdown of normal healthy tissue, from which we infer higher mortality risk of the host. We classify this breakdown into three phases of increasing toxicant stress, and demonstrate the range of conditions under which toxicant exposure causes failure at the within-host level. These phases are determined by the relationship between the immunity status, overall cellular health and the level of toxicant exposure. We discuss the implications of our model in the context of individual honey bee health. Our model provides an assessment of how pesticide stress and infection interact to cause the synergistic breakdown of the within-host dynamics of individual honey bees.

epidemiology↗

bioRxiv2017

Nasal and aerosol shedding of infectious influenza virus - a community based study

Little is known about the amount and infectiousness of influenza virus shed into exhaled breath. This contributes to uncertainty about the importance of airborne influenza transmission. We screened 355 symptomatic volunteers with acute respiratory illness and report 142 cases with confirmed influenza infection who provided 218 paired nasopharyngeal (NP) and 30-minute breath samples (coarse >5 m and fine <5 m fractions) on days 1 to 3 post symptom onset. We assessed viral RNA copy number for all samples and cultured NP swabs and fine aerosols. We recovered infectious virus from 52 (39%) of the fine aerosols and 150 (89%) of the NP swabs with valid cultures. The geometric mean RNA copy numbers were 3.8x104/30-min fine, 1.2x104/30-min coarse aerosol sample, and 8.2x108 per NP swab. Fine and coarse aerosol viral RNA was positively associated with body mass index (fine p<0.05, coarse p<0.10) and number of coughs (fine p<0.001, coarse p<0.01) and negatively associated with increasing days since symptom onset (fine p<0.05 to p<0.01, coarse p<0.10) in adjusted models. Fine aerosol viral RNA was also positively associated with having influenza vaccination for both the current and prior season (p<0.01). NP swab viral RNA was positively associated with upper respiratory symptoms (p<0.01) and negatively associated with age (p<0.01) but was not significantly associated with fine or coarse aerosol viral RNA or their predictors. Sneezing was rare, and sneezing and coughing were not necessary for infectious aerosol generation. Our observations suggest that influenza infection in the upper and lower airways are compartmentalized and independent.\n\nSignificanceLack of human data on influenza virus aerosol shedding fuels debate over the importance of airborne transmission. We provide overwhelming evidence that humans generate infectious aerosols and quantitative data to improve mathematical models of transmission and public health interventions. We show that sneezing is rare and not important for, and that coughing is not required for influenza virus aerosolization. Our findings, that upper and lower airway infection are independent and that fine particle exhaled aerosols reflect infection in the lung, open a new pathway for understanding the human biology of influenza infection and transmission. Our observation of an association between repeated vaccination and increased viral aerosol generation demonstrated the power of our method, but needs confirmation.

epidemiology↗