Pathogen spillover driven by rapid changes in bat ecology.

During recent decades, pathogens that originated in bats have become an increasing public health concern. A major challenge is to identify how those pathogens spill over into human populations to generate a pandemic threat1. Many correlational studies associate spillover with changes in land use or other anthropogenic stressors2,3, although the mechanisms underlying the observed correlations have not been identified4. One limitation is the lack of spatially and temporally explicit data on multiple spillovers, and on the connections among spillovers, reservoir host ecology and behaviour and viral dynamics. We present 25 years of data on land-use change, bat behaviour and spillover of Hendra virus from Pteropodid bats to horses in subtropical Australia. These data show that bats are responding to environmental change by persistently adopting behaviours that were previously transient responses to nutritional stress. Interactions between land-use change and climate now lead to persistent bat residency in agricultural areas, where periodic food shortages drive clusters of spillovers. Pulses of winter flowering of trees in remnant forests appeared to prevent spillover. We developed integrative Bayesian network models based on these phenomena that accurately predicted the presence or absence of clusters of spillovers in each of the 25 years. Our long-term study identifies the mechanistic connections between habitat loss, climate and increased spillover risk. It provides a framework for examining causes of bat virus spillover and for developing ecological countermeasures to prevent pandemics.

Assessing COVID-19 pandemic policies and behaviours and their economic and educational trade-offs across US states from Jan 1, 2020, to July 31, 2022: an observational analysis.

BACKGROUND: The USA struggled in responding to the COVID-19 pandemic, but not all states struggled equally. Identifying the factors associated with cross-state variation in infection and mortality rates could help to improve responses to this and future pandemics. We sought to answer five key policy-relevant questions regarding the following: 1) what roles social, economic, and racial inequities had in interstate variation in COVID-19 outcomes; 2) whether states with greater health-care and public health capacity had better outcomes; 3) how politics influenced the results; 4) whether states that imposed more policy mandates and sustained them longer had better outcomes; and 5) whether there were trade-offs between a state having fewer cumulative SARS-CoV-2 infections and total COVID-19 deaths and its economic and educational outcomes. METHODS: Data disaggregated by US state were extracted from public databases, including COVID-19 infection and mortality estimates from the Institute for Health Metrics and Evaluation's (IHME) COVID-19 database; Bureau of Economic Analysis data on state gross domestic product (GDP); Federal Reserve economic data on employment rates; National Center for Education Statistics data on student standardised test scores; and US Census Bureau data on race and ethnicity by state. We standardised infection rates for population density and death rates for age and the prevalence of major comorbidities to facilitate comparison of states' successes in mitigating the effects of COVID-19. We regressed these health outcomes on prepandemic state characteristics (such as educational attainment and health spending per capita), policies adopted by states during the pandemic (such as mask mandates and business closures), and population-level behavioural responses (such as vaccine coverage and mobility). We explored potential mechanisms connecting state-level factors to individual-level behaviours using linear regression. We quantified reductions in state GDP, employment, and student test scores during the pandemic to identify policy and behavioural responses associated with these outcomes and to assess trade-offs between these outcomes and COVID-19 outcomes. Significance was defined as p<0·05. FINDINGS: Standardised cumulative COVID-19 death rates for the period from Jan 1, 2020, to July 31, 2022 varied across the USA (national rate 372 deaths per 100 000 population [95% uncertainty interval [UI] 364-379]), with the lowest standardised rates in Hawaii (147 deaths per 100 000 [127-196]) and New Hampshire (215 per 100 000 [183-271]) and the highest in Arizona (581 per 100 000 [509-672]) and Washington, DC (526 per 100 000 [425-631]). A lower poverty rate, higher mean number of years of education, and a greater proportion of people expressing interpersonal trust were statistically associated with lower infection and death rates, and states where larger percentages of the population identify as Black (non-Hispanic) or Hispanic were associated with higher cumulative death rates. Access to quality health care (measured by the IHME's Healthcare Access and Quality Index) was associated with fewer total COVID-19 deaths and SARS-CoV-2 infections, but higher public health spending and more public health personnel per capita were not, at the state level. The political affiliation of the state governor was not associated with lower SARS-CoV-2 infection or COVID-19 death rates, but worse COVID-19 outcomes were associated with the proportion of a state's voters who voted for the 2020 Republican presidential candidate. State governments' uses of protective mandates were associated with lower infection rates, as were mask use, lower mobility, and higher vaccination rate, while vaccination rates were associated with lower death rates. State GDP and student reading test scores were not associated with state COVD-19 policy responses, infection rates, or death rates. Employment, however, had a statistically significant relationship with restaurant closures and greater infections and deaths: on average, 1574 (95% UI 884-7107) additional infections per 10 000 population were associated in states with a one percentage point increase in employment rate. Several policy mandates and protective behaviours were associated with lower fourth-grade mathematics test scores, but our study results did not find a link to state-level estimates of school closures. INTERPRETATION: COVID-19 magnified the polarisation and persistent social, economic, and racial inequities that already existed across US society, but the next pandemic threat need not do the same. US states that mitigated those structural inequalities, deployed science-based interventions such as vaccination and targeted vaccine mandates, and promoted their adoption across society were able to match the best-performing nations in minimising COVID-19 death rates. These findings could contribute to the design and targeting of clinical and policy interventions to facilitate better health outcomes in future crises. FUNDING: Bill & Melinda Gates Foundation, J Stanton, T Gillespie, J and E Nordstrom, and Bloomberg Philanthropies.

The duration of travel impacts the spatial dynamics of infectious diseases.

Humans can impact the spatial transmission dynamics of infectious diseases by introducing pathogens into susceptible environments. The rate at which this occurs depends in part on human-mobility patterns. Increasingly, mobile-phone usage data are used to quantify human mobility and investigate the impact on disease dynamics. Although the number of trips between locations and the duration of those trips could both affect infectious-disease dynamics, there has been limited work to quantify and model the duration of travel in the context of disease transmission. Using mobility data inferred from mobile-phone calling records in Namibia, we calculated both the number of trips between districts and the duration of these trips from 2010 to 2014. We fit hierarchical Bayesian models to these data to describe both the mean trip number and duration. Results indicate that trip duration is positively related to trip distance, but negatively related to the destination population density. The highest volume of trips and shortest trip durations were among high-density districts, whereas trips among low-density districts had lower volume with longer duration. We also analyzed the impact of including trip duration in spatial-transmission models for a range of pathogens and introduction locations. We found that inclusion of trip duration generally delays the rate of introduction, regardless of pathogen, and that the variance and uncertainty around spatial spread increases proportionally with pathogen-generation time. These results enhance our understanding of disease-dispersal dynamics driven by human mobility, which has potential to elucidate optimal spatial and temporal scales for epidemic interventions.

Sample size calculation for phylogenetic case linkage.

Sample size calculations are an essential component of the design and evaluation of scientific studies. However, there is a lack of clear guidance for determining the sample size needed for phylogenetic studies, which are becoming an essential part of studying pathogen transmission. We introduce a statistical framework for determining the number of true infector-infectee transmission pairs identified by a phylogenetic study, given the size and population coverage of that study. We then show how characteristics of the criteria used to determine linkage and aspects of the study design can influence our ability to correctly identify transmission links, in sometimes counterintuitive ways. We test the overall approach using outbreak simulations and provide guidance for calculating the sensitivity and specificity of the linkage criteria, the key inputs to our approach. The framework is freely available as the R package phylosamp, and is broadly applicable to designing and evaluating a wide array of pathogen phylogenetic studies.

Trip duration drives shift in travel network structure with implications for the predictability of spatial disease spread.

Human travel is one of the primary drivers of infectious disease spread. Models of travel are often used that assume the amount of travel to a specific destination decreases as cost of travel increases with higher travel volumes to more populated destinations. Trip duration, the length of time spent in a destination, can also impact travel patterns. We investigated the spatial patterns of travel conditioned on trip duration and find distinct differences between short and long duration trips. In short-trip duration travel networks, trips are skewed towards urban destinations, compared with long-trip duration networks where travel is more evenly spread among locations. Using gravity models to inform connectivity patterns in simulations of disease transmission, we show that pathogens with shorter generation times exhibit initial patterns of spatial propagation that are more predictable among urban locations. Further, pathogens with a longer generation time have more diffusive patterns of spatial spread reflecting more unpredictable disease dynamics.

Is consanguinity an impediment to child development?

Marriages between blood relatives-also known as consanguineous unions-are widespread in North Africa, Central and West Asia, and South Asia. Researchers have suggested that consanguinity has adverse effects on child development, but assessing its impact is not straightforward, as the decision to marry a relative might be endogenous to other socio-economic factors. Using a unique data set collected in rural Pakistan, this paper assesses the extent to which consanguinity is linked to children's cognitive and physical development. It exploits grandfathers' land ownership (current and past) and maternal grandparent mortality to identify the effect of endogenous consanguinity on child development. Children born into consanguineous unions have lower cognitive scores, lower height-for-age, and a higher likelihood of being severely stunted. More importantly, adverse effects are greater after accounting for the endogeneity of consanguinity, suggesting that impacts on child development are substantial, and likely to be larger than suggested in previous studies.

One country, two systems: evidence on retirement patterns in China.

This paper documents the patterns and correlates of retirement in China using a nationally representative survey, the China Health and Retirement Longitudinal Study. After documenting stark differences in retirement ages between urban and rural residents, the paper shows that China's urban residents retire earlier than workers in many Organization for Economic Co-operation and Development countries and that rural residents continue to work until advanced ages. Differences in access to generous pensions and economic resources explain much of the urban-rural difference in retirement rates. The paper suggests that reducing disincentives created by China's Urban Employee Pension system, improving health status, providing childcare and elder care support may all facilitate longer working lives. Given spouse preferences for joint retirement, creating incentives for women to retire later may facilitate longer working lives for both men and women.

Impact of disruptions to routine vaccination programs, quantifying burden of measles, and mapping targeted supplementary immunization activities.

Measles is a highly transmissible disease that requires high levels of vaccination coverage for control and elimination. Areas that are unable to achieve and maintain high coverage levels are at risk for measles outbreaks resulting in increased morbidity and mortality. Public health emergencies, such as the current COVID-19 pandemic, pose a threat to the functioning of health systems by disrupting immunization services which can derail measles vaccination efforts. Efforts to bridge coverage gaps in immunization include the rapid return to fully functioning services as well as deploying supplementary immunization activities (SIAs), which are additional vaccination campaigns intended to catch-up children who have missed routine services. However, SIAs, which to date tend to be national efforts, can be difficult to mobilize quickly, resource-intensive, and even more challenging to deploy during a public health crisis. By mapping expected burden of measles, more effective SIAs that are setting-specific and resource-efficient can be planned and mobilized. Using a spatial transmission model of measles dynamics, we projected and estimated the expected burden of national and local measles outbreaks in Zambia with the current COVID-19 pandemic as a framework to inform disruptions to routine vaccination. We characterize the impact of disruptions to routine immunization services on measles incidence, map expected case burden, and explore SIA strategies to mitigate measles outbreaks. We find that disruptions lasting six months or longer as well as having low MCV1 coverage prior to disruptions resulted in an observable increase of measles cases across provinces. Targeting provinces at higher risk of measles outbreaks for SIAs is an effective strategy to curb measles virus incidence following disruptions to routine immunization services.

The effect of height on earnings: Is stature just a proxy for cognitive and non-cognitive skills?

While taller workers are regularly observed to earn more, there is debate concerning the independent contribution of stature to labor earnings. This study investigates the degree to which the association of height and earnings in Pakistan is independent of other cognitive and socio-emotional skills. Next, the relationship between height and earnings is explored when measures of cognitive ability and an index of socio-emotional capacity are included separately. The paper finds only a modest attenuation in the contribution of height to earnings after controlling for additional dimensions of human capital, suggesting that height provides independent information on labor productivity. This result is robust to treating height as endogenous. The paper also examines non-linearities in the relationship between height and earnings. In contrast to results from relatively few other contributions to research on this non-linear relationship, height is associated with earnings only when an individual is taller than the median height. This lends some support to the role of status and confidence in the yet unresolved question as to the relative contribution of direct and indirect influence of height on earnings.

Optimizing noninvasive sampling of a zoonotic bat virus.

Outbreaks of infectious viruses resulting from spillover events from bats have brought much attention to bat-borne zoonoses, which has motivated increased ecological and epidemiological studies on bat populations. Field sampling methods often collect pooled samples of bat excreta from plastic sheets placed under-roosts. However, positive bias is introduced because multiple individuals may contribute to pooled samples, making studies of viral dynamics difficult. Here, we explore the general issue of bias in spatial sample pooling using Hendra virus in Australian bats as a case study. We assessed the accuracy of different under-roost sampling designs using generalized additive models and field data from individually captured bats and pooled urine samples. We then used theoretical simulation models of bat density and under-roost sampling to understand the mechanistic drivers of bias. The most commonly used sampling design estimated viral prevalence 3.2 times higher than individual-level data, with positive bias 5-7 times higher than other designs due to spatial autocorrelation among sampling sheets and clustering of bats in roosts. Simulation results indicate using a stratified random design to collect 30-40 pooled urine samples from 80 to 100 sheets, each with an area of 0.75-1 m2, and would allow estimation of true prevalence with minimum sampling bias and false negatives. These results show that widely used under-roost sampling techniques are highly sensitive to viral presence, but lack specificity, providing limited information regarding viral dynamics. Improved estimation of true prevalence can be attained with minor changes to existing designs such as reducing sheet size, increasing sheet number, and spreading sheets out within the roost area. Our findings provide insight into how spatial sample pooling is vulnerable to bias for a wide range of systems in disease ecology, where optimal sampling design is influenced by pathogen prevalence, host population density, and patterns of aggregation.

Characterizing human mobility patterns in rural settings of sub-Saharan Africa.

Human mobility is a core component of human behavior and its quantification is critical for understanding its impact on infectious disease transmission, traffic forecasting, access to resources and care, intervention strategies, and migratory flows. When mobility data are limited, spatial interaction models have been widely used to estimate human travel, but have not been extensively validated in low- and middle-income settings. Geographic, sociodemographic, and infrastructure differences may impact the ability for models to capture these patterns, particularly in rural settings. Here, we analyzed mobility patterns inferred from mobile phone data in four Sub-Saharan African countries to investigate the ability for variants on gravity and radiation models to estimate travel. Adjusting the gravity model such that parameters were fit to different trip types, including travel between more or less populated areas and/or different regions, improved model fit in all four countries. This suggests that alternative models may be more useful in these settings and better able to capture the range of mobility patterns observed.

Interaction of tumour biology and tumour burden in determining outcome after hepatic resection for colorectal metastases.

AIMS: To determine the outcome of colorectal liver metastasis (CRLM) patients based on tumour burden, represented by tumour number and size, and tumour biology as assessed by an inflammatory response to tumour (IRT) and margin positivity. METHODS: Data were collated from CRLM patients undergoing resection from January 1993 to March 2007. Patients were divided into: low (3-or=8 metastases and/or >5 cm) tumour burden. RESULTS: Seven hundred and five patients underwent resection, of which 154 (21.8%), 262 (37.2%) and 289 (41.0%) patients were in the low, moderate and high tumour burden groups, respectively. The 5-year disease-free (P < 0.001) and overall (P < 0.001) survival were significantly different between the groups. IRT (P < 0.001), extent of resection (P < 0.001) and margin (P < 0.001) also differed between the groups. Sub-group analysis revealed that IRT was the only adverse predictor for disease-free and overall survival in the low group. In the moderate group, IRT predicted poorer disease-free survival on multi-variate analysis. In the high group, R1 resection and transfusion were predictors of poorer disease-free survival and age >or=65 years, R1 resection and IRT were adverse predictors of overall survival. CONCLUSION: Resection margin influenced the outcome of patients with high tumour burden, hence the importance of achieving clear margins. IRT influenced the outcome of patients with less aggressive disease.

The use of mobile phone data to inform analysis of COVID-19 pandemic epidemiology.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has heightened discussion of the use of mobile phone data in outbreak response. Mobile phone data have been proposed to monitor effectiveness of non-pharmaceutical interventions, to assess potential drivers of spatiotemporal spread, and to support contact tracing efforts. While these data may be an important part of COVID-19 response, their use must be considered alongside a careful understanding of the behaviors and populations they capture. Here, we review the different applications for mobile phone data in guiding and evaluating COVID-19 response, the relevance of these applications for infectious disease transmission and control, and potential sources and implications of selection bias in mobile phone data. We also discuss best practices and potential pitfalls for directly integrating the collection, analysis, and interpretation of these data into public health decision making.

Synchronous shedding of multiple bat paramyxoviruses coincides with peak periods of Hendra virus spillover.

Within host-parasite communities, viral co-circulation and co-infections of hosts are the norm, yet studies of significant emerging zoonoses tend to focus on a single parasite species within the host. Using a multiplexed paramyxovirus bead-based PCR on urine samples from Australian flying foxes, we show that multi-viral shedding from flying fox populations is common. We detected up to nine bat paramyxoviruses shed synchronously. Multi-viral shedding infrequently coalesced into an extreme, brief and spatially restricted shedding pulse, coinciding with peak spillover of Hendra virus, an emerging fatal zoonotic pathogen of high interest. Such extreme pulses of multi-viral shedding could easily be missed during routine surveillance yet have potentially serious consequences for spillover of novel pathogens to humans and domestic animal hosts. We also detected co-occurrence patterns suggestive of the presence of interactions among viruses, such as facilitation and cross-immunity. We propose that multiple viruses may be interacting, influencing the shedding and spillover of zoonotic pathogens. Understanding these interactions in the context of broader scale drivers, such as habitat loss, may help predict shedding pulses of Hendra virus and other fatal zoonoses.

Gender Patterns of Eldercare in China.

Using the baseline wave of the China Health and Retirement Longitudinal Study (CHARLS), collected from 2011 to 2012, this study finds that among those age 60 and above, women are 7.6 percent more likely than men to have care needs and 29.3 percent more likely than men to have unmet needs; and that most of the gender gap in unmet needs is explained by the existence and health status of a spouse. Further analysis reveals a sharp gender division in patterns of family care in China. While men are more likely to receive care from their wives, women are primarily cared for by their children. Marital status and spouse health also affect provision of care, with infirm women who have healthy husbands less likely to receive care than infirm men with healthy wives. The findings have important implications for designing gender-sensitive policies in eldercare.

Environmental drivers of spatiotemporal foraging intensity in fruit bats and implications for Hendra virus ecology.

In the Australian subtropics, flying-foxes (family Pteropididae) play a fundamental ecological role as forest pollinators. Flying-foxes are also reservoirs of the fatal zoonosis, Hendra virus. Understanding flying fox foraging ecology, particularly in agricultural areas during winter, is critical to determine their role in transmitting Hendra virus to horses and humans. We developed a spatiotemporal model of flying-fox foraging intensity based on foraging patterns of 37 grey-headed flying-foxes (Pteropus poliocephalus) using GPS tracking devices and boosted regression trees. We validated the model with independent population counts and summarized temporal patterns in terms of spatial resource concentration. We found that spatial resource concentration was highest in late-summer and lowest in winter, with lowest values in winter 2011, the same year an unprecedented cluster of spillover events occurred in Queensland and New South Wales. Spatial resource concentration was positively correlated with El Niño Southern Oscillation at 3-8 month time lags. Based on shared foraging traits with the primary reservoir of Hendra virus (Pteropus alecto), we used our results to develop hypotheses on how regional climatic history, eucalypt phenology, and foraging behaviour may contribute to the predominance of winter spillovers, and how these phenomena connote foraging habitat conservation as a public health intervention.

Models of Eucalypt phenology predict bat population flux.

Fruit bats (Pteropodidae) have received increased attention after the recent emergence of notable viral pathogens of bat origin. Their vagility hinders data collection on abundance and distribution, which constrains modeling efforts and our understanding of bat ecology, viral dynamics, and spillover. We addressed this knowledge gap with models and data on the occurrence and abundance of nectarivorous fruit bat populations at 3 day roosts in southeast Queensland. We used environmental drivers of nectar production as predictors and explored relationships between bat abundance and virus spillover. Specifically, we developed several novel modeling tools motivated by complexities of fruit bat foraging ecology, including: (1) a dataset of spatial variables comprising Eucalypt-focused vegetation indices, cumulative precipitation, and temperature anomaly; (2) an algorithm that associated bat population response with spatial covariates in a spatially and temporally relevant way given our current understanding of bat foraging behavior; and (3) a thorough statistical learning approach to finding optimal covariate combinations. We identified covariates that classify fruit bat occupancy at each of our three study roosts with 86-93% accuracy. Negative binomial models explained 43-53% of the variation in observed abundance across roosts. Our models suggest that spatiotemporal heterogeneity in Eucalypt-based food resources could drive at least 50% of bat population behavior at the landscape scale. We found that 13 spillover events were observed within the foraging range of our study roosts, and they occurred during times when models predicted low population abundance. Our results suggest that, in southeast Queensland, spillover may not be driven by large aggregations of fruit bats attracted by nectar-based resources, but rather by behavior of smaller resident subpopulations. Our models and data integrated remote sensing and statistical learning to make inferences on bat ecology and disease dynamics. This work provides a foundation for further studies on landscape-scale population movement and spatiotemporal disease dynamics.

Citrullination of myofilament proteins in heart failure.

AIMS: Citrullination, the post-translational conversion of arginine to citrulline by the enzyme family of peptidylarginine deiminases (PADs), is associated with several diseases, and specific citrullinated proteins have been shown to alter function while others act as auto-antigens. In this study, we identified citrullinated proteins in human myocardial samples, from healthy and heart failure patients, and determined several potential functional consequences. Further we investigated PAD isoform cell-specific expression in the heart. METHODS AND RESULTS: A citrullination-targeted proteomic strategy using data-independent (SWATH) acquisition method was used to identify the modified cardiac proteins. Citrullinated-induced sarcomeric proteins were validated using two-dimensional gel electrophoresis and investigated using biochemical and functional assays. Myocardial PAD isoforms were confirmed by RT-PCR with PAD2 being the major isoform in myocytes. In total, 304 citrullinated sites were identified that map to 145 proteins among the three study groups: normal, ischaemia, and dilated cardiomyopathy. Citrullination of myosin (using HMM fragment) decreased its intrinsic ATPase activity and inhibited the acto-HMM-ATPase activity. Citrullinated TM resulted in stronger F-actin binding and inhibited the acto-HMM-ATPase activity. Citrullinated TnI did not alter the binding to F-actin or acto-HMM-ATPase activity. Overall, citrullination of sarcomeric proteins caused a decrease in Ca(2+) sensitivity in skinned cardiomyocytes, with no change in maximal calcium-activated force or hill coefficient. CONCLUSION: Citrullination unique to the cardiac proteome was identified. Our data indicate important structural and functional alterations to the cardiac sarcomere and the contribution of protein citrullination to this process.