Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution.

BACKGROUND: Mass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of amplifying macrolide resistance. The effects on the gut resistome, a reservoir of antimicrobial resistance genes in the body, of twice-yearly administration of azithromycin for a longer period are unclear. METHODS: We investigated the gut resistome of children after they received twice-yearly distributions of azithromycin for 4 years. In the Niger site of the MORDOR trial, we enrolled 30 villages in a concurrent trial in which they were randomly assigned to receive mass distribution of either azithromycin or placebo, offered to all children 1 to 59 months of age every 6 months for 4 years. Rectal swabs were collected at baseline, 36 months, and 48 months for analysis of the participants' gut resistome. The primary outcome was the ratio of macrolide-resistance determinants in the azithromycin group to those in the placebo group at 48 months. RESULTS: Over the entire 48-month period, the mean (±SD) coverage was 86.6±12% in the villages that received placebo and 83.2±16.4% in the villages that received azithromycin. A total of 3232 samples were collected during the entire trial period; of the samples obtained at the 48-month monitoring visit, 546 samples from 15 villages that received placebo and 504 from 14 villages that received azithromycin were analyzed. Determinants of macrolide resistance were higher in the azithromycin group than in the placebo group: 7.4 times as high (95% confidence interval [CI], 4.0 to 16.7) at 36 months and 7.5 times as high (95% CI, 3.8 to 23.1) at 48 months. Continued mass azithromycin distributions also selected for determinants of nonmacrolide resistance, including resistance to beta-lactam antibiotics, an antibiotic class prescribed frequently in this region of Africa. CONCLUSIONS: Among villages assigned to receive mass distributions of azithromycin or placebo twice yearly for 4 years, antibiotic resistance was more common in the villages that received azithromycin than in those that received placebo. This trial showed that mass azithromycin distributions may propagate antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02047981.).

Modeling scenarios for mitigating outbreaks in congregate settings.

The explosive outbreaks of COVID-19 seen in congregate settings such as prisons and nursing homes, has highlighted a critical need for effective outbreak prevention and mitigation strategies for these settings. Here we consider how different types of control interventions impact the expected number of symptomatic infections due to outbreaks. Introduction of disease into the resident population from the community is modeled as a stochastic point process coupled to a branching process, while spread between residents is modeled via a deterministic compartmental model that accounts for depletion of susceptible individuals. Control is modeled as a proportional decrease in the number of susceptible residents, the reproduction number, and/or the proportion of symptomatic infections. This permits a range of assumptions about the density dependence of transmission and modes of protection by vaccination, depopulation and other types of control. We find that vaccination or depopulation can have a greater than linear effect on the expected number of cases. For example, assuming a reproduction number of 3.0 with density-dependent transmission, we find that preemptively reducing the size of the susceptible population by 20% reduced overall disease burden by 47%. In some circumstances, it may be possible to reduce the risk and burden of disease outbreaks by optimizing the way a group of residents are apportioned into distinct residential units. The optimal apportionment may be different depending on whether the goal is to reduce the probability of an outbreak occurring, or the expected number of cases from outbreak dynamics. In other circumstances there may be an opportunity to implement reactive disease control measures in which the number of susceptible individuals is rapidly reduced once an outbreak has been detected to occur. Reactive control is most effective when the reproduction number is not too high, and there is minimal delay in implementing control. We highlight the California state prison system as an example for how these findings provide a quantitative framework for understanding disease transmission in congregate settings. Our approach and accompanying interactive website (https://phoebelu.shinyapps.io/DepopulationModels/) provides a quantitative framework to evaluate the potential impact of policy decisions governing infection control in outbreak settings.

An open challenge to advance probabilistic forecasting for dengue epidemics.

A wide range of research has promised new tools for forecasting infectious disease dynamics, but little of that research is currently being applied in practice, because tools do not address key public health needs, do not produce probabilistic forecasts, have not been evaluated on external data, or do not provide sufficient forecast skill to be useful. We developed an open collaborative forecasting challenge to assess probabilistic forecasts for seasonal epidemics of dengue, a major global public health problem. Sixteen teams used a variety of methods and data to generate forecasts for 3 epidemiological targets (peak incidence, the week of the peak, and total incidence) over 8 dengue seasons in Iquitos, Peru and San Juan, Puerto Rico. Forecast skill was highly variable across teams and targets. While numerous forecasts showed high skill for midseason situational awareness, early season skill was low, and skill was generally lowest for high incidence seasons, those for which forecasts would be most valuable. A comparison of modeling approaches revealed that average forecast skill was lower for models including biologically meaningful data and mechanisms and that both multimodel and multiteam ensemble forecasts consistently outperformed individual model forecasts. Leveraging these insights, data, and the forecasting framework will be critical to improve forecast skill and the application of forecasts in real time for epidemic preparedness and response. Moreover, key components of this project-integration with public health needs, a common forecasting framework, shared and standardized data, and open participation-can help advance infectious disease forecasting beyond dengue.

Gut Resistome of Preschool Children After Prolonged Mass Azithromycin Distribution: A Cluster-randomized Trial.

We evaluated the gut resistome of children from communities treated with 10 twice-yearly azithromycin distributions. Although the macrolide resistance remained higher in the azithromycin arm, the selection of non-macrolide resistance observed at earlier time points did not persist. Longitudinal resistance monitoring should be a critical component of mass distribution programs. CLINICAL TRIALS REGISTRATION: NCT02047981.

Reduction of Coronavirus Burden With Mass Azithromycin Distribution.

We evaluated the potential antiviral effects of azithromycin on the nasopharyngeal virome of Nigerien children who had received multiple rounds of mass drug administration. We found that the respiratory burden of non-severe acute respiratory syndrome coronaviruses was decreased with azithromycin distributions. Clinical Trials Registration. NCT02047981.

Conservation of community functional structure across changes in composition in consumer-resource models.

High-throughput sequencing techniques such as metagenomic and metatranscriptomic technologies allow cataloguing of functional characteristics of microbial community members as well as their phylogenetic identity. Such studies have found that a community's makeup in terms of ecologically relevant functional traits or guilds can be conserved more strictly across varying settings than its composition is in terms of taxa. I use a standard ecological resource-consumer model to examine the dynamics of traits relevant to resource consumption, and analyze determinants of functional structure. This model demonstrates that interaction with essential resources can regulate the community-wide abundances of ecologically relevant traits, keeping them at consistent levels despite large changes in the abundances of the species housing those traits in response to changes in the environment, and across variation between communities in species composition. Functional structure is shown to be able to track differences in environmental conditions faithfully across differences in species composition. Mathematical conditions on consumers' vital rates and functional responses necessary and sufficient to produce conservation of functional community structure across differences in species composition in these models are presented. These conditions imply a nongeneric relation between biochemical rates, and avenues for further research are discussed.

Anatomy of a Hotspot: Chain and Seroepidemiology of Ebola Virus Transmission, Sukudu, Sierra Leone, 2015-16.

Studies have yet to include minimally symptomatic Ebola virus (EBOV) infections and unrecognized Ebola virus disease (EVD) in Ebola-related transmission chains and epidemiologic risk estimates. We conducted a cross-sectional, sero-epidemiological survey from October 2015 to January 2016 among 221 individuals living in quarantined households from November 2014 to February 2015 during the Ebola outbreak in the village of Sukudu, Sierra Leone. Of 48 EBOV-infected persons, 25% (95% confidence interval [CI], 14%-40%) had minimally symptomatic EBOV infections and 4% (95% CI, 1%-14%) were unrecognized EVD cases. The pattern of minimally symptomatic EBOV infections in the transmission chain was nonrandom (P < .001, permutation test). Not having lived in the same house as an EVD case was significantly associated with minimally symptomatic infection. This is the first study to investigate a chain of EBOV transmission inclusive of minimally symptomatic EBOV infections and unrecognized EVD. Our findings provide new insights into Ebola transmission dynamics and quarantine practices.

Genotype-Specific Measles Transmissibility: A Branching Process Analysis.

Background: Substantial heterogeneity in measles outbreak sizes may be due to genotype-specific transmissibility. Using a branching process analysis, we characterize differences in measles transmission by estimating the association between genotype and the reproduction number R among postelimination California measles cases during 2000-2015 (400 cases, 165 outbreaks). Methods: Assuming a negative binomial secondary case distribution, we fit a branching process model to the distribution of outbreak sizes using maximum likelihood and estimated the reproduction number R for a multigenotype model. Results: Genotype B3 is found to be significantly more transmissible than other genotypes (P = .01) with an R of 0.64 (95% confidence interval [CI], .48-.71), while the R for all other genotypes combined is 0.43 (95% CI, .28-.54). This result is robust to excluding the 2014-2015 outbreak linked to Disneyland theme parks (referred to as "outbreak A" for conciseness and clarity) (P = .04) and modeling genotype as a random effect (P = .004 including outbreak A and P = .02 excluding outbreak A). This result was not accounted for by season of introduction, age of index case, or vaccination of the index case. The R for outbreaks with a school-aged index case is 0.69 (95% CI, .52-.78), while the R for outbreaks with a non-school-aged index case is 0.28 (95% CI, .19-.35), but this cannot account for differences between genotypes. Conclusions: Variability in measles transmissibility may have important implications for measles control; the vaccination threshold required for elimination may not be the same for all genotypes or age groups.

Rates of SARS-CoV-2 transmission between and into California state prisons.

Correctional institutions are a crucial hotspot amplifying SARS-CoV-2 spread and disease disparity in the U.S. In the California state prison system, multiple massive outbreaks have been caused by transmission between prisons. Correctional staff are a likely vector for transmission into the prison system from surrounding communities. We used publicly available data to estimate the magnitude of flows to and between California state prisons, estimating rates of transmission from communities to prison staff and residents, among and between residents and staff within facilities, and between staff and residents of distinct facilities in the state's 34 prisons through March 22, 2021. We use a mechanistic model, the Hawkes process, reflecting the dynamics of SARS-CoV-2 transmission, for joint estimation of transmission rates. Using nested models for hypothesis testing, we compared the results to simplified models (i) without transmission between prisons, and (ii) with no distinction between prison staff and residents. We estimated that transmission between different facilities' staff is a significant cause of disease spread, and that staff are a vector of transmission between resident populations and outside communities. While increased screening and vaccination of correctional staff may help reduce introductions, large-scale decarceration remains crucially needed as more limited measures are not likely to prevent large-scale disease spread.

A complex systems model of breast cancer etiology: The Paradigm II Model.

BACKGROUND: Complex systems models of breast cancer have previously focused on prediction of prognosis and clinical events for individual women. There is a need for understanding breast cancer at the population level for public health decision-making, for identifying gaps in epidemiologic knowledge and for the education of the public as to the complexity of this most common of cancers. METHODS AND FINDINGS: We developed an agent-based model of breast cancer for the women of the state of California using data from the U.S. Census, the California Health Interview Survey, the California Cancer Registry, the National Health and Nutrition Examination Survey and the literature. The model was implemented in the Julia programming language and R computing environment. The Paradigm II model development followed a transdisciplinary process with expertise from multiple relevant disciplinary experts from genetics to epidemiology and sociology with the goal of exploring both upstream determinants at the population level and pathophysiologic etiologic factors at the biologic level. The resulting model reproduces in a reasonable manner the overall age-specific incidence curve for the years 2008-2012 and incidence and relative risks due to specific risk factors such as BRCA1, polygenic risk, alcohol consumption, hormone therapy, breastfeeding, oral contraceptive use and scenarios for environmental toxin exposures. CONCLUSIONS: The Paradigm II model illustrates the role of multiple etiologic factors in breast cancer from domains of biology, behavior and the environment. The value of the model is in providing a virtual laboratory to evaluate a wide range of potential interventions into the social, environmental and behavioral determinants of breast cancer at the population level.

Assessing the Risk of Cascading COVID-19 Outbreaks from Prison-to-Prison Transfers.

COVID-19 transmission has been widespread across the California prison system, and at least two of these outbreaks were caused by transfer of infected individuals between prisons. Risks of individual prison outbreaks due to introduction of the virus and of widespread transmission within prisons due to poor conditions have been documented. We examine the additional risk potentially posed by transfer between prisons that can lead to large-scale spread of outbreaks across the prison system if the rate of transfer is sufficiently high. We estimated the threshold number of individuals transferred per prison per month to generate supercritical transmission between prisons, a condition that could lead to large-scale spread across the prison system. We obtained numerical estimates from a range of representative quantitative assumptions, and derived the percentage of transfers that must be performed with effective quarantine measures to prevent supercritical transmission given known rates of transfers occurring between California prisons. Our mean estimate of the critical threshold rate of transfers was 14.38 individuals transferred per prison per month in the absence of quarantine measures. Available data documents transfers occurring at a rate of 60 transfers per prison per month. At that rate, estimates of the threshold rate of adherence to quarantine precautions had mean 76.03%. While the impact of vaccination and possible decarceration measures is unclear, we include estimates of the above quantities given reductions in the probability and extent of outbreaks. We conclude that the risk of supercritical transmission between California prisons has been substantial, requiring quarantine protocols to be followed rigorously to manage this risk. The rate of outbreaks occurring in California prisons suggests that supercritical transmission may have occurred. We stress that the thresholds we estimate here do not define a safe level of transfers, even if supercritical transmission between prisons is avoided, since even low rates of transfer can cause very large outbreaks. We note that risks may persist after vaccination, due for example to variant strains, and in prison systems where widespread vaccination has not occurred. Decarceration remains urgently needed as a public health measure.

Assessing the risk of cascading COVID-19 outbreaks from prison-to-prison transfers.

COVID-19 transmission has been widespread across the California prison system, and at least two of these outbreaks were caused by transfer of infected individuals between prisons. Risks of individual prison outbreaks due to introduction of the virus and of widespread transmission within prisons due to poor conditions have been documented. We examine the additional risk potentially posed by transfer between prisons that can lead to large-scale spread of outbreaks across the prison system if the rate of transfer is sufficiently high. We estimated the threshold number of individuals transferred per prison per month to generate supercritical transmission between prisons, a condition that could lead to large-scale spread across the prison system. We obtained numerical estimates from a range of representative quantitative assumptions, and derived the percentage of transfers that must be performed with effective quarantine measures to prevent supercritical transmission given known rates of transfers occurring between California prisons. Our mean estimate of the critical threshold rate of transfers was 27 individuals transferred per prison per month, with standard deviation 26, in the absence of quarantine measures. Available data documents transfers occurring at a rate of 61 transfers per prison per month. At that rate, estimates of the threshold rate of adherence to quarantine precautions had mean 61%, with standard deviation 32%. While the impact of vaccination and possible decarceration measures is unclear, we include estimates of the above quantities given reductions in the probability and extent of outbreaks. We conclude that the risk of supercritical transmission between California prisons has been substantial, requiring quarantine protocols to be followed rigorously to manage this risk. The rate of outbreaks occurring in California prisons suggests that supercritical transmission may have occurred. We stress that the thresholds we estimate here do not define a safe level of transfers, even if supercritical transmission between prisons is avoided, since even low rates of transfer can cause very large outbreaks. We note that risks may persist after vaccination, due for example to variant strains, and in prison systems where widespread vaccination has not occurred. Decarceration remains urgently needed as a public health measure.

Mitigating outbreaks in congregate settings by decreasing the size of the susceptible population.

While many transmission models have been developed for community spread of respiratory pathogens, less attention has been given to modeling the interdependence of disease introduction and spread seen in congregate settings, such as prisons or nursing homes. As demonstrated by the explosive outbreaks of COVID-19 seen in congregate settings, the need for effective outbreak prevention and mitigation strategies for these settings is critical. Here we consider how interventions that decrease the size of the susceptible populations, such as vaccination or depopulation, impact the expected number of infections due to outbreaks. Introduction of disease into the resident population from the community is modeled as a branching process, while spread between residents is modeled via a compartmental model. Control is modeled as a proportional decrease in both the number of susceptible residents and the reproduction number. We find that vaccination or depopulation can have a greater than linear effect on anticipated infections. For example, assuming a reproduction number of 3.0 for density-dependent COVID-19 transmission, we find that reducing the size of the susceptible population by 20% reduced overall disease burden by 47%. We highlight the California state prison system as an example for how these findings provide a quantitative framework for implementing infection control in congregate settings. Additional applications of our modeling framework include optimizing the distribution of residents into independent residential units, and comparison of preemptive versus reactive vaccination strategies.

Reparations for Black American descendants of persons enslaved in the U.S. and their potential impact on SARS-CoV-2 transmission.

BACKGROUND: In the United States, Black Americans are suffering from a significantly disproportionate incidence of COVID-19. Going beyond mere epidemiological tallying, the potential for racial-justice interventions, including reparations payments, to ameliorate these disparities has not been adequately explored. METHODS: We compared the COVID-19 time-varying Rt curves of relatively disparate polities in terms of social equity (South Korea vs. Louisiana). Next, we considered a range of reproductive ratios to back-calculate the transmission rates ßi→j for 4 cells of the simplified next-generation matrix (from which R0 is calculated for structured models) for the outbreak in Louisiana. Lastly, we considered the potential structural effects monetary payments as reparations for Black American descendants of persons enslaved in the U.S. would have had on pre-intervention ßi→j and consequently R0. RESULTS: Once their respective epidemics begin to propagate, Louisiana displays Rt values with an absolute difference of 1.3-2.5 compared to South Korea. It also takes Louisiana more than twice as long to bring Rt below 1. Reasoning through the consequences of increased equity via matrix transmission models, we demonstrate how the benefits of a successful reparations program (reflected in the ratio ßb→b/ßw→w) could reduce R0 by 31-68%. DISCUSSION: While there are compelling moral and historical arguments for racial-injustice interventions such as reparations, our study considers potential health benefits in the form of reduced SARS-CoV-2 transmission risk. A restitutive program targeted towards Black individuals would not only decrease COVID-19 risk for recipients of the wealth redistribution; the mitigating effects would also be distributed across racial groups, benefiting the population at large.

Indirect effect of oral azithromycin on the gut resistome of untreated children: a randomized controlled trial.

BACKGROUND: Antibiotic use by one individual may affect selection for antimicrobial resistance in close contacts. Here we evaluated whether oral antibiotic treatment of one child within a household affected the gut resistome of an untreated cohabiting child. METHODS: Households with at least two children <5 y of age were randomized in a 1:1 fashion to a 5d course of azithromycin or placebo. To evaluate indirect effects of azithromycin treatment on the gut resistome, we randomly assigned one child in the house to azithromycin and one to placebo. In placebo households, each child received placebo. We performed DNA sequencing of rectal swabs collected 5 d after the last antibiotic dose. We estimated risk ratios for the presence of genetic resistance determinants at the class level using modified Poisson models for children in azithromycin households compared with placebo households and assessed the composition of the resistome using permutational analysis of variance (PERMANOVA). RESULTS: Of 58 children (n = 30 azithromycin households, n = 28 placebo households) with post-treatment rectal swabs, genetic resistance determinants were common but there was no significant difference at the class (p = 0.54 for macrolides) or gene (p = 0.94 for structure by PERMANOVA, p = 0.94 for diversity) level between untreated children in azithromycin households compared with placebo households. CONCLUSIONS: The results are encouraging that one child's antibiotic use may not influence the resistome of another child. Trial registration: ClinicalTrials.gov NCT03187834.

Frequency responses of age-structured populations: Pacific salmon as an example.

Increasing evidence of the effects of changing climate on physical ocean conditions and long-term changes in fish populations adds to the need to understand the effects of stochastic forcing on marine populations. Cohort resonance is of particular interest because it involves selective sensitivity to specific time scales of environmental variability, including that of mean age of reproduction, and, more importantly, very low frequencies (i.e., trends). We present an age-structured model for two Pacific salmon species with environmental variability in survival rate and in individual growth rate, hence spawning age distribution. We use computed frequency response curves and analysis of the linearized dynamics to obtain two main results. First, the frequency response of the population is affected by the life history stage at which variability affects the population; varying growth rate tends to excite periodic resonance in age structure, while varying survival tends to excite low frequency fluctuation with more effect on total population size. Second, decreasing adult survival strengthens the cohort resonance effect at all frequencies, a finding that addresses the question of how fishing and climate change will interact.

Measles transmission during a large outbreak in California.

A large measles outbreak in 2014-2015, linked to Disneyland theme parks, attracted international attention, and led to changes in California vaccine policy. We use dates of symptom onset and known epidemic links for California cases in this outbreak to estimate time-varying transmission in the outbreak, and to estimate generation membership of cases probabilistically. We find that transmission declined significantly during the course of the outbreak (p = 0.012), despite also finding that estimates of transmission rate by day or by generation can overestimate temporal decline. We additionally find that the outbreak size and duration alone are sufficient in this case to distinguish temporal decline from time-invariant transmission (p = 0.014). As use of a single large outbreak can lead to underestimates of immunity, however, we urge caution in interpretation of quantities estimated from this outbreak alone. Further research is needed to distinguish causes of temporal decline in transmission rates.

Estimation of effects of contact tracing and mask adoption on COVID-19 transmission in San Francisco: a modeling study.

The current COVID-19 pandemic has spurred concern about what interventions may be effective at reducing transmission. The city and county of San Francisco imposed a shelter-in-place order in March 2020, followed by use of a contact tracing program and a policy requiring use of cloth face masks. We used statistical estimation and simulation to estimate the effectiveness of these interventions in San Francisco. We estimated that self-isolation and other practices beginning at the time of San Francisco's shelter-in-place order reduced the effective reproduction number of COVID-19 by 35.4% (95% CI, -20.1%-81.4%). We estimated the effect of contact tracing on the effective reproduction number to be a reduction of approximately 44% times the fraction of cases that are detected, which may be modest if the detection rate is low. We estimated the impact of cloth mask adoption on reproduction number to be approximately 8.6%, and note that the benefit of mask adoption may be substantially greater for essential workers and other vulnerable populations, residents return to circulating outside the home more often. We estimated the effect of those interventions on incidence by simulating counterfactual scenarios in which contact tracing was not adopted, cloth masks were not adopted, and neither contact tracing nor cloth masks was adopted, and found increases in case counts that were modest, but relatively larger than the effects on reproduction numbers. These estimates and model results suggest that testing coverage and timing of testing and contact tracing may be important, and that modest effects on reproduction numbers can nonetheless cause substantial effects on case counts over time.