Point-of-care HCV RNA testing improves hepatitis C testing rates and allows rapid treatment initiation among people who inject drugs attending a medically supervised injecting facility.

BACKGROUND: To achieve hepatitis C virus (HCV) elimination targets, simplified care engaging people who inject drugs is required. We evaluated whether fingerstick HCV RNA point-of-care testing (PoCT) increased the proportion of clients attending a supervised injecting facility who were tested for hepatitis C. METHODS: Prospective single-arm study with recruitment between 9 November 2020 and 28 January 2021 and follow-up to 31 July 2021. Clients attending the supervised injecting facility were offered HCV RNA testing using the Xpert® HCV Viral Load Fingerstick (Cepheid, Sunnyvale, CA) PoCT. Participants with a positive HCV RNA test were prescribed direct acting antiviral (DAA) therapy. The primary endpoint was the proportion of clients who engaged in HCV RNA PoCT, compared to a historical comparator group when venepuncture-based hepatitis C testing was standard of care. RESULTS: Among 1618 clients who attended the supervised injecting facility during the study period, 228 (14%) engaged in PoCT. This was significantly higher than that observed in the historical comparator group (61/1,775, 3%; p < 0.001). Sixty-five (28%) participants were HCV RNA positive, with 40/65 (62%) receiving their result on the same day as testing. Sixty-one (94%) HCV RNA positive participants were commenced on DAA therapy; 14/61 (23%) started treatment on the same day as diagnosis. There was no difference in the proportion of HCV RNA positive participants commenced on treatment with DAA therapy when compared to the historical comparator group (61/65, 94% vs 22/26, 85%; p = 0.153). However, the median time to treatment initiation was significantly shorter in the PoCT cohort (2 days (IQR 1-20) vs 41 days (IQR 22-76), p < 0.001). Among participants who commenced treatment and had complete follow-up data available, 27/36 (75%) achieved hepatitis C cure. CONCLUSIONS: HCV RNA PoCT led to a significantly higher proportion of clients attending a supervised injecting facility engaging in hepatitis C testing, whilst also reducing the time to treatment initiation.

Leaping through Tree Space: Continuous Phylogenetic Inference for Rooted and Unrooted Trees.

Phylogenetics is now fundamental in life sciences, providing insights into the earliest branches of life and the origins and spread of epidemics. However, finding suitable phylogenies from the vast space of possible trees remains challenging. To address this problem, for the first time, we perform both tree exploration and inference in a continuous space where the computation of gradients is possible. This continuous relaxation allows for major leaps across tree space in both rooted and unrooted trees, and is less susceptible to convergence to local minima. Our approach outperforms the current best methods for inference on unrooted trees and, in simulation, accurately infers the tree and root in ultrametric cases. The approach is effective in cases of empirical data with negligible amounts of data, which we demonstrate on the phylogeny of jawed vertebrates. Indeed, only a few genes with an ultrametric signal were generally sufficient for resolving the major lineages of vertebrates. Optimization is possible via automatic differentiation and our method presents an effective way forward for exploring the most difficult, data-deficient phylogenetic questions.

The limits of the constant-rate birth-death prior for phylogenetic tree topology inference.

Birth-death models are stochastic processes describing speciation and extinction through time and across taxa, and are widely used in biology for inference of evolutionary timescales. Previous research has highlighted how the expected trees under the constant-rate birth-death (crBD) model tend to differ from empirical trees, for example with respect to the amount of phylogenetic imbalance. However, our understanding of how trees differ between the crBD model and the signal in empirical data remains incomplete. In this Point of View, we aim to expose the degree to which the crBD model differs from empirically inferred phylogenies and test the limits of the model in practice. Using a wide range of topology indices to compare crBD expectations against a comprehensive dataset of 1189 empirically estimated trees, we confirm that crBD model trees frequently differ topologically compared with empirical trees. To place this in the context of standard practice in the field, we conducted a meta-analysis for a subset of the empirical studies. When comparing studies that used Bayesian methods and crBD priors with those that used other non-crBD priors and non-Bayesian methods (i.e., maximum likelihood methods), we do not find any significant differences in tree topology inferences. To scrutinize this finding for the case of highly imbalanced trees, we selected the 100 trees with the greatest imbalance from our dataset, simulated sequence data for these tree topologies under various evolutionary rates, and re-inferred the trees under maximum likelihood and using the crBD model in a Bayesian setting. We find that when the substitution rate is low, the crBD prior results in overly balanced trees, but the tendency is negligible when substitution rates are sufficiently high. Overall, our findings demonstrate the general robustness of crBD priors across a broad range of phylogenetic inference scenarios, but also highlights that empirically observed phylogenetic imbalance is highly improbable under the crBD model, leading to systematic bias in data sets with limited information content.

Unifying incidence and prevalence under a time-varying general branching process.

Renewal equations are a popular approach used in modelling the number of new infections, i.e., incidence, in an outbreak. We develop a stochastic model of an outbreak based on a time-varying variant of the Crump-Mode-Jagers branching process. This model accommodates a time-varying reproduction number and a time-varying distribution for the generation interval. We then derive renewal-like integral equations for incidence, cumulative incidence and prevalence under this model. We show that the equations for incidence and prevalence are consistent with the so-called back-calculation relationship. We analyse two particular cases of these integral equations, one that arises from a Bellman-Harris process and one that arises from an inhomogeneous Poisson process model of transmission. We also show that the incidence integral equations that arise from both of these specific models agree with the renewal equation used ubiquitously in infectious disease modelling. We present a numerical discretisation scheme to solve these equations, and use this scheme to estimate rates of transmission from serological prevalence of SARS-CoV-2 in the UK and historical incidence data on Influenza, Measles, SARS and Smallpox.

Optimality of Maximal-Effort Vaccination.

It is widely acknowledged that vaccinating at maximal effort in the face of an ongoing epidemic is the best strategy to minimise infections and deaths from the disease. Despite this, no one has proved that this is guaranteed to be true if the disease follows multi-group SIR (Susceptible-Infected-Recovered) dynamics. This paper provides a novel proof of this principle for the existing SIR framework, showing that the total number of deaths or infections from an epidemic is decreasing in vaccination effort. Furthermore, it presents a novel model for vaccination which assumes that vaccines assigned to a subgroup are distributed randomly to the unvaccinated population of that subgroup. It suggests, using COVID-19 data, that this more accurately captures vaccination dynamics than the model commonly found in the literature. However, as the novel model provides a strictly larger set of possible vaccination policies, the results presented in this paper hold for both models.

Eliminating hepatitis C in Australia: a novel model of hepatitis C testing and treatment for people who inject drugs at a medically supervised injecting facility.

OBJECTIVE: To evaluate the feasibility of testing and treating people who inject drugs at a supervised injecting facility for hepatitis C virus (HCV) infection. DESIGN: Retrospective cohort study. SETTING, PARTICIPANTS: People who inject drugs who attended the Melbourne supervised injecting facility, 30 June 2018 - 30 June 2020. MAIN OUTCOME MEASURES: Proportion of people tested for hepatitis C; proportions of people positive for anti-HCV antibody and HCV RNA, and of eligible people prescribed direct-acting antiviral (DAA) treatment; sustained virological response twelve weeks or more after treatment completion. RESULTS: Of 4649 people who attended the supervised injecting facility during 2018-20, 321 were tested for hepatitis C (7%); 279 were anti-HCV antibody-positive (87%), of whom 143 (51%) were also HCV RNA-positive. Sixty-four of 321 had previously been treated for hepatitis C (20%), 21 had clinically identified cirrhosis (7%), eight had hepatitis B infections (2%), and four had human immunodeficiency virus infections (1%). In multivariate analyses, people tested for hepatitis C were more likely than untested clients to report psychiatric illness (adjusted odds ratio [aOR], 9.65; 95% confidence interval [CI], 7.26-12.8), not have a fixed address (aOR, 1.59; 95% CI, 1.18-2.14), and to report significant alcohol use (aOR, 1.57; 95% CI, 1.06-2.32). The median number of injecting facility visits was larger for those tested for hepatitis C (101; interquartile range [IQR], 31-236) than for those not tested (20; IQR, 3-90). DAA treatment was prescribed for 126 of 143 HCV RNA-positive clients (88%); 41 of 54 with complete follow-up data were cured (76%). CONCLUSIONS: People who attend supervised injecting facilities can be tested and treated for hepatitis C on site. Models that provide streamlined, convenient hepatitis C care promote engagement with treatment in a group in which the prevalence of hepatitis C is high.

Asymptotic Analysis of Optimal Vaccination Policies.

Targeted vaccination policies can have a significant impact on the number of infections and deaths in an epidemic. However, optimising such policies is complicated, and the resultant solution may be difficult to explain to policy-makers and to the public. The key novelty of this paper is a derivation of the leading-order optimal vaccination policy under multi-group susceptible-infected-recovered dynamics in two different cases. Firstly, it considers the case of a small vulnerable subgroup in a population and shows that (in the asymptotic limit) it is optimal to vaccinate this group first, regardless of the properties of the other groups. Then, it considers the case of a small vaccine supply and transforms the optimal vaccination problem into a simple knapsack problem by linearising the final size equations. Both of these cases are then explored further through numerical examples, which show that these solutions are also directly useful for realistic parameter values. Moreover, the findings of this paper give some general principles for optimal vaccination policies which will help policy-makers and the public to understand the reasoning behind optimal vaccination programs in more generic cases.

Intrinsic randomness in epidemic modelling beyond statistical uncertainty.

Uncertainty can be classified as either aleatoric (intrinsic randomness) or epistemic (imperfect knowledge of parameters). The majority of frameworks assessing infectious disease risk consider only epistemic uncertainty. We only ever observe a single epidemic, and therefore cannot empirically determine aleatoric uncertainty. Here, we characterise both epistemic and aleatoric uncertainty using a time-varying general branching process. Our framework explicitly decomposes aleatoric variance into mechanistic components, quantifying the contribution to uncertainty produced by each factor in the epidemic process, and how these contributions vary over time. The aleatoric variance of an outbreak is itself a renewal equation where past variance affects future variance. We find that, superspreading is not necessary for substantial uncertainty, and profound variation in outbreak size can occur even without overdispersion in the offspring distribution (i.e. the distribution of the number of secondary infections an infected person produces). Aleatoric forecasting uncertainty grows dynamically and rapidly, and so forecasting using only epistemic uncertainty is a significant underestimate. Therefore, failure to account for aleatoric uncertainty will ensure that policymakers are misled about the substantially higher true extent of potential risk. We demonstrate our method, and the extent to which potential risk is underestimated, using two historical examples.

Foodborne illness outbreaks linked to unpasteurised milk and relationship to changes in state laws - United States, 1998-2018.

Consumption of unpasteurised milk in the United States has presented a public health challenge for decades because of the increased risk of pathogen transmission causing illness outbreaks. We analysed Foodborne Disease Outbreak Surveillance System data to characterise unpasteurised milk outbreaks. Using Poisson and negative binomial regression, we compared the number of outbreaks and outbreak-associated illnesses between jurisdictions grouped by legal status of unpasteurised milk sale based on a May 2019 survey of state laws. During 2013-2018, 75 outbreaks with 675 illnesses occurred that were linked to unpasteurised milk; of these, 325 illnesses (48%) were among people aged 0-19 years. Of 74 single-state outbreaks, 58 (78%) occurred in states where the sale of unpasteurised milk was expressly allowed. Compared with jurisdictions where retail sales were prohibited (n = 24), those where sales were expressly allowed (n = 27) were estimated to have 3.2 (95% CI 1.4-7.6) times greater number of outbreaks; of these, jurisdictions where sale was allowed in retail stores (n = 14) had 3.6 (95% CI 1.3-9.6) times greater number of outbreaks compared with those where sale was allowed on-farm only (n = 13). This study supports findings of previously published reports indicating that state laws resulting in increased availability of unpasteurised milk are associated with more outbreak-associated illnesses and outbreaks.

Analysis of a double Poisson model for predicting football results in Euro 2020.

First developed in 1982, the double Poisson model, where goals scored by each team are assumed to be Poisson distributed with a mean depending on attacking and defensive strengths, remains a popular choice for predicting football scores, despite the multitude of newer methods that have been developed. This paper examines the pre-tournament predictions made using this model for the Euro 2020 football tournament. These predictions won the Royal Statistical Society's prediction competition, demonstrating that even this simple model can produce high-quality results. Moreover, the paper also presents a range of novel analytic results which exactly quantify the conditions for the existence and uniqueness of the solution to the equations for the model parameters. After deriving these results, it provides a novel examination of a potential problem with the model-the over-weighting of the results of weaker teams-and illustrates the effectiveness of ignoring results against the weakest opposition. It also compares the predictions with the actual results of Euro 2020, showing that they were extremely accurate in predicting the number of goals scored. Finally, it considers the choice of start date for the dataset, and illustrates that the choice made by the authors (which was to start the dataset just after the previous major international tournament) was close to optimal, at least in this case. The findings of this study give a better understanding of the mathematical behaviour of the double Poisson model and provide evidence for its effectiveness as a match prediction tool.

A method for continuous study of soaring and windhovering birds.

Avian flight continues to inspire aircraft designers. Reducing the scale of autonomous aircraft to that of birds and large insects has resulted in new control challenges when attempting to hold steady flight in turbulent atmospheric wind. Some birds, however, are capable of remarkably stable hovering flight in the same conditions. This work describes the development of a wind tunnel configuration that facilitates the study of flapless windhovering (hanging) and soaring bird flight in wind conditions replicating those in nature. Updrafts were generated by flow over replica "hills" and turbulence was introduced through upstream grids, which had already been developed to replicate atmospheric turbulence in prior studies. Successful flight tests with windhovering nankeen kestrels (Falco cenchroides) were conducted, verifying that the facility can support soaring and wind hovering bird flight. The wind tunnel allows the flow characteristics to be carefully controlled and measured, providing great advantages over outdoor flight tests. Also, existing wind tunnels may be readily configured using this method, providing a simpler alternative to the development of dedicated bird flight wind tunnels such as tilting wind tunnels, and the large test section allows for the replication of orographic soaring. This methodology holds promise for future testing investigating the flight behaviour and control responses employed by soaring and windhovering birds.

Public Health Strategies: A Pathway for Public Health Practice to Leverage Law in Advancing Equity.

This article outlines a pathway for public health departments and practitioners to incorporate law into their efforts to advance equity in health outcomes. We assert that examining and applying law can accelerate public health efforts to mitigate structural and systemic inequities, including racism. Recent events such as the COVID-19 pandemic and the community impacts of policing have brought into sharp relief the inequities faced by many populations. These stark and explosive examples arise out of long-standing, persistent, and sometimes hidden structural and systemic inequities that are difficult to trace because they are embedded in laws and accompanying policies and practices. We emphasize this point with a case study involving a small, majority Black community in semirural Appalachia that spent almost 50 years attempting to gain access to the local public water system, despite being surrounded by water lines. We suggest that public health practitioners have a role to play in addressing these kinds of public health problems, which are so clearly tied to the ways laws and policies are developed and executed. We further suggest that public health practitioners, invoking the 10 Essential Public Health Services, can employ law as a tool to increase their capacity to craft and implement evidence-based interventions.

Evolution of Federalism in Environmental Health: Federal, State, and Local Government Control.

Environmental health sits at the intersection of public health and environmental protection. Governments often confront environmental health concerns through environmental laws. Authority to take actions like passing these laws is determined by federalism, which divides the authority to make laws and policies on various issues between those levels of government. However, tensions often arise when these levels of government attempt to share regulatory authority over environmental issues. Issues of federalism are especially prevalent in environmental health issues, where incidents not only cross state and local borders and affect different levels of government but may also involve both environmental and health agencies. This article describes the history of environmental federalism in the United States through the lens of public health, including how the regulatory structure transitioned from primarily state control to a more centralized federal system of governance. It also describes modern federalism in environmental health, the levels of government involved in environmental health decisions, and the legal authorities that allow these governments to regulate environmental health in the United States. Finally, this article describes the implications of federalism in environmental health.

Building the Legal Capacity of the Public Health Workforce: Introducing the Public Health Law Academy.

Knowledge of the law and its impact on health outcomes is increasingly important in public health practice. The CDC's Public Health Law Academy helps satisfy this need by providing online trainings, facilitator toolkits, and legal epidemiology tools to aid practitioners in learning about the law's role in promoting public health.

Emergency Declarations for Public Health Issues: Expanding Our Definition of Emergency.

Emergency declarations are a vital legal authority that can activate funds, personnel, and material and change the legal landscape to aid in the response to a public health threat. Traditionally, declarations have been used against immediate and unforeseen threats such as hurricanes, tornadoes, wildfires, and pandemic influenza. Recently, however, states have used emergency declarations to address public health issues that have existed in communities for months and years and have risk factors such as poverty and substance misuse. Leaders in these states have chosen to use emergency powers that are normally reserved for sudden catastrophes to address these enduring public health issues. This article will explore emergency declarations as a legal mechanism for response; describe recent declarations to address hepatitis A and the opioid overdose epidemic; and seek to answer the question of whether it is appropriate to use emergency powers to address public health issues that are not traditionally the basis for an emergency declaration.

Association of HIV Preexposure Prophylaxis With Incidence of Sexually Transmitted Infections Among Individuals at High Risk of HIV Infection.

Importance: Emerging evidence suggests that risk of bacterial sexually transmitted infections (STIs) increases among gay and bisexual men following initiation of HIV preexposure prophylaxis (PrEP). Objective: To describe STI incidence and behavioral risk factors among a cohort of predominantly gay and bisexual men who use PrEP, and to explore changes in STI incidence following PrEP commencement. Design, Setting, and Participants: The Pre-exposure Prophylaxis Expanded (PrEPX) Study, a multisite, open-label intervention study, was nested within the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS) clinic network. A total of 4275 participants were enrolled (July 26, 2016-April 1, 2018) in Victoria, Australia. Of these, 2981 enrolled at 5 ACCESS clinics (3 primary care, 1 sexual health, and 1 community-based HIV rapid testing service), had at least 1 follow-up visit, and were monitored until April 30, 2018. Exposures: Upon enrollment, participants received daily oral tenofovir disoproxil fumurate and emtricitabine for HIV PrEP, quarterly HIV and STI testing, and clinical monitoring. Main Outcomes and Measures: The primary outcome was incidence of chlamydia, gonorrhea, or syphilis. Incidence rates and hazard ratios describing behavioral risk factors of STI diagnosis were calculated. Incidence rate ratios (IRRs), adjusted for change in testing frequency, described changes in STI incidence from 1-year preenrollment to study follow-up among participants with preenrollment testing data (n = 1378). Results: Among the 2981 individuals (median age, 34 years [interquartile range, 28-42]), 98.5% identified as gay or bisexual males, 29% used PrEP prior to enrollment, 89 (3%) withdrew and were censored at date of withdrawal, leaving 2892 (97.0%) enrolled at final follow-up. During a mean follow-up of 1.1 years (3185.0 person-years), 2928 STIs were diagnosed among 1427 (48%) participants (1434 chlamydia, 1242 gonorrhea, 252 syphilis). STI incidence was 91.9 per 100 person-years, with 736 participants (25%) accounting for 2237 (76%) of all STIs. Among 2058 participants with complete data for multivariable analysis, younger age, greater partner number, and group sex were associated with greater STI risk, but condom use was not. Among 1378 participants with preenrollment testing data, STI incidence increased from 69.5 per 100 person-years prior to enrollment to 98.4 per 100 person-years during follow-up (IRR, 1.41 [95% CI, 1.29-1.56]). After adjusting for testing frequency, the increase in incidence from 1 year preenrollment to follow-up was significant for any STI (adjusted IRR, 1.12 [95% CI, 1.02-1.23]) and for chlamydia (adjusted IRR, 1.17 [95% CI, 1.04-1.33]). Conclusions and Relevance: Among gay and bisexual men using PrEP, STIs were highly concentrated among a subset, and receipt of PrEP after study enrollment was associated with an increased incidence of STIs compared with preenrollment. These findings highlight the importance of frequent STI testing among gay and bisexual men using PrEP.

An Assessment of State Laws Providing Gubernatorial Authority to Remove Legal Barriers to Emergency Response.

Legal Perspectives is aimed at informing healthcare providers, emergency planners, public health practitioners, and other decision makers about important legal issues related to public health and healthcare preparedness and response. The articles describe these potentially challenging topics and conclude with the authors' suggestions for further action. The articles do not provide legal advice. Therefore, those affected by the issues discussed in this column should seek further guidance from legal counsel. Readers may submit topics of interest to the column's editor, Lainie Rutkow, JD, PhD, MPH, at lrutkow@jhu.edu. Governors play a fundamental role in emergency preparedness and can help facilitate rapid responses to emergencies. However, laws that operate successfully under normal circumstances can inadvertently create barriers during emergencies, delaying a timely response. State laws could thus limit, or even prohibit, necessary response efforts. To combat this risk, legislatures have passed emergency powers laws in each state granting governors the authority to declare a state of emergency and to exercise certain emergency powers to meet the needs of the emergency. Researchers conducted a 50-state legal assessment, which identified and examined state laws that give governors the discretion to modify existing laws or create new laws to respond effectively to any type of declared emergency. This article outlines the findings of that assessment, which identified 35 states that explicitly permit governors to suspend or amend both statutes and regulations; 7 states in which governors are permitted to amend regulations during a declared emergency but are not explicitly authorized to modify or remove statutes; and 8 states and the District of Columbia that provide no explicit authority to governors to change statutes or regulations during a declared emergency. The article also provides examples of how this power has been used in the past to demonstrate the utility and scope of this authority in a variety of public health threats.