Potential impact of curative and preventive interventions toward hepatitis C elimination in people who inject drugs-A network modeling study.

BACKGROUND: Injection-equipment-sharing networks play an important role in hepatitis C virus (HCV) transmission among people who inject drugs (PWID). Direct-acting antiviral (DAA) treatments for HCV infection and interventions to prevent HCV transmission are critical components of an overall hepatitis C elimination strategy, but how they contribute to the elimination outcomes in different PWID network settings are unclear. METHODS: We developed an agent-based network model of HCV transmission through the sharing of injection equipment among PWID and parameterized and calibrated the model with rural PWID data in the United States. We modeled curative and preventive interventions at annual coverage levels of 12.5 %, 25 %, or 37.5 % (cumulative percentage of eligible individuals engaged), and two allocation approaches: random vs targeting PWID with more injection partners (hereafter 'degree-based'). We compared the impact of these intervention strategies on prevalence and incidence of HCV infections. We conducted sensitivity analysis on key parameters governing the effects of curative and preventive interventions and PWID network characteristics. RESULTS: Combining curative and preventive interventions at 37.5 % annual coverage with degree-based allocation decreased prevalence and incidence of HCV infection by 67 % and 70 % over two years, respectively. Curative interventions decreased prevalence by six to 12 times more than preventive interventions, while curative and preventive interventions had comparable effectiveness on reducing incidence. Intervention impact increased with coverage almost linearly across all intervention strategies, and degree-based allocation was always more effective than random allocation, especially for preventive interventions. Results were sensitive to parameter values defining intervention effects and network mean degree. CONCLUSION: DAA treatments are effective in reducing both prevalence and incidence of HCV infection in PWID, but preventive interventions play a significant role in reducing incidence when intervention coverage is low. Increasing coverage, including efforts in reaching individuals with the most injection partners, preventing reinfection, and improving compliance and retention in preventive services can substantially improve the outcomes. PWID network characteristics should be considered when designing hepatitis C elimination programs.

The Risk for Readmission to Juvenile Detention: The Role of Trauma Exposure and Trauma-related Mental Health Disorders.

The purpose of this study was to examine the impact of childhood trauma exposure, posttraumatic stress disorder, and trauma-related comorbid diagnoses on the risk for readmission to juvenile detention among youth in a large metropolitan area (N = 1282). The following research questions were addressed: 1) Does a greater number of childhood traumas increase the risk for readmission to detention following release? 2) Does the risk for readmission differ by type of trauma? 3) Do PTSD and other co-morbid diagnoses increase the risk for readmission? and 4) What role do demographic factors play in the relationship between trauma-related variables and risk for readmission? This study utilized the screening results of 1282 youth who were voluntarily screened for PTSD, depressive symptoms and substance use during their initial intake to detention. More than half of the sample was readmitted during the three-year study period, with readmissions most likely to occur within one year of release. Returning to detention within one year was also associated with increased risk for multiple readmissions. Youth readmitted to detention were more likely to have a history of sexual abuse and problematic substance use. No other significant relationships were found between risk for readmission and trauma-related variables. Although trauma-related symptoms may be crucial targets for treatment, focusing solely on trauma exposure and traumatic stress symptoms without considering the impact of other risk factors may not be enough to decrease the likelihood of readmission for youth of color in a large urban environment.

The role of socio-economic disparities in the relative success and persistence of SARS-CoV-2 variants in New York City in early 2021.

Socio-economic disparities were associated with disproportionate viral incidence between neighborhoods of New York City (NYC) during the first wave of SARS-CoV-2. We investigated how these disparities affected the co-circulation of SARS-CoV-2 variants during the second wave in NYC. We tested for correlation between the prevalence, in late 2020/early 2021, of Alpha, Iota, Iota with E484K mutation (Iota-E484K), and B.1-like genomes and pre-existing immunity (seropositivity) in NYC neighborhoods. In the context of varying seroprevalence we described socio-economic profiles of neighborhoods and performed migration and lineage persistence analyses using a Bayesian phylogeographical framework. Seropositivity was greater in areas with high poverty and a larger proportion of Black and Hispanic or Latino residents. Seropositivity was positively correlated with the proportion of Iota-E484K and Iota genomes, and negatively correlated with the proportion of Alpha and B.1-like genomes. The proportion of persisting Alpha lineages declined over time in locations with high seroprevalence, whereas the proportion of persisting Iota-E484K lineages remained the same in high seroprevalence areas. During the second wave, the geographic variation of standing immunity, due to disproportionate disease burden during the first wave of SARS-CoV-2 in NYC, allowed for the immune evasive Iota-E484K variant, but not the more transmissible Alpha variant, to circulate in locations with high pre-existing immunity.

Examining the social and behavioral dynamics of substance use in a longitudinal network study in rural Appalachia.

BACKGROUND: Prior studies have shown that individuals and their peers often have similar substance use behaviors, but the mechanisms driving these similarities - particularly in rural settings, are not well understood. The primary objectives of this analysis are to (1) identify factors that contribute to relationship turnover and maintenance within a rural network of persons who use drugs (PWUD), (2) determine whether assimilation and/or homophily shape participants use of injection drugs, heroin, and stimulants (methamphetamine and cocaine), and (3) assess the extent that these mechanisms influence networks ties and/or behaviors and whether these effects vary across time. METHODS: Sociometric network data were collected from a cohort of PWUD in rural Eastern Kentucky at baseline (2008-2010) and at four follow-up visits conducted approximately semiannually. Stochastic actor-oriented models (SAOMS) were used to model network structure and participant behaviors as jointly dependent variables and to identify characteristics associated with the maintenance, dissolution, and formation of network ties and changes in drug use behaviors. RESULTS: Findings suggest (1) greater network stability over time for reciprocal and transitive relationships, (2) both homophily and assimilation played a greater role in shaping injection drug use (IDU) initiation and cessation than they did in shaping heroin and stimulant use, and (3) the importance of these mechanisms appeared consistent over time. CONCLUSION: Given the stability of particular network structures and evidence of both homophily and assimilation with respect to drug-use behaviors, interventions that leverage social networks could be used to motivate health-promoting behaviors.

Predictors of engagement in screening for a hepatitis C virus (HCV) treatment trial in a rural Appalachian community.

An HCV treatment trial was initiated in September 2019 to address the opioid/hepatitis C virus (HCV) syndemic in rural Kentucky. The focus of the current analysis is on participation in diagnostic screening for the trial. Initial eligibility (≥18 years of age, county resident) was established by phone followed by in-person HCV viremia testing. 900 rural residents met the inclusion criteria and comprised the analytic sample. Generalized linear models were specified to estimate the relative risk of non-attendance at the in-person visit determining HCV eligibility. Approximately one-quarter (22.1%) of scheduled participants were no-shows. People who inject drugs were no more likely than people not injecting drugs to be a no-show; however, participants ≤35 years of age were significantly less likely to attend. While the median time between phone screening and scheduled in-person screening was only 2 days, each additional day increased the odds of no-show by 3% (95% confidence interval: 2%-3%). Finally, unknown HCV status predicted no-show even after adjustment for age, gender, days between screenings and injection status. We found that drug injection did not predict no-show, further justifying expanded access to HCV treatment among people who inject drugs. Those 35 years and younger were more likely to no-show, suggesting that younger individuals may require targeted strategies for increasing testing and treatment uptake. Finally, streamlining the treatment cascade may also improve outcomes, as participants in the current study were more likely to attend if there were fewer days between phone screening and scheduled in-person screening.

A Two-Generation, Early Childhood Advanced Primary Care Model.

It is well recognized that early experiences produce long-term impacts on health outcomes, yet many children are at risk of not achieving their full potential because of health and service disparities related largely to poverty and racism. Although many pediatric primary care (PPC) models address these needs, most are isolated, add-on efforts that struggle to be scalable and sustainable. We describe 3-2-1 IMPACT (Integrated Model for Parents and Children Together), an initiative to transform the model of PPC delivered within New York City Health + Hospitals, the largest public hospital system in the United States, to address the full range of child and family needs in early childhood. Taking advantage of the frequent contact with PPC in the early years and linking to prenatal services, the model assesses family mental, social, and physical health needs and offers evidence-based parenting supports and integrated mental health services. Launching and sustaining the model in our large health system has required coalition building and sustained advocacy at the state, city, and health system levels. Long-term sustainability of the IMPACT model will depend on the implementation of early childhood-focused advanced payment models, on which we have made substantial progress with our major contracted Medicaid managed care plans. By integrating multiple interventions into PPC and prenatal care across a large public-healthcare system, we hope to synergize evidence-based and evidence-informed interventions that individually have relatively small effect sizes, but combined, could substantially improve child and maternal health outcomes and positively impact health disparities.

Kentucky Outreach Service Kiosk (KyOSK) Study protocol: a community-level, controlled quasi-experimental, type 1 hybrid effectiveness study to assess implementation, effectiveness and cost-effectiveness of a community-tailored harm reduction kiosk on HIV, HCV and overdose risk in rural Appalachia.

INTRODUCTION: Many rural communities bear a disproportionate share of drug-related harms. Innovative harm reduction service models, such as vending machines or kiosks, can expand access to services that reduce drug-related harms. However, few kiosks operate in the USA, and their implementation, impact and cost-effectiveness have not been adequately evaluated in rural settings. This paper describes the Kentucky Outreach Service Kiosk (KyOSK) Study protocol to test the effectiveness, implementation outcomes and cost-effectiveness of a community-tailored, harm reduction kiosk in reducing HIV, hepatitis C and overdose risk in rural Appalachia. METHODS AND ANALYSIS: KyOSK is a community-level, controlled quasi-experimental, non-randomised trial. KyOSK involves two cohorts of people who use drugs, one in an intervention county (n=425) and one in a control county (n=325). People who are 18 years or older, are community-dwelling residents in the target counties and have used drugs to get high in the past 6 months are eligible. The trial compares the effectiveness of a fixed-site, staffed syringe service programme (standard of care) with the standard of care supplemented with a kiosk. The kiosk will contain various harm reduction supplies accessible to participants upon valid code entry, allowing dispensing data to be linked to participant survey data. The kiosk will include a call-back feature that allows participants to select needed services and receive linkage-to-care services from a peer recovery coach. The cohorts complete follow-up surveys every 6 months for 36 months (three preceding kiosk implementation and four post-implementation). The study will test the effectiveness of the kiosk on reducing risk behaviours associated with overdose, HIV and hepatitis C, as well as implementation outcomes and cost-effectiveness. ETHICS AND DISSEMINATION: The University of Kentucky Institutional Review Board approved the protocol. Results will be disseminated in academic conferences and peer-reviewed journals, online and print media, and community meetings. TRIAL REGISTRATION NUMBER: NCT05657106.

"They make it too hard and too many hoops to jump": system and organizational barriers to drug treatment during epidemic rates of opioid overdose.

INTRODUCTION: The United States is currently facing an opioid overdose crisis. Research suggests that multiple interventions are needed to reduce overdose deaths including increasing access and retention to medications to treat opioid use disorders (MOUD, i.e., methadone, buprenorphine, and naltrexone) and increasing the distribution and use of naloxone, a medication that can reverse the respiratory depression that occurs during opioid overdoses. However, barriers to MOUD initiation and retention persist and discontinuations of MOUD carry a heightened risk of overdose. Many times, MOUD is not sought as a first line of treatment by people with opioid use disorder (OUD), many of whom seek treatment from medically managed withdrawal (detox) programs. Among those who do initiate MOUD, retention is generally low. The present study examines the treatment experiences of people who use opioids in three states, Connecticut, Kentucky, and Wisconsin. METHODS: We conducted in-depth interviews with people who use opioids in a rural, urban, and suburban area of three states: Connecticut, Kentucky and Wisconsin. Data analysis was collaborative and key themes were identified through multiple readings, coding of transcripts and discussion with all research team members. RESULTS: Results reveal a number of systemic issues that reduce the likelihood that people initiate and are retained on MOUD including the ubiquity of detox as a first step in drug treatment, abstinence requirements and requiring patients to attend group treatment. MOUD-related stigma was a significant factor in the kinds of treatment participants chose and their experiences in treatment. CONCLUSIONS: Interventions to reduce MOUD stigma are needed to encourage MOUD as a first course of treatment. Eliminating abstinence-based rules for MOUD treatment may improve treatment retention and decrease overdose risk.

The recency and geographical origins of the bat viruses ancestral to SARS-CoV and SARS-CoV-2.

The emergence of SARS-CoV in 2002 and SARS-CoV-2 in 2019 has led to increased sampling of related sarbecoviruses circulating primarily in horseshoe bats. These viruses undergo frequent recombination and exhibit spatial structuring across Asia. Employing recombination-aware phylogenetic inference on bat sarbecoviruses, we find that the closest-inferred bat virus ancestors of SARS-CoV and SARS-CoV-2 existed just ~1-3 years prior to their emergence in humans. Phylogeographic analyses examining the movement of related sarbecoviruses demonstrate that they traveled at similar rates to their horseshoe bat hosts and have been circulating for thousands of years in Asia. The closest-inferred bat virus ancestor of SARS-CoV likely circulated in western China, and that of SARS-CoV-2 likely circulated in a region comprising southwest China and northern Laos, both a substantial distance from where they emerged. This distance and recency indicate that the direct ancestors of SARS-CoV and SARS-CoV-2 could not have reached their respective sites of emergence via the bat reservoir alone. Our recombination-aware dating and phylogeographic analyses reveal a more accurate inference of evolutionary history than performing only whole-genome or single gene analyses. These results can guide future sampling efforts and demonstrate that viral genomic fragments extremely closely related to SARS-CoV and SARS-CoV-2 were circulating in horseshoe bats, confirming their importance as the reservoir species for SARS viruses.

Chemical Inhibition of Bromodomain Proteins in Insect-Stage African Trypanosomes Perturbs Silencing of the Variant Surface Glycoprotein Repertoire and Results in Widespread Changes in the Transcriptome.

The eukaryotic protozoan parasite Trypanosoma brucei is transmitted by the tsetse fly to both humans and animals, where it causes a fatal disease called African trypanosomiasis. While the parasite lacks canonical DNA sequence-specific transcription factors, it does possess histones, histone modifications, and proteins that write, erase, and read histone marks. Chemical inhibition of chromatin-interacting bromodomain proteins has previously been shown to perturb bloodstream specific trypanosome processes, including silencing of the variant surface glycoprotein (VSG) genes and immune evasion. Transcriptomic changes that occur in bromodomain-inhibited bloodstream parasites mirror many of the changes that occur as parasites developmentally progress from the bloodstream to the insect stage. We performed transcriptome sequencing (RNA-seq) time courses to determine the effects of chemical bromodomain inhibition in insect-stage parasites using the compound I-BET151. We found that treatment with I-BET151 causes large changes in the transcriptome of insect-stage parasites and also perturbs silencing of VSG genes. The transcriptomes of bromodomain-inhibited parasites share some features with early metacyclic-stage parasites in the fly salivary gland, implicating bromodomain proteins as important for regulating transcript levels for developmentally relevant genes. However, the downregulation of surface procyclin protein that typically accompanies developmental progression is absent in bromodomain-inhibited insect-stage parasites. We conclude that chemical modulation of bromodomain proteins causes widespread transcriptomic changes in multiple trypanosome life cycle stages. Understanding the gene-regulatory processes that facilitate transcriptome remodeling in this highly diverged eukaryote may shed light on how these mechanisms evolved. IMPORTANCE The disease African trypanosomiasis imposes a severe human and economic burden for communities in sub-Saharan Africa. The parasite that causes the disease is transmitted to the bloodstream of a human or ungulate via the tsetse fly. Because the environments of the fly and the bloodstream differ, the parasite modulates the expression of its genes to accommodate two different lifestyles in these disparate niches. Perturbation of bromodomain proteins that interact with histone proteins around which DNA is wrapped (chromatin) causes profound changes in gene expression in bloodstream-stage parasites. This paper reports that gene expression is also affected by chemical bromodomain inhibition in insect-stage parasites but that the genes affected differ depending on life cycle stage. Because trypanosomes diverged early from model eukaryotes, an understanding of how trypanosomes regulate gene expression may lend insight into how gene-regulatory mechanisms evolved. This could also be leveraged to generate new therapeutic strategies.

Changes in Attitudes and Knowledge after Trainings in a Clinical Care Pathway for Autism Spectrum Disorder.

Caring for individuals with autism spectrum disorder (ASD) can be complicated, especially when challenging behaviors are present. Providers may feel unprepared to work with these individuals because specialized training for medical and social service providers is limited. To increase access to specialized training, we modified an effective half-day ASD-Care Pathway training (Kuriakose et al. 2018) and disseminated it within five different settings. This short, focused training on strategies for preventing and reducing challenging behaviors of patients with ASD resulted in significant improvements in staff perceptions of challenging behaviors, increased comfort in working with the ASD population, and increased staff knowledge for evidence-informed practices. Implications, including the impact of sociodemographic characteristics on pre/post changes, and future directions are discussed.

Assessing Motivations for Nonprescribed Buprenorphine Use Among Rural Appalachian Substance Users.

OBJECTIVE: Buprenorphine (Suboxone) is an effective treatment for opioid use disorder (OUD). However, there have been widespread reports of diversion and misuse. This study examined motivations for nonprescribed buprenorphine use among rural residents. METHODS: Eligible participants (N = 200) were at least 18 years old, had used any illegal or prescription drugs to get high, and had ever used nonprescribed buprenorphine. A questionnaire administered by a trained interviewer assessed demographic characteristics, substance use, and motivations for use. RESULTS: Primary motivations for first nonprescribed buprenorphine use included avoiding withdrawal and getting high, while at most recent nonprescribed use, motivations shifted toward maintaining abstinence from other drugs. In adjusted logistic regression analyses, past month use of stimulants decreased odds of nonprescribed buprenorphine use for the purposes of self-treatment by 68% (adjusted odds ratio, 0.26; 95% confidence interval, 0.11-0.61), whereas history of treatment for OUD more than doubled odds of use for self-treatment (adjusted odds ratio, 2.71; 95% confidence interval, 1.11-6.63). CONCLUSIONS: Results indicate that many individuals used buprenorphine without a prescription, motivated largely by behaviors consistent with self-treatment, and diversion of buprenorphine may be driven by these motivations more than desire to get high. While many participants attempted to access treatment, many were still using nonprescribed buprenorphine for self-treatment, and many were dissatisfied with care they had received as part of a treatment program. Thus, increasing quantity of providers may not be adequate to address the opioid epidemic, but particular attention should be paid to providing care targeted to the needs of those with OUD in rural areas.

Phylogeographic analysis reveals an ancient East African origin of human herpes simplex virus 2 dispersal out-of-Africa.

Human herpes simplex virus 2 (HSV-2) is a ubiquitous, slowly evolving DNA virus. HSV-2 has two primary lineages, one found in West and Central Africa and the other found worldwide. Competing hypotheses have been proposed to explain how HSV-2 migrated out-of-Africa (i)HSV-2 followed human migration out-of-Africa 50-100 thousand years ago, or (ii)HSV-2 migrated via the trans-Atlantic slave trade 150-500 years ago. Limited geographic sampling and lack of molecular clock signal has precluded robust comparison. Here, we analyze newly sequenced HSV-2 genomes from Africa to resolve geography and timing of divergence events within HSV-2. Phylogeographic analysis consistently places the ancestor of worldwide dispersal in East Africa, though molecular clock is too slow to be detected using available data. Rates 4.2 × 10-8-5.6 × 10-8 substitutions/site/year, consistent with previous age estimates, suggest a worldwide dispersal 22-29 thousand years ago. Thus, HSV-2 likely migrated with humans from East Africa and dispersed after the Last Glacial Maximum.

Regional connectivity drove bidirectional transmission of SARS-CoV-2 in the Middle East during travel restrictions.

Regional connectivity and land travel have been identified as important drivers of SARS-CoV-2 transmission. However, the generalizability of this finding is understudied outside of well-sampled, highly connected regions. In this study, we investigated the relative contributions of regional and intercontinental connectivity to the source-sink dynamics of SARS-CoV-2 for Jordan and the Middle East. By integrating genomic, epidemiological and travel data we show that the source of introductions into Jordan was dynamic across 2020, shifting from intercontinental seeding in the early pandemic to more regional seeding for the travel restrictions period. We show that land travel, particularly freight transport, drove introduction risk during the travel restrictions period. High regional connectivity and land travel also drove Jordan's export risk. Our findings emphasize regional connectedness and land travel as drivers of transmission in the Middle East.

The molecular epidemiology of multiple zoonotic origins of SARS-CoV-2.

Understanding the circumstances that lead to pandemics is important for their prevention. We analyzed the genomic diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early in the coronavirus disease 2019 (COVID-19) pandemic. We show that SARS-CoV-2 genomic diversity before February 2020 likely comprised only two distinct viral lineages, denoted "A" and "B." Phylodynamic rooting methods, coupled with epidemic simulations, reveal that these lineages were the result of at least two separate cross-species transmission events into humans. The first zoonotic transmission likely involved lineage B viruses around 18 November 2019 (23 October to 8 December), and the separate introduction of lineage A likely occurred within weeks of this event. These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans before November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported. As with other coronaviruses, SARS-CoV-2 emergence likely resulted from multiple zoonotic events.

Extent and implications of omitted ties on network measures in a longitudinal social network survey of people who use drugs.

BACKGROUND: Previous research has revealed under-reporting of personal network members (i.e., alters) in studies involving people who use drugs (PWUD). This analysis (1) characterizes relationships that were more likely to be omitted but later recalled with prompting and (2) identifies network structural characteristics most impacted by these omissions among a sample of PWUD in rural Appalachian Kentucky, an epicenter of the opioid epidemic. METHODS: Data were collected through longitudinal assessments as part of the Social Networks Among Appalachian People (SNAP) study (2008-2017). Study participants completed interviewer-administered questionnaires that collected social network data via free-listing at baseline and six-month intervals. At visit 5, after free-listing, interviewers prompted participants with the names of previously reported alters. We used modified Poisson regression with generalized estimating equations to identify individual- and relationship-level characteristics associated with an alter being reported only after prompting. We examined the impact of including vs. excluding relationships reported after prompting on local and global sociometric network measures (i.e., betweenness centrality, bridging, density, mean degree, transitivity, cliques, and 2-cores). RESULTS: Relationships reported only after prompting were more likely to be immediate family (Adjusted Prevalence Ratio [APR]:1.29; 95% Confidence Interval [CI]: 1.03-1.63) and less likely to involve sex (APR:0.54; 95% CI: 0.43-0.67). Considerable differences were observed for participant positional rankings of betweenness centrality and bridging, and differences in network density and average degree pre- and post-prompting were statistically significant. CONCLUSION: Longitudinal network studies that aim to assess transmission dynamics, information diffusion, or peer influence should consider the effects of omitted relationships.

Diagnoses and Treatment in Juvenile Detention Before and After Evaluation by Facility-Based Mental Health Service.

As of 2018, more than 37,000 American youth were residing in juvenile detention or residential placement facilities.1 Prevalence studies have demonstrated high rates of psychiatric illness in this population, with estimates ranging from 50% to 75%.2,3 Comorbidity is common: Abram et al. found that 75% of juvenile detainees meeting criteria for one disorder met criteria for two or more disorders.4 Compared to psychiatric morbidity in justice-involved youth, there is a paucity of data describing mental health services within juvenile justice settings, treatments delivered by these services, or outcomes following treatment. We performed a retrospective study to compare diagnoses and medications prescribed to youth in the community prior to detention with those received after evaluation by the facility-based juvenile justice mental health service (JJMHS) staffing secure detention facilities in New York, NY.

Introduction and Establishment of SARS-CoV-2 Gamma Variant in New York City in Early 2021.

BACKGROUND: Monitoring the emergence and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is an important public health objective. We investigated how the Gamma variant was established in New York City (NYC) in early 2021 in the presence of travel restrictions that aimed to prevent viral spread from Brazil, the country where the variant was first identified. METHODS: We performed phylogeographic analysis on 15 967 Gamma sequences sampled between 10 March and 1 May 2021, to identify geographic sources of Gamma lineages introduced into NYC. We identified locally circulating Gamma transmission clusters and inferred the timing of their establishment in NYC. RESULTS: We identified 16 phylogenetically distinct Gamma clusters established in NYC (cluster sizes ranged 2-108 genomes); most of them were introduced from Florida and Illinois and only 1 directly from Brazil. By the time the first Gamma case was reported by genomic surveillance in NYC on 10 March, the majority (57%) of circulating Gamma lineages had already been established in the city for at least 2 weeks. CONCLUSIONS: Although travel from Brazil to the United States was restricted from May 2020 through the end of the study period, this restriction did not prevent Gamma from becoming established in NYC as most introductions occurred from domestic locations.