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Syphilis, which is caused by the sexually transmitted bacterium Treponema pallidum subsp. pallidum, has an estimated 6.3 million cases worldwide per annum. In the past ten years, the incidence of syphilis has increased by more than 150% in some high-income countries, but the evolution and epidemiology of the epidemic are poorly understood. To characterize the global population structure of T. pallidum, we assembled a geographically and temporally diverse collection of 726 genomes from 626 clinical and 100 laboratory samples collected in 23 countries. We applied phylogenetic analyses and clustering, and found that the global syphilis population comprises just two deeply branching lineages, Nichols and SS14. Both lineages are currently circulating in 12 of the 23 countries sampled. We subdivided T. p. pallidum into 17 distinct sublineages to provide further phylodynamic resolution. Importantly, two Nichols sublineages have expanded clonally across 9 countries contemporaneously with SS14. Moreover, pairwise genome analyses revealed examples of isolates collected within the last 20 years from 14 different countries that had genetically identical core genomes, which might indicate frequent exchange through international transmission. It is striking that most samples collected before 1983 are phylogenetically distinct from more recently isolated sublineages. Using Bayesian temporal analysis, we detected a population bottleneck occurring during the late 1990s, followed by rapid population expansion in the 2000s that was driven by the dominant T. pallidum sublineages circulating today. This expansion may be linked to changing epidemiology, immune evasion or fitness under antimicrobial selection pressure, since many of the contemporary syphilis lineages we have characterized are resistant to macrolides.

Background: Syphilis is an important sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum. The last two decades have seen syphilis incidence rise in many high-income countries, yet the evolutionary and epidemiological relationships that underpin this are poorly understood, as is the global T. pallidum population structure. Methods: We assembled a geographically and temporally diverse collection of clinical and laboratory samples, performing direct sequencing on the majority, and combining these with 133 publicly available sequences to compile a dataset comprising 726 T. pallidum genomes. We analysed the resulting genomes using detailed phylogenetic analysis and clustering. Results: We show that syphilis globally can be described by only two deeply branching lineages, Nichols and SS14. We show that both of these lineages can be found circulatingcon currently in 12 of the 23 countries sampled. To provide further phylodynamic resolution we subdivided Treponema pallidum subspecies pallidum into 17 distinct sublineages. Importantly, like SS14, we provide evidence that two Nichols sublineages have expanded clonally across 9 countries contemporaneously with SS14. Moreover, pairwise genome analysis showed that recent isolates circulating in 14 different countries were genetically identical in their core genome to those from other countries, suggesting frequent exchange through international transmission pathways. This contrasts with the majority of samples collected prior to 1983, which are phylogenetically distinct from these more recently isolated sublineages. Bayesian temporal analysis provided evidence of a population bottleneck and decline occurring during the late 1990s, followed by a rapid population expansion a decade later. This was driven by the dominant T. pallidum sublineages circulating today, many of which are resistant to macrolides. Conclusion: Combined we show that the population of contemporary syphilis in high-inco

BACKGROUND: Vaccination remains one of the most effective means of reducing the burden of infectious diseases globally. Improving our understanding of the molecular basis for effective vaccine response is of paramount importance if we are to ensure the success of future vaccine development efforts. METHODS: We applied cutting edge multi-omics approaches to extensively characterize temporal molecular responses following vaccination with hepatitis B virus (HBV) vaccine. Data were integrated across cellular, epigenomic, transcriptomic, proteomic, and fecal microbiome profiles, and correlated to final HBV antibody titres. RESULTS: Using both an unsupervised molecular-interaction network integration method (NetworkAnalyst) and a data-driven integration approach (DIABLO), we uncovered baseline molecular patterns and pathways associated with more effective vaccine responses to HBV. Biological associations were unravelled, with signalling pathways such as JAK-STAT and interleukin signalling, Toll-like receptor cascades, interferon signalling, and Th17 cell differentiation emerging as important pre-vaccination modulators of response. CONCLUSION: This study provides further evidence that baseline cellular and molecular characteristics of an individual's immune system influence vaccine responses, and highlights the utility of integrating information across many parallel molecular datasets.

Background: Population-level monitoring of hepatitis C virus (HCV) infected people across cascades of care identifies gaps in access and engagement in care and treatment. We characterized the population-level care cascade for HCV in British Columbia (BC), Canada before and after introduction of Direct Acting Antiviral (DAA) treatment. Methods: BC Hepatitis Testers Cohort (BC-HTC) includes 1.7 million individuals tested for HCV, HIV, reported cases of hepatitis B, and active tuberculosis in BC from 1990 to 2018 linked to medical visits, hospitalizations, cancers, prescription drugs and mortality data. We defined six HCV care cascade stages: (a) antibody diagnosed; (b) RNA tested; (c) RNA positive; (d) genotyped; (e) initiated treatment; and (f) achieved sustained virologic response (SVR). Results: We estimated 61 127 people were HCV antibody positive in BC in 2018 (undiagnosed: 7686, 13%; diagnosed: 53 441, 87%). Of those diagnosed, 83% (44 507) had HCV RNA testing, and of those RNA positive, 90% (28 716) were genotyped. Of those genotyped, 61% (17 441) received therapy, with 90% (15 672) reaching SVR. Individuals from older birth cohorts had lower progression to HCV RNA testing. While people who currently inject drugs had the highest proportional progression to RNA testing, this group had the lowest proportional treatment uptake. Conclusions: Although gaps in HCV RNA and genotype testing after antibody diagnosis exist, the largest gap in the care cascade is treatment initiation, despite introduction of DAA treatment and removal of treatment eligibility restrictions. Further interventions are required to ensure testing and treatment is equitably accessible in BC.

OBJECTIVES: Internet-based sexually transmitted and blood-borne infection (STBBI) testing services reduce testing barriers through bypassing face-to-face clinical encounters, potentially enabling clients at ongoing sexual risk to test more frequently. To our knowledge, this hypothesis has not been previously tested. We compared the frequency of repeat testing between Vancouver-based clients of GetCheckedOnline (GCO)-an internet-based STBBI testing service in British Columbia, Canada-and clients of three sexually transmitted infection (STI) clinics in Vancouver for 29 months after GCO launched. METHODS: An administrative data cohort (n=19 497) was assembled using GCO, clinical and laboratory databases. We included all individuals who tested for HIV, gonorrhoea/chlamydia, syphilis or hepatitis C at three STI clinics or using GCO, between September 2014 and February 2017. The rate of repeat testing (>30 days after first episode) was compared between clients who used GCO at least once and those who tested only in STI clinics. Poisson regression was used to generate relative rate (RR) for repeat testing, with adjustment for age, gender/sexual orientation, risk factors (eg, history of STI diagnosis) and rate of testing before GCO launched. RESULTS: 1093 GCO clients were identified, of whom 434 (40%) had repeat test episodes; 8200/18 404 (45%) of clinic clients tested more than once. During the 29-month analysis period, GCO clients repeat tested 1.87 times per person-year, whereas clinic clients repeat tested 1.53 times per person-year, resulting in a crude RR of 1.22 (95% CI: 1.14 to 1.31). Adjustment for covariates increased the RR to 1.26 (95% CI: 1.15 to 1.37). CONCLUSIONS: In this cohort, individuals using internet-based STBBI testing had a rate of repeat testing 22% greater than clinic-based clients. This effect was increased after adjusting for characteristics associated with higher test frequency. The online interface of GCO may facilitate more frequent testing and

OBJECTIVES: Internet-based STI testing programmes may overcome barriers posed by in-clinic testing, though uptake could reflect social gradients. The role these services play in comparison to clinical testing services is unknown. We compared experiences of testing barriers between STI clinic clients to clients of GetCheckedOnline.com (GCO; where clients take a printed lab form to a lab). METHODS: Our 10-month cross-sectional study was conducted after GCO was promoted to STI clinic clients and men who have sex with men (MSM). Clinic and GCO clients completed an online survey assessing testing barriers and facilitators; responses were compared using bivariate analysis (level of significance P<0.01; significant results below). RESULTS: Compared with 321 clinic clients, the 73 GCO clients were more likely to be older (median 35 vs 30 years), MSM (45% vs 16%), be testing routinely (67% vs 39%), have delayed testing for any reason (76% vs 54%) and due to clinic distance (28% vs 9%), report delays due to wait times (50% vs 17%), embarrassment with testing (16% vs 6%), discomfort discussing sexual health where they usually go for testing (39% vs 22%), as well as discomfort discussing sexual history with (19% vs 5%) and fearing judgement from (30% vs 15%) any healthcare provider. GCO clients were less likely to have found clinic hours convenient (59% vs 77%) and clinic appointments easy to make (49% vs 66%), and more likely to report long wait times (50% vs 17%). We found no differences in technology skills/use. CONCLUSIONS: In this urban setting, an internet-based testing service effectively engaged individuals experiencing testing barriers, with few social gradients in uptake. While some testing barriers could be addressed through increasing access to clinical services, others require social and structural changes, highlighting the importance of internet-based STI testing services to increasing test uptake.

Background: The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate viral hepatitis by 2030. Although no virological cure exists for hepatitis B virus (HBV) infection, existing therapies to control viral replication and prophylaxis to minimise mother-to-child transmission make elimination of HBV feasible. We aimed to estimate the national, regional, and global prevalence of HBsAg in the general population and in the population aged 5 years in 2016, as well as coverage of prophylaxis, diagnosis, and treatment. Method(s): In this modelling study, we used a Delphi process that included a literature review in PubMed and Embase, followed by interviews with experts, to quantify the historical epidemiology of HBV infection. We then used a dynamic HBV transmission and progression model to estimate the country-level and regional-level prevalence of HBsAg in 2016 and the effect of prophylaxis and treatment on disease burden. Finding(s): We developed models for 120 countries, 78 of which were populated with data approved by experts. Using these models, we estimated that the global prevalence of HBsAg in 2016 was 3.9% (95% uncertainty interval [UI] 3.4-4.6), corresponding to 291 992 000 (251 513 000-341 114 000) infections. Of these infections, around 29 million (10%) were diagnosed, and only 4.8 million (5%) of 94 million individuals eligible for treatment actually received antiviral therapy. Around 1.8 (1.6-2.2) million infections were in children aged 5 years, with a prevalence of 1.4% (1.2-1.6). We estimated that 87% of infants had received the three-dose HBV vaccination in the first year of life, 46% had received timely birth-dose vaccination, and 13% had received hepatitis B immunoglobulin along with the full vaccination regimen. Less than 1% of mothers with a high viral load had received antiviral therapy to reduce mother-to-child transmission. Interpretation(s): Our estimate of HBV prevalence in 2016 differs from previous studies, potentia

Background The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of-and expansion on-the 2014 analysis, which reported 80 million (95% CI 64-103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1.0% (95% uncertainty interval 0.8-1.1) in 2015, corresponding to 71.1 million (62.5-79.4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections. Funding John C Martin Foundation.Copyright © 2017 Elsevier Ltd