Stable population structure in Europe since the Iron Age, despite high mobility.

Ancient DNA research in the past decade has revealed that European population structure changed dramatically in the prehistoric period (14,000-3000 years before present, YBP), reflecting the widespread introduction of Neolithic farmer and Bronze Age Steppe ancestries. However, little is known about how population structure changed from the historical period onward (3000 YBP - present). To address this, we collected whole genomes from 204 individuals from Europe and the Mediterranean, many of which are the first historical period genomes from their region (e.g. Armenia and France). We found that most regions show remarkable inter-individual heterogeneity. At least 7% of historical individuals carry ancestry uncommon in the region where they were sampled, some indicating cross-Mediterranean contacts. Despite this high level of mobility, overall population structure across western Eurasia is relatively stable through the historical period up to the present, mirroring geography. We show that, under standard population genetics models with local panmixia, the observed level of dispersal would lead to a collapse of population structure. Persistent population structure thus suggests a lower effective migration rate than indicated by the observed dispersal. We hypothesize that this phenomenon can be explained by extensive transient dispersal arising from drastically improved transportation networks and the Roman Empire's mobilization of people for trade, labor, and military. This work highlights the utility of ancient DNA in elucidating finer scale human population dynamics in recent history.

A genetic history of continuity and mobility in the Iron Age central Mediterranean.

The Iron Age was a dynamic period in central Mediterranean history, with the expansion of Greek and Phoenician colonies and the growth of Carthage into the dominant maritime power of the Mediterranean. These events were facilitated by the ease of long-distance travel following major advances in seafaring. We know from the archaeological record that trade goods and materials were moving across great distances in unprecedented quantities, but it is unclear how these patterns correlate with human mobility. Here, to investigate population mobility and interactions directly, we sequenced the genomes of 30 ancient individuals from coastal cities around the central Mediterranean, in Tunisia, Sardinia and central Italy. We observe a meaningful contribution of autochthonous populations, as well as highly heterogeneous ancestry including many individuals with non-local ancestries from other parts of the Mediterranean region. These results highlight both the role of local populations and the extreme interconnectedness of populations in the Iron Age Mediterranean. By studying these trans-Mediterranean neighbours together, we explore the complex interplay between local continuity and mobility that shaped the Iron Age societies of the central Mediterranean.

Monitoring of the HIV Epidemic Using Routinely Collected Data: The Case of the United Kingdom.

We report on measures used to monitor the response to the UK HIV epidemic. We present analyses of routine data on HIV testing, diagnosis and care, and of CD4 back-calculation models to estimate country of HIV acquisition and incidence. Over the past decade, HIV and AIDS diagnoses and deaths declined while HIV testing coverage increased. Linkage into care, retention in care, and viral suppression was high with few socio-demographic differences. However, in 2013, incidence among MSM, and undiagnosed infection, also remained high, and more than half of heterosexuals newly diagnosed with HIV (the majority of whom were born-abroad) probably acquired HIV in the UK and were diagnosed late. HIV care following diagnosis is excellent in the UK. Improvements in testing and prevention are required to reduce undiagnosed infection, incidence and late diagnoses. Routinely collected laboratory and clinic data is a low cost, robust and timely mechanism to monitor the public health response to national HIV epidemics.

Effect of pre-exposure prophylaxis and combination HIV prevention for men who have sex with men in the UK: a mathematical modelling study.

BACKGROUND: HIV transmission in men who have sex with men (MSM) in the UK has shown no sign of decreasing in the past decade. Additional prevention measures are needed. We aimed to estimate the effect of various potential interventions implemented individually and in combination on prevention of HIV infection. METHODS: We extended a deterministic partnership-based mathematical model for HIV transmission, informed by detailed behavioural and surveillance data, to assess the effect of seven different HIV interventions implemented in MSM (aged 15-64 years) in the UK during 2014-20, including increasing rates of HIV testing, test-and-treat programmes, pre-exposure prophylaxis (PrEP), and sexual behavioural changes. We did sensitivity analyses on risk compensation. FINDINGS: We predicted a baseline of 16 955 new infections (IQR 13 156-21 669) in MSM in the UK during 2014-20. At a coverage of ≤50%, testing twice a year outperformed all other interventions. Of all intervention combinations, only the combined effect of test and treat and annual HIV testing (61·8%, IQR 47·2-81·8, of total incidence) was greater than the sum of effects of the two interventions individually (32·6%, 23·7-46·0, and 23·9%, 16·5-33·3, respectively). Simultaneous PrEP, expansion of HIV testing, and initiation of test-and-treat programme in 25% of high-activity MSM could save 7399 (IQR 5587-9813) UK MSM from HIV infection (43·6%, IQR 32·9-57·9, of total incidence). An increase in unsafe sex or sexual partners to 50% or more could substantially reduce the effect of interventions, but is unlikely to negate the prevention benefit completely. INTERPRETATION: PrEP could prevent a large number of new HIV infections if other key strategies including HIV testing and treatment are simultaneously expanded and improved. Without PrEP, HIV incidence in MSM in the UK is unlikely to decrease substantially by the end of this decade. FUNDING: Health Protection Agency (now Public Health England).

Calibration of complex models through Bayesian evidence synthesis: a demonstration and tutorial.

Decision-analytic models must often be informed using data that are only indirectly related to the main model parameters. The authors outline how to implement a Bayesian synthesis of diverse sources of evidence to calibrate the parameters of a complex model. A graphical model is built to represent how observed data are generated from statistical models with unknown parameters and how those parameters are related to quantities of interest for decision making. This forms the basis of an algorithm to estimate a posterior probability distribution, which represents the updated state of evidence for all unknowns given all data and prior beliefs. This process calibrates the quantities of interest against data and, at the same time, propagates all parameter uncertainties to the results used for decision making. To illustrate these methods, the authors demonstrate how a previously developed Markov model for the progression of human papillomavirus (HPV-16) infection was rebuilt in a Bayesian framework. Transition probabilities between states of disease severity are inferred indirectly from cross-sectional observations of prevalence of HPV-16 and HPV-16-related disease by age, cervical cancer incidence, and other published information. Previously, a discrete collection of plausible scenarios was identified but with no further indication of which of these are more plausible. Instead, the authors derive a Bayesian posterior distribution, in which scenarios are implicitly weighted according to how well they are supported by the data. In particular, we emphasize the appropriate choice of prior distributions and checking and comparison of fitted models.

Increased uptake and new therapies are needed to avert rising hepatitis C-related end stage liver disease in England: modelling the predicted impact of treatment under different scenarios.

BACKGROUND & AIMS: Hepatitis C (HCV) related disease in England is predicted to rise, and it is unclear whether treatment at current levels will be able to avert this. The aim of this study was to estimate the number of people with chronic HCV infection in England that are treated and assess the impact and costs of increasing treatment uptake. METHODS: Numbers treated were estimated using national data sources for pegylated interferon supplied, dispensed, or purchased from 2006 to 2011. A back-calculation approach was used to project disease burden over the next 30 years and determine outcomes under various scenarios of treatment uptake. RESULTS: 5000 patients were estimated to have been treated in 2011 and 28,000 in total from 2006 to 2011; approximately 3.1% and 17% respectively of estimated chronic infections. Without treatment, incident cases of decompensated cirrhosis and hepatocellular carcinoma were predicted to increase until 2035 and reach 2290 cases per year. Treatment at current levels should reduce incidence by 600 cases per year, with a peak around 2030. Large increases in treatment are needed to halt the rise; and with more effective treatment the best case scenario predicts incidence of around 500 cases in 2030, although treatment uptake must still be increased considerably to achieve this. CONCLUSIONS: If the infected population is left untreated, the number of patients with severe HCV-related disease will continue to increase and represent a substantial future burden on healthcare resources. This can be mitigated by increasing treatment uptake, which will have the greatest impact if implemented quickly.

Risk of pelvic inflammatory disease following Chlamydia trachomatis infection: analysis of prospective studies with a multistate model.

Our objective in this study was to estimate the probability that a Chlamydia trachomatis (CT) infection will cause an episode of clinical pelvic inflammatory disease (PID) and the reduction in such episodes among women with CT that could be achieved by annual screening. We reappraised evidence from randomized controlled trials of screening and controlled observational studies that followed untreated CT-infected and -uninfected women to measure the development of PID. Data from these studies were synthesized using a continuous-time Markov model which takes into account the competing risk of spontaneous clearance of CT. Using a 2-step piecewise homogenous Markov model that accounts for the distinction between prevalent and incident infections, we investigated the possibility that the rate of PID due to CT is greater during the period immediately following infection. The available data were compatible with both the homogenous and piecewise homogenous models. Given a homogenous model, the probability that a CT episode will cause clinical PID was 0.16 (95% credible interval (CrI): 0.06, 0.25), and annual screening would prevent 61% (95% CrI: 55, 67) of CT-related PID in women who became infected with CT. Assuming a piecewise homogenous model with a higher rate during the first 60 days, corresponding results were 0.16 (95% CrI: 0.07, 0.26) and 55% (95% CrI: 32, 72), respectively.

Estimating the effectiveness of isolation and decolonization measures in reducing transmission of methicillin-resistant Staphylococcus aureus in hospital general wards.

Infection control for hospital pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) often takes the form of a package of interventions, including the use of patient isolation and decolonization treatment. Such interventions, though widely used, have generated controversy because of their significant resource implications and the lack of robust evidence with regard to their effectiveness at reducing transmission. The aim of this study was to estimate the effectiveness of isolation and decolonization measures in reducing MRSA transmission in hospital general wards. Prospectively collected MRSA surveillance data from 10 general wards at Guy's and St. Thomas' hospitals, London, United Kingdom, in 2006-2007 were used, comprising 14,035 patient episodes. Data were analyzed with a Markov chain Monte Carlo algorithm to model transmission dynamics. The combined effect of isolation and decolonization was estimated to reduce transmission by 64% (95% confidence interval: 37, 79). Undetected MRSA-positive patients were estimated to be the source of 75% (95% confidence interval: 67, 86) of total transmission events. Isolation measures combined with decolonization treatment were strongly associated with a reduction in MRSA transmission in hospital general wards. These findings provide support for active methods of MRSA control, but further research is needed to determine the relative importance of isolation and decolonization in preventing transmission.

HIV incidence in men who have sex with men in England and Wales 2001-10: a nationwide population study.

BACKGROUND: Control of HIV transmission could be achievable through an expansion of HIV testing of at-risk populations together with ready access and adherence to antiretroviral therapy. To examine whether increases in testing rates and antiretroviral therapy coverage correspond to the control of HIV transmission, we estimated HIV incidence in men who have sex with men (MSM) in England and Wales since 2001. METHODS: A CD4-staged back-calculation model of HIV incidence was used to disentangle the competing contributions of time-varying rates of diagnosis and HIV incidence to observed HIV diagnoses. Estimated trends in time to diagnosis, incidence, and undiagnosed infection in MSM were interpreted against a backdrop of increased HIV testing rates and antiretroviral-therapy coverage over the period 2001-10. FINDINGS: The observed 3·7 fold expansion in HIV testing in MSM was mirrored by a decline in the estimated mean time-to-diagnosis interval from 4·0 years (95% credible interval [CrI] 3·8-4·2) in 2001 to 3·2 years (2·6-3·8) by the end of 2010. However, neither HIV incidence (2300-2500 annual infections) nor the number of undiagnosed HIV infections (7370, 95% CrI 6990-7800, in 2001, and 7690, 5460-10 580, in 2010) changed throughout the decade, despite an increase in antiretroviral uptake from 69% in 2001 to 80% in 2010. INTERPRETATION: CD4 cell counts at HIV diagnosis are fundamental to the production of robust estimates of incidence based on HIV diagnosis data. Improved frequency and targeting of HIV testing, as well as the introduction of ART at higher CD4 counts than is currently recommended, could begin a decline in HIV transmission among MSM in England and Wales. FUNDING: UK Medical Research Council, UK Health Protection Agency.

A synthesis of convenience survey and other data to estimate undiagnosed HIV infection among men who have sex with men in England and Wales.

BACKGROUND: Hard-to-reach population subgroups are typically investigated using convenience sampling, which may give biased estimates. Combining information from such surveys, a probability survey and clinic surveillance, can potentially minimize the bias. We developed a methodology to estimate the prevalence of undiagnosed HIV infection among men who have sex with men (MSM) in England and Wales aged 16-44 years in 2003, making fuller use of the available data than earlier work. METHODS: We performed a synthesis of three data sources: genitourinary medicine clinic surveillance (11 380 tests), a venue-based convenience survey including anonymous HIV testing (3702 MSM) and a general population sexual behaviour survey (134 MSM). A logistic regression model to predict undiagnosed infection was fitted to the convenience survey data and then applied to the MSMs in the population survey to estimate the prevalence of undiagnosed infection in the general MSM population. This estimate was corrected for selection biases in the convenience survey using clinic surveillance data. A sensitivity analysis addressed uncertainty in our assumptions. RESULTS: The estimated prevalence of undiagnosed HIV in MSM was 2.4% [95% confidence interval (95% CI 1.7-3.0%)], and between 1.6% (95% CI 1.1-2.0%) and 3.3% (95% CI 2.4-4.1%) depending on assumptions; corresponding to 5500 (3390-7180), 3610 (2180-4740) and 7570 (4790-9840) men, and undiagnosed fractions of 33, 24 and 40%, respectively. CONCLUSIONS: Our estimates are consistent with earlier work that did not make full use of data sources. Reconciling data from multiple sources, including probability-, clinic- and venue-based convenience samples can reduce bias in estimates. This methodology could be applied in other settings to take full advantage of multiple imperfect data sources.

The Edinburgh Addiction Cohort: recruitment and follow-up of a primary care based sample of injection drug users and non drug-injecting controls.

BACKGROUND: Injection drug use is an important public health problem. Epidemiological understanding of this problem is incomplete as longitudinal studies in the general population are difficult to undertake. In particular little is known about early life risk factors for later drug injection or about the life course of injection once established including the influence of medical and social interventions. METHODS: Individuals thought to be drug injectors were identified through a single primary medical care facility in Edinburgh between 1980 and 2006 and flagged with the General Registry Office. From October 2005 - October 2007, these cases were traced and invited to undergo interview assessment covering early life experience, substance use, health and social histories. Age and sex matched controls for confirmed cases (alive and dead) were later recruited through the same health facility. Controls for living cases completed the same structured interview schedule. Data were also collected on cases and controls through linkage to routine primary care records, death registrations, hospital contact statistics and police and prison records. All interviews were conducted with the knowledge and permission of the current GP. RESULTS: The initial cohort size was 814. At start of follow up 227 had died. Of the remaining 587: 20 had no contact details and 5 had embarked from the UK; 40 declined participation; 38 did not respond to invitations; 14 were excluded by their GP on health or social grounds and 22 had their contact details withheld by administrative authorities. 448 were interviewed of whom 16 denied injection and were excluded. Of 191 dead cases with medical records 4 were excluded as their records contained no evidence of injection. 5 interviewed cases died before follow up was concluded though these individuals were counted as "live" cases. 1 control per case (dead and alive) was recruited. Linkage to Scottish Morbidity Records data (available from 1981 onwards) on general acute inpatient and day cases, mental health inpatient and day cases and cancer was provided by Information Services, NHS Scotland, for all cases interviewed and all dead cases. The Scottish Prison Service provided records for 198 (46%) of cases interviewed, 48 cases not interviewed and 34 (18%) of dead cases. For a sub-sample of 100 interviewees a search of the Lothian and Borders police database was made for official criminal records and 94 had criminal records. Data linkage for controls is ongoing. CONCLUSIONS: Injecting drug users recruited from a community setting can be successfully followed-up through interviews and record linkage. Information from injecting cases is being analysed in terms of injecting patterns and possible influences on these. Comparisons between cases and controls will allow identification of possibly modifiable early life risk factors for drug injection and will also clarify the burden of disease associated with injection and the influence on this of different health and social interventions.

Gene expression of nucleic acid-sensing pattern recognition receptors in children hospitalized for respiratory syncytial virus-associated acute bronchiolitis.

Given the critical role of pattern recognition receptors (PRRs) in acid nucleic recognition in the initiation of innate immunity and the orchestration of adaptive immunity, the aim of this study was to determine whether any heterogeneity of PRR expression in the airway tracts of infants with respiratory syncytial virus (RSV) infection might explain the broad clinical spectrum of RSV-associated bronchiolitis in infants. For this purpose, the levels of melanoma differentiation-associated protein-5 (MDA-5), retinoic acid inducible gene-1 (RIG-1), and Toll-like receptor 3 (TLR-3), TLR-7, TLR-8, and TLR-9 mRNAs were evaluated, using TaqMan quantitative reverse transcription-PCR, in cells from nasopharyngeal washes collected from 157 infants suffering from acute bronchiolitis whether or not they were associated with respiratory viruses. High interindividual variability was observed in both virus-positive and -negative infants; however, the relative gene expression levels of MDA-5, RIG-1, TLR-7, and TLR-8 were significantly higher in the virus-infected group, whereas the expression levels of TLR-3 and TLR-9 were not significantly different. The differences in the gene expression of MDA-5, RIG-1, TLR-7, and TLR-8 were more evident in infants with RSV infection than in those with bocavirus or rhinovirus infection. In RSV-infected infants, PRR-mRNA levels also were analyzed in relation to interferon protein levels, viral load, clinical severity, days of hospitalization, age, and body weight. A significant positive correlation was observed only between RSV viral load and RIG-1 mRNA levels. These findings provide the first direct evidence that, in infants with respiratory virus-associated bronchiolitis, especially RSV, there are substantial changes in PRR gene expression; this likely is an important determinant of the clinical outcome of bronchiolitis.

Estimated progression rates in three United Kingdom hepatitis C cohorts differed according to method of recruitment.

OBJECTIVES: To estimate hepatitis C virus (HCV) progression rates between disease stages prior to cirrhosis, using data from liver biopsies in three observational cohorts. To demonstrate how the method of cohort recruitment can influence the estimation of HCV-progression rates. STUDY DESIGN AND SETTING: Data came from three United Kingdom observational cohorts, assembled from different referral sources. In total, 987 HCV-infected patients with an estimated (or known) date of infection and at least one histologically scored liver biopsy were eligible for inclusion in the analysis. Liver biopsy scores were used to determine the stage of HCV-related liver disease. A three-state continuous time Markov model was used to estimate covariate-specific average probabilities of progression of disease. RESULTS: After adjusting for confounders, considerably different rates of disease progression were estimated in the three cohorts. For a group of patients with the same demographics, the estimated 20-year probability of progression to cirrhosis was 12% (95% confidence interval CI = 6-22) in a hospital-based cohort, 6% (95% CI = 3-13) in a posttransfusion cohort, and 23% (95% CI = 14-37) in a cohort recruited from a tertiary referral center. CONCLUSION: Researchers using estimates of disease progression should be aware that the method of cohort recruitment has considerable influence on the progression rates that are derived.