A Bayesian multivariate factor analysis model for causal inference using time-series observational data on mixed outcomes.

Assessing the impact of an intervention by using time-series observational data on multiple units and outcomes is a frequent problem in many fields of scientific research. Here, we propose a novel Bayesian multivariate factor analysis model for estimating intervention effects in such settings and develop an efficient Markov chain Monte Carlo algorithm to sample from the high-dimensional and nontractable posterior of interest. The proposed method is one of the few that can simultaneously deal with outcomes of mixed type (continuous, binomial, count), increase efficiency in the estimates of the causal effects by jointly modeling multiple outcomes affected by the intervention, and easily provide uncertainty quantification for all causal estimands of interest. Using the proposed approach, we evaluate the impact that Local Tracing Partnerships had on the effectiveness of England's Test and Trace programme for COVID-19.

Comparative transmission of SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) variants and the impact of vaccination: national cohort study, England.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) rapidly replaced Delta (B.1.617.2) to become dominant in England. Our study assessed differences in transmission between Omicron and Delta using two independent data sources and methods. Omicron and Delta cases were identified through genomic sequencing, genotyping and S-gene target failure in England from 5-11 December 2021. Secondary attack rates for named contacts were calculated in household and non-household settings using contact tracing data, while household clustering was identified using national surveillance data. Logistic regression models were applied to control for factors associated with transmission for both methods. For contact tracing data, higher secondary attack rates for Omicron vs. Delta were identified in households (15.0% vs. 10.8%) and non-households (8.2% vs. 3.7%). For both variants, in household settings, onward transmission was reduced from cases and named contacts who had three doses of vaccine compared to two, but this effect was less pronounced for Omicron (adjusted risk ratio, aRR 0.78 and 0.88) than Delta (aRR 0.62 and 0.68). In non-household settings, a similar reduction was observed only in contacts who had three doses vs. two doses for both Delta (aRR 0.51) and Omicron (aRR 0.76). For national surveillance data, the risk of household clustering, was increased 3.5-fold for Omicron compared to Delta (aRR 3.54 (3.29-3.81)). Our study identified increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta. We identified a reduced effectiveness of vaccination in lowering risk of transmission, a likely contributor for the rapid propagation of Omicron.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infectivity by Viral Load, S Gene Variants and Demographic Factors, and the Utility of Lateral Flow Devices to Prevent Transmission.

BACKGROUND: How severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity varies with viral load is incompletely understood. Whether rapid point-of-care antigen lateral flow devices (LFDs) detect most potential transmission sources despite imperfect clinical sensitivity is unknown. METHODS: We combined SARS-CoV-2 testing and contact tracing data from England between 1 September 2020 and 28 February 2021. We used multivariable logistic regression to investigate relationships between polymerase chain reaction (PCR)-confirmed infection in contacts of community-diagnosed cases and index case viral load, S gene target failure (proxy for B.1.1.7 infection), demographics, SARS-CoV-2 incidence, social deprivation, and contact event type. We used LFD performance to simulate the proportion of cases with a PCR-positive contact expected to be detected using 1 of 4 LFDs. RESULTS: In total, 231 498/2 474 066 (9%) contacts of 1 064 004 index cases tested PCR-positive. PCR-positive results in contacts independently increased with higher case viral loads (lower cycle threshold [Ct] values), for example, 11.7% (95% confidence interval [CI] 11.5-12.0%) at Ct = 15 and 4.5% (95% CI 4.4-4.6%) at Ct = 30. B.1.1.7 infection increased PCR-positive results by ~50%, (eg, 1.55-fold, 95% CI 1.49-1.61, at Ct = 20). PCR-positive results were most common in household contacts (at Ct = 20.1, 8.7% [95% CI 8.6-8.9%]), followed by household visitors (7.1% [95% CI 6.8-7.3%]), contacts at events/activities (5.2% [95% CI 4.9-5.4%]), work/education (4.6% [95% CI 4.4-4.8%]), and least common after outdoor contact (2.9% [95% CI 2.3-3.8%]). Contacts of children were the least likely to test positive, particularly following contact outdoors or at work/education. The most and least sensitive LFDs would detect 89.5% (95% CI 89.4-89.6%) and 83.0% (95% CI 82.8-83.1%) of cases with PCR-positive contacts, respectively. CONCLUSIONS: SARS-CoV-2 infectivity varies by case viral load, contact event type, and age. Those with high viral loads are the most infectious. B.1.1.7 increased transmission by ~50%. The best performing LFDs detect most infectious cases.

Comparative symptomatology of infection with SARS-CoV-2 variants Omicron (B.1.1.529) and Delta (B.1.617.2) from routine contact tracing data in England.

Symptoms are currently used as testing indicators for SARS-CoV-2 in England. In this study, we analysed national contact tracing data for England (NHS Test and Trace) for the period 1 December to 28 December 2021 to explore symptom differences between the variants, Delta and Omicron. We found that at least one of the symptoms currently used as indicators (fever, cough and loss of smell and taste) were reported in 61.5% of Omicron cases and 72.2% in Delta cases, suggesting that these symptoms are less predictive of Omicron infections. Nearly 40% of Omicron infections did not report any of the three key indicative symptoms, reinforcing the importance of the entire spectrum of symptoms for targeted testing. After adjusting for potential confounding factors, fever and cough were more commonly associated with Omicron infections compared to Delta, showing the importance of considering age and vaccination status when assessing symptom profiles. Sore throat was also more commonly reported in Omicron infections, and loss of smell and taste more commonly reported in Delta infections. Our study shows the value of continued monitoring of symptoms associated with SARS-CoV-2, as changes may influence the effectiveness of testing policy and case ascertainment approaches.

Workplace exposures associated with COVID-19: evidence from a case-control study with multiple sampling periods in England, August-October 2020.

We investigated risk factors associated with COVID-19 by conducting a retrospective, frequency-matched case-control study, with three sampling periods (August-October 2020). We compared cases completing routine contact tracing to asymptomatic population controls. Multivariable analyses estimated adjusted odds ratios (aORs) for non-household community settings. Meta-analyses using random effects provided pooled odds ratios (pORs). Working in healthcare (pOR 2.87; aORs 2.72, 2.81, 3.08, for study periods 1-3 respectively), social care (pOR 4.15; aORs 2.46, 5.06, 5.41, for study periods 1-3 respectively) or hospitality (pOR 2.36; aORs 2.01, 2.54, 2.63, for study periods 1-3 respectively) were associated with increased odds of being a COVID-19 case. Additionally, working in bars, pubs and restaurants, warehouse settings, construction, educational settings were significantly associated. While definitively determining where transmission occurs is impossible, we provide evidence that in certain sectors, the impact of mitigation measures may only be partial and reinforcement of measures should be considered in these settings.

Outbreak of STEC O157:H7 linked to a milk pasteurisation failure at a dairy farm in England, 2019.

In November 2019, an outbreak of Shiga toxin-producing Escherichia coli O157:H7 was detected in South Yorkshire, England. Initial investigations established consumption of milk from a local dairy as a common exposure. A sample of pasteurised milk tested the next day failed the phosphatase test, indicating contamination of the pasteurised milk by unpasteurised (raw) milk. The dairy owner agreed to immediately cease production and initiate a recall. Inspection of the pasteuriser revealed a damaged seal on the flow divert valve. Ultimately, there were 21 confirmed cases linked to the outbreak, of which 11 (52%) were female, and 12/21 (57%) were either <15 or >65 years of age. Twelve (57%) patients were treated in hospital, and three cases developed haemolytic uraemic syndrome. Although the outbreak strain was not detected in the milk samples, it was detected in faecal samples from the cattle on the farm. Outbreaks of gastrointestinal disease caused by milk pasteurisation failures are rare in the UK. However, such outbreaks are a major public health concern as, unlike unpasteurised milk, pasteurised milk is marketed as 'safe to drink' and sold to a larger, and more dispersed, population. The rapid, co-ordinated multi-agency investigation initiated in response to this outbreak undoubtedly prevented further cases.

Managing student mental health: The challenges faced by academics on professional healthcare courses.

AIMS: To explore how academics on nursing and healthcare programmes are managing their roles and responsibility in relation to student mental health. BACKGROUND: There is growing concern about the mental health of university students in general and healthcare students in particular. Shifts in Higher Education policy, encouraging a "whole university approach," may place greater responsibility for student mental health on academics. However, little is known about the challenges that poor student mental health creates for academics on healthcare programmes. DESIGN: A qualitative approach, using semi-structured interviews and focus groups, provided the opportunity for in-depth analysis. METHODS: Fourteen academics on healthcare programmes, including seven lecturers from nursing programmes, were interviewed between May-June 2017. Constant comparison analysis was followed to support grounded theory. RESULTS: Four key themes emerged. Academics had difficulty identifying and maintaining boundaries due to competing academic and professional identities. Student disclosures are accompanied by challenges arising due to professional responsibilities. Supporting student mental health on placement is difficult. Academics are aware and concerned about the potential negative impact of course content and practice on student mental health. CONCLUSION: This is the first study to explore in-depth the challenges faced by academics on healthcare programmes by the rising prevalence of and concern for, student mental health. The findings indicate that leaders of nursing education programmes and their managers, need to be aware that academics face complex challenges in managing and responding student mental health and may struggle to maintain boundaries due, in part, to competing professional identities.

Increased Invasive Pneumococcal Disease, North East England, UK.

Since April 2014, invasive pneumococcal disease incidence has increased substantially across North East England, United Kingdom, reversing the decline that followed the 2006 introduction of pneumococcal conjugate vaccines. Significant increases occurred in 23-valent polysaccharide vaccine serotypes and nonvaccine serotypes. Trends in other regions and long-term effects of multivalent vaccines require further investigation.

Stratification of Treatment in a Community-Based Musculoskeletal Service: A Mixed-Methods Study to Assess Predictors of Requiring Complex Care.

OBJECTIVE: To explore factors that might be relevant when designing a triage tool. DESIGN: A mixed-methods study using multivariable logistic regression analysis to identify significant factors associated with requiring different levels of care, and qualitative focus groups exploring views of patients and physiotherapy clinicians regarding case complexity. SETTING: A community-based adult musculoskeletal service delivering tier 1 (standard physiotherapy) and tier 2 care (complex care beyond the scope of standard physiotherapy) and providing onward referral to orthopedic clinics (tier 3). PARTICIPANTS: Quantitative data were extracted from a random sample of patients (N=484) who had received treatment for musculoskeletal conditions. Patients and physiotherapists who had received care or who worked in the service participated in focus groups. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Themes that emerged from focus groups were compared against predictors of requiring complex care found to be significant (P<.05) after quantitative data analysis. RESULTS: A total of 184 patients (38.0%; 95% confidence interval, 33.8-42.4) received complex care. Peripheral joint problems, unclear diagnosis, and symptoms affecting sleep were significant independent predictors of requiring complex care. These data supported some of the main themes raised at focus groups. CONCLUSIONS: A substantial proportion of patients receive tier 2 complex care. Further studies are needed to evaluate whether the predictive factors found to be significant in our study might be useful for developing a tool for more effective triage to the most appropriate tier of musculoskeletal care.

Living conditions are associated with increased antibiotic resistance in community isolates of Escherichia coli.

OBJECTIVES: The objective of this study was to measure the associations between domains of deprivation and antibiotic resistance of Escherichia coli. METHODS: Routine surveillance data for antibiotic susceptibility of E. coli isolates were obtained from urine specimens taken from patients presenting with suspected urinary tract infection in 2010-12 to healthcare practitioners based in the community in Leeds and Bradford. Eight antibiotics were included in the analyses. Postcodes were linked to lower super output areas (average populations of 1500). The 2010 Indices of Deprivation were used as neighbourhood characteristics for each lower super output area. Multilevel logistic regression models were used to estimate the independent effect of structural components on the odds of resistance to each antibiotic. RESULTS: With respect to living conditions, residence in the most-deprived areas compared with the least-deprived areas was associated with increased odds of antibiotic resistance for all eight antibiotics analysed. The magnitude of these associations included an OR of 2.04 (95% CI 1.03-3.07) for cefalexin, 2.16 (95% CI 1.16-4.05) for ciprofloxacin, 2.47 (95% CI 1.08-5.66) for nitrofurantoin and 1.33 (95% CI 1.07-1.75) for trimethoprim. CONCLUSIONS: Social deprivation in the form of living conditions is associated with increased antibiotic resistance for E. coli. This evidence suggests there is a need for further individual-level studies to explore the potential mechanism for these associations.

Transmission network parameters estimated from HIV sequences for a nationwide epidemic.

BACKGROUND: Many studies of sexual behavior have shown that individuals vary greatly in their number of sexual partners over time, but it has proved difficult to obtain parameter estimates relating to the dynamics of human immunodeficiency virus (HIV) transmission except in small-scale contact tracing studies. Recent developments in molecular phylodynamics have provided new routes to obtain these parameter estimates, and current clinical practice provides suitable data for entire infected populations. METHODS: A phylodynamic analysis was performed on partial pol gene sequences obtained for routine clinical care from 14,560 individuals, representing approximately 60% of the HIV-positive men who have sex with men (MSM) under care in the United Kingdom. RESULTS: Among individuals linked to others in the data set, 29% are linked to only 1 individual, 41% are linked to 2-10 individuals, and 29% are linked to ≥10 individuals. The right-skewed degree distribution can be approximated by a power law, but the data are best fitted by a Waring distribution for all time depths. For time depths of 5-7 years, the distribution parameter ρ lies within the range that indicates infinite variance. CONCLUSIONS: The transmission network among UK MSM is characterized by preferential association such that a randomly distributed intervention would not be expected to stop the epidemic.

Real-world clinical effectiveness and sustainability of universal bloodborne virus testing in an urban emergency department in the UK.

Innovative testing approaches and care pathways are required to meet HIV, hepatitis B (HBV) and hepatitis C (HCV) elimination goals. Routine testing for blood-borne viruses (BBVs) within emergency departments (EDs) is suggested by the European Centre for Disease Prevention and Control but there is a paucity of supporting evidence. We evaluated the introduction of routine BBV testing in EDs at a large teaching hospital in northern England. In October 2018, we modified the electronic laboratory ordering system to reflex opt-out HIV, HBV and HCV testing for all ED attendees aged 16-65 years who had a routine blood test for urea and electrolytes (U&Es). Linkage to care (LTC) was attempted for newly diagnosed patients, those never referred and those who had previously disengaged from care. The project operated for 18 months, here we present evaluation of the initial nine months (2 October 2018-1 July 2019). We analysed testing uptake, BBV seropositivity, LTC and treatment initiation within six months post-diagnosis. Over 9 months, 17,026/28,178 (60.4%) ED attendees who had U&Es performed were tested for ≥ 1 BBV. 299 active BBV infections were identified: 70 HIV Ab/Ag-positive (0.4% seroprevalence), 73 HBsAg-positive (0.4%) and 156 HCV RNA-positive (1.0%). Only 24.3% (17/70) HIV Ab/Ag-positive individuals required LTC, compared to 94.9% (148/156) HCV RNA-positive and 53.4% (39/73) HBsAg-positive individuals. LTC was successful in 94.1% (16/17) HIV Ab/Ag-positive and 69.3% (27/39) HBsAg-positive individuals. However, at 6 months LTC was just 39.2% (58/148) for HCV RNA-positive individuals, with 64% (37/58) of these commencing treatment. Universal opt-out ED BBV testing proved feasible and effective in identifying active BBV infections, especially among marginalised populations with reduced healthcare access. Our integrated approach achieved good LTC rates although further service development is necessary, particularly for HCV RNA-positive people who inject drugs.

Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission.

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16-20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement.

United Kingdom standards for non-invasive cardiac imaging: recommendations from the Imaging Council of the British Cardiovascular Society.

Heart and circulatory diseases affect more than seven million people in the UK. Non-invasive cardiac imaging is a critical element of contemporary cardiology practice. Progressive improvements in technology over the last 20 years have increased diagnostic accuracy in all modalities and led to the incorporation of non-invasive imaging into many standard cardiac clinical care pathways. Cardiac imaging tests are requested by a variety of healthcare practitioners and performed in a range of settings from the most advanced hospitals to local health centres. Imaging is used to detect the presence and consequences of cardiovascular disease, as well as to monitor the response to therapies. The previous UK national imaging strategy statement which brought together all of the non-invasive imaging modalities was published in 2010. The purpose of this document is to collate contemporary standards developed by the modality-specific professional organisations which make up the British Cardiovascular Society Imaging Council, bringing together common and essential recommendations. The development process has been inclusive and iterative. Imaging societies (representing both cardiology and radiology) reviewed and agreed on the initial structure. The final document therefore represents a position, which has been generated inclusively, presents rigorous standards, is applicable to clinical practice and deliverable. This document will be of value to a variety of healthcare professionals including imaging departments, the National Health Service or other organisations, regulatory bodies, commissioners and other purchasers of services, and service users, i.e., patients, and their relatives.

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission.

Understanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.

Molecular phylodynamics of the heterosexual HIV epidemic in the United Kingdom.

The heterosexual risk group has become the largest HIV infected group in the United Kingdom during the last 10 years, but little is known of the network structure and dynamics of viral transmission in this group. The overwhelming majority of UK heterosexual infections are of non-B HIV subtypes, indicating viruses originating among immigrants from sub-Saharan Africa. The high rate of HIV evolution, combined with the availability of a very high density sample of viral sequences from routine clinical care has allowed the phylodynamics of the epidemic to be investigated for the first time. Sequences of the viral protease and partial reverse transcriptase coding regions from 11,071 patients infected with HIV of non-B subtypes were studied. Of these, 2774 were closely linked to at least one other sequence by nucleotide distance. Including the closest sequences from the global HIV database identified 296 individuals that were in UK-based groups of 3 or more individuals. There were a total of 8 UK-based clusters of 10 or more, comprising 143/2774 (5%) individuals, much lower than the figure of 25% obtained earlier for men who have sex with men (MSM). Sample dates were incorporated into relaxed clock phylogenetic analyses to estimate the dates of internal nodes. From the resulting time-resolved phylogenies, the internode lengths, used as estimates of maximum transmission intervals, had a median of 27 months overall, over twice as long as obtained for MSM (14 months), with only 2% of transmissions occurring in the first 6 months after infection. This phylodynamic analysis of non-B subtype HIV sequences representing over 40% of the estimated UK HIV-infected heterosexual population has revealed heterosexual HIV transmission in the UK is clustered, but on average in smaller groups and is transmitted with slower dynamics than among MSM. More effective intervention to restrict the epidemic may therefore be feasible, given effective diagnosis programmes.

CT imaging prior to transcatheter aortic valve implantation in the UK.

Objective: This cross-sectional observational study sought to describe variations in CT in the context of transcatheter aortic valve implantation (CT-TAVI) as currently performed in the UK. Methods: 408 members of the British Society of Cardiovascular Imaging were invited to complete a 27-item online CT-TAVI survey. Results: 47 responses (12% response rate) were received from 40 cardiac centres, 23 (58%) of which performed TAVI on-site (TAVI centres). Only six respondents (13%) performed high-volume activity (>200 scans per year) compared with 13 (28%) performing moderate (100-200 scans per year) and 27 (59%) performing low (0-99 scans per year) volume activity. Acquisition protocols varied (41% retrospective, 12% prospective with wide padding, 47% prospective with narrow padding), as did the phase of reporting (45% systolic, 37% diastolic, 11% both, 6% unreported). Median dose length product was 675 mGy.cm (IQR 477-954 mGy.cm). Compared with non-TAVI centres, TAVI centres were more likely to report minimum iliofemoral luminal diameter (n=25, 96% vs n=7, 58%, p=0.003) and optimal tube angulation for intervention (n=12, 46% vs n=1, 8%, p=0.02). Conclusions: This national survey formally describes current CT-TAVI practice in the UK. High-volume activity was only present at one in seven cardiac CT centres. There is wide variation in scan acquisition, scan reporting and radiation dose exposure in cardiac CT centres.

An international outbreak of Salmonella enterica serotype Enteritidis linked to eggs from Poland: a microbiological and epidemiological study.

BACKGROUND: Salmonella spp are a major cause of food-borne outbreaks in Europe. We investigated a large multi-country outbreak of Salmonella enterica serotype Enteritidis in the EU and European Economic Area (EEA). METHODS: A confirmed case was defined as a laboratory-confirmed infection with the outbreak strains of S Enteritidis based on whole-genome sequencing (WGS), occurring between May 1, 2015, and Oct 31, 2018. A probable case was defined as laboratory-confirmed infection with S Enteritidis with the multiple-locus variable-number tandem repeat analysis outbreak profile. Multi-country epidemiological, trace-back, trace-forward, and environmental investigations were done. We did a case-control study including confirmed and probable cases and controls randomly sampled from the population registry (frequency matched by age, sex, and postal code). Odds ratios (ORs) for exposure rates between cases and controls were calculated with unmatched univariable and multivariable logistic regression. FINDINGS: 18 EU and EEA countries reported 838 confirmed and 371 probable cases. 509 (42%) cases were reported in 2016, after which the number of cases steadily increased. The case-control study results showed that cases more often ate in food establishments than did controls (OR 3·4 [95% CI 1·6-7·3]), but no specific food item was identified. Recipe-based food trace-back investigations among cases who ate in food establishments identified eggs from Poland as the vehicle of infection in October, 2016. Phylogenetic analysis identified two strains of S Enteritidis in human cases that were subsequently identified in salmonella-positive eggs and primary production premises in Poland, confirming the source of the outbreak. After control measures were implemented, the number of cases decreased, but increased again in March, 2017, and the increase continued into 2018. INTERPRETATION: This outbreak highlights the public health value of multi-country sharing of epidemiological, trace-back, and microbiological data. The re-emergence of cases suggests that outbreak strains have continued to enter the food chain, although changes in strain population dynamics and fewer cases indicate that control measures had some effect. Routine use of WGS in salmonella surveillance and outbreak response promises to identify and stop outbreaks in the future. FUNDING: European Centre for Disease Prevention and Control; Directorate General for Health and Food Safety, European Commission; and National Public Health and Food Safety Institutes of the authors' countries (see Acknowledgments for full list).

Episodic sexual transmission of HIV revealed by molecular phylodynamics.

BACKGROUND: The structure of sexual contact networks plays a key role in the epidemiology of sexually transmitted infections, and their reconstruction from interview data has provided valuable insights into the spread of infection. For HIV, the long period of infectivity has made the interpretation of contact networks more difficult, and major discrepancies have been observed between the contact network and the transmission network revealed by viral phylogenetics. The high rate of HIV evolution in principle allows for detailed reconstruction of links between virus from different individuals, but often sampling has been too sparse to describe the structure of the transmission network. The aim of this study was to analyze a high-density sample of an HIV-infected population using recently developed techniques in phylogenetics to infer the short-term dynamics of the epidemic among men who have sex with men (MSM). METHODS AND FINDINGS: Sequences of the protease and reverse transcriptase coding regions from 2,126 patients, predominantly MSM, from London were compared: 402 of these showed a close match to at least one other subtype B sequence. Nine large clusters were identified on the basis of genetic distance; all were confirmed by Bayesian Monte Carlo Markov chain (MCMC) phylogenetic analysis. Overall, 25% of individuals with a close match with one sequence are linked to 10 or more others. Dated phylogenies of the clusters using a relaxed clock indicated that 65% of the transmissions within clusters took place between 1995 and 2000, and 25% occurred within 6 mo after infection. The likelihood that not all members of the clusters have been identified renders the latter observation conservative. CONCLUSIONS: Reconstruction of the HIV transmission network using a dated phylogeny approach has revealed the HIV epidemic among MSM in London to have been episodic, with evidence of multiple clusters of transmissions dating to the late 1990s, a period when HIV prevalence is known to have doubled in this population. The quantitative description of the transmission dynamics among MSM will be important for parameterization of epidemiological models and in designing intervention strategies.

A reassessment of the emergence time of European bat lyssavirus type 1.

The previous study of the evolutionary rates of European bat lyssavirus type 1 (EBLV-1) used a strict molecular clock to estimate substitution rates of the nucleoprotein gene and in turn times of the most recent common ancestor (tMRCA) of the entire genotype and the two major EBLV-1 lineages (EBLV-1A and EBLV-1B). The results of that study suggested that the evolutionary rate of EBLV-1 was one of the lowest recorded for RNA viruses and that genetic diversity of EBLV-1 arose 500-750 years ago. Here I have shown that the use of a relaxed molecular clock (allowing branch rates to vary within a phylogeny) shows that these previous estimates should be revised. The relaxed clock provides a significantly better fit to all datasets. The substitution rate of EBLV-1B is compatible to that expected given previous estimates for the N gene of rabies virus whilst rate estimations for EBLV-1A appear to be confounded by substantial rate variation within the phylogeny. The relaxed clock substitution rate for EBLV-1 (1.1 x 10(-4)) is higher than had been estimated previously, and closer to that expected for the N gene. Moreover, tMRCA estimates for EBLV-1 are substantially reduced using the relaxed molecular clock (70-300 years) although the differing dynamics of EBLV-1A and EBLV-1B confound the confidence in this estimate. Current diversity of both EBLV-1A and EBLV-1B appears to have emerged within the last 100 years. Reconstruction of the population histories suggests that EBLV-1B may be emerging whilst the signal derived from the EBLV-1A phylogeny may be dampened by clade-specific dynamics.