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We report fatal West Nile virus (WNV) infection in a 7-year-old mare returning to the United Kingdom from Spain. Case timeline and clustering of virus sequence with recent WNV isolates suggest that transmission occurred in Andalusía, Spain. Our findings highlight the importance of vaccination for horses traveling to WNV-endemic regions.

Usutu virus (USUV) is an emerging zoonotic arbovirus in Europe, where it primarily impacts Eurasian blackbirds (Turdus merula). For mosquito-borne viruses to persist in temperate areas, transovarial transmission in vectors or overwintering in either hosts or diapausing vectors must occur to facilitate autochthonous transmission. We undertook surveillance of hosts and vectors in 2021 to elucidate whether USUV had overwintered in the United Kingdom (UK) following its initial detection there in 2020. From 175 dead bird submissions, we detected 1 case of USUV infection, in a blackbird, from which a full USUV genome was derived. Using a molecular clock analysis, we demonstrate that the 2021 detection shared a most recent common ancestor with the 2020 Greater London, UK, USUV sequence. In addition, we identified USUV-specific neutralizing antibodies in 10 out of 86 serum samples taken from captive birds at the index site, demonstrating in situ cryptic infection and potential sustained transmission. However, from 4966 mosquitoes, we detected no USUV RNA suggesting that prevalence in the vector community was absent or low during sampling. Combined, these results suggest that USUV overwintered in the UK, thus providing empirical evidence for the continued northward expansion of this vector-borne viral disease. Currently, our detection indicates geographically restricted virus persistence. Further detections over time will be required to demonstrate long-term establishment. It remains unclear whether the UK, and by extension other high-latitude regions, can support endemic USUV infection., (© 2022 The Authors. Transboundary and Emerging Diseases published by Wiley-VCH GmbH.)

Following the first detection in the United Kingdom of Usutu virus (USUV) in wild birds in 2020, we undertook a multidisciplinary investigation that combined screening host and vector populations with interrogation of national citizen science monitoring datasets to assess the potential for population impacts on avian hosts. Pathological findings from six USUV-positive wild passerines were non-specific, highlighting the need for molecular and immunohistochemical examinations to confirm infection. Mosquito surveillance at the index site identified USUV RNA in Culex pipiens s.l. following the outbreak. Although the Eurasian blackbird (Turdus merula) is most frequently impacted by USUV in Europe, national syndromic surveillance failed to detect any increase in occurrence of clinical signs consistent with USUV infection in this species. Furthermore, there was no increase in recoveries of dead blackbirds marked by the national ringing scheme. However, there was regional clustering of blackbird disease incident reports centred near the index site in 2020 and a contemporaneous marked reduction in the frequency with which blackbirds were recorded in gardens in this area, consistent with a hypothesis of disease-mediated population decline. Combining results from multidisciplinary schemes, as we have done, in real-time offers a model for the detection and impact assessment of future disease emergence events., (© 2022. Crown.)

Where ticks are found, tick-borne diseases can present a threat to human and animal health. The aetiology of many of these important diseases, including Lyme disease, bovine babesiosis, tick-borne fever and louping ill, have been known for decades whilst others have only recently been documented in the United Kingdom (UK). Further threats such as the importation of exotic ticks through human activity or bird migration, combined with changes to either the habitat or climate could increase the risk of tick-borne disease persistence and transmission. Prevention of tick-borne diseases for the human population and animals (both livestock and companion) is dependent on a thorough understanding of where and when pathogen transmission occurs. This information can only be gained through surveillance that seeks to identify where tick populations are distributed, which pathogens are present within those populations, and the periods of the year when ticks are active. To achieve this, a variety of approaches can be applied to enhance knowledge utilising a diverse range of stakeholders (public health professionals and veterinarians through to citizen scientists). Without this information, the application of mitigation strategies to reduce pathogen transmission and impact is compromised and the ability to monitor the effects of climate change or landscape modification on the risk of tick-borne disease is more challenging. However, as with many public and animal health interventions, there needs to be a cost-benefit assessment on the most appropriate intervention applied. This review will assess the challenges of tick-borne diseases in the UK and argue for a cross-disciplinary approach to their surveillance and control.

Louping ill virus (LIV) is a single-stranded, positive-sense RNA virus within the genus Flavivirus that is transmitted to vertebrate hosts by bites from infected ticks, the arthropod vector. The virus affects livestock in upland areas of Great Britain and Ireland, resulting in a febrile illness that can progress to fatal encephalitis. Prevention of the disease is facilitated by combining acaricide treatment, land management and vaccination strategies. However, vaccines have been discontinued in recent years. Although rare, LIV can be transmitted to and cause disease in humans. Consequently, LIV infection is a threat to human and veterinary health and can impact on the rural economy.

Background: The incidence of both non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (ALD) are expected to grow as a consequence of the ongoing obesity and alcohol consumption trends., Objective: We examined the joint associations of adiposity (body mass index (BMI) and waist circumference (WC)) and alcohol consumption on ALD, NAFLD and liver disease incidence and mortality (n = 465,437)., Methods: Alcohol consumption was categorised based on current UK guidelines (14 units/week). Data were analysed using Cox proportional hazard models. A total of 1090 liver disease deaths, 230 ALD deaths and 192 NAFLD deaths occurred over an average follow-up length of 10.5 ± 1.7 years., Results: In multivariate models, we observed greater point estimates for risk of ALD, NAFLD and liver disease incidence and mortality among overweight/obese participants who consumed alcohol at the same level as normal weight participants. We found that overweight/obese participants who reported alcohol consumption above the guidelines had a greater HR for liver disease incidence and mortality (HR 1.52, 95% CI 1.32, 1.75 and HR 2.20, 95% CI 1.41, 3.44, respectively) than normal weight individuals (HR 0.95, 95% CI 0.83, 1.09 and HR 1.24, 95% CI 0.8, 1.93, respectively). The results for the associations of alcohol consumption and WC with ALD, NAFLD and liver disease mortality were similar. Participants with high WC who reported alcohol consumption above the guidelines had a greater HR for liver disease incidence (HR 1.59, 95% CI 1.35, 1.87) than normal WC individuals (HR 0.85, 95% CI 0.72, 1.01)., Conclusions: We found evidence that being overweight/obese amplified the harmful effect of alcohol on the liver incidence and mortality., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Lyssaviruses are an important genus of zoonotic viruses which cause the disease rabies. The United Kingdom is free of classical rabies (RABV). However, bat rabies due to European bat lyssavirus 2 (EBLV-2), has been detected in Daubenton's bats ( Myotis daubentonii ) in Great Britain since 1996, including a fatal human case in Scotland in 2002. Across Europe, European bat lyssavirus 1 (EBLV-1) is commonly associated with serotine bats ( Eptesicus serotinus ). Despite the presence of serotine bats across large parts of southern England, EBLV-1 had not previously been detected in this population. However, in 2018, EBLV-1 was detected through passive surveillance in a serotine bat from Dorset, England, using a combination of fluorescent antibody test, reverse transcription-PCR, Sanger sequencing and immunohistochemical analysis. Subsequent EBLV-1 positive serotine bats have been identified in South West England, again through passive surveillance, during 2018, 2019 and 2020. Here, we confirm details of seven cases of EBLV-1 and present similarities in genetic sequence indicating that emergence of EBLV-1 is likely to be recent, potentially associated with the natural movement of bats from the near continent.

Objectives: The aim of the study was to find evidence of SARS-CoV-2 infection in UK cats., Design: Tissue samples were tested for SARS-CoV-2 antigen using immunofluorescence and for viral RNA by in situ hybridisation. A set of 387 oropharyngeal swabs that had been submitted for routine respiratory pathogen testing was tested for SARS-CoV-2 RNA using reverse transcriptase quantitative PCR., Results: Lung tissue collected post-mortem from cat 1 tested positive for both SARS-CoV-2 nucleocapsid antigen and RNA. SARS-CoV-2 RNA was detected in an oropharyngeal swab collected from cat 2 that presented with rhinitis and conjunctivitis. High throughput sequencing of the viral genome revealed five single nucleotide polymorphisms (SNPs) compared to the nearest UK human SARS-CoV-2 sequence, and this human virus contained eight SNPs compared to the original Wuhan-Hu-1 reference sequence. An analysis of the viral genome of cat 2 together with nine other feline-derived SARS-CoV-2 sequences from around the world revealed no shared cat-specific mutations., Conclusions: These findings indicate that human-to-cat transmission of SARS-CoV-2 occurred during the COVID-19 pandemic in the UK, with the infected cats developing mild or severe respiratory disease. Given the ability of the new coronavirus to infect different species, it will be important to monitor for human-to-cat, cat-to-cat and cat-to-human transmission., (© 2021 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is the main cause of viral encephalitis in Asia. However, with changing climate JEV has the potential to emerge in novel temperate regions. Here, we have assessed the vector competence of the temperate mosquito Culex pipiens f. pipiens to vector JEV genotype III at temperatures representative of those experienced, or predicted in the future during the summer months, in the United Kingdom. Our results show that Cx. pipiens is susceptible to JEV infection at both temperatures. In addition, at 25 °C, JEV disseminated from the midgut and was recovered in saliva samples, indicating the potential for transmission. At a lower temperature, 20 °C, following an incubation period of fourteen days, there were reduced levels of JEV dissemination and virus was not detected in saliva samples. The virus present in the bodies of these mosquitoes was restricted to the posterior midgut as determined by microscopy and viable virus was successfully recovered. Apart from the influence on virus dissemination, mosquito mortality was significantly increased at the higher temperature. Overall, our results suggest that temperature is a critical factor for JEV vector competence and infected-mosquito survival. This may in turn influence the vectorial capacity of Cx. pipiens to vector JEV genotype III in temperate areas.

Background: West Nile virus (WNV) is a single-stranded RNA virus that can cause neurological disease in both humans and horses. Due to the movement of competent vectors and viraemic hosts, WNV has repeatedly emerged globally and more recently in western Europe. Within the UK, WNV is a notifiable disease in horses, and vaccines against the virus are commercially available. However, there has been no investigation into the seroprevalence of WNV in the UK equine population to determine the extent of vaccination or to provide evidence of recent infection., Methods: Equine serum samples were obtained from the Animal and Plant Health Agency's equine testing service between August and November 2019. A total of 988 serum samples were selected for horses resident in South East England. WNV seroprevalence was determined using two enzyme-linked immunosorbent assays (ELISAs) to detect total flavivirus antibodies and WNV-specific immunoglobulin M (IgM) antibodies. Positive IgM results were investigated by contacting the submitting veterinarian to establish the clinical history or evidence of prior vaccination of the horses in question., Results: Within the cohort, 274 samples tested positive for flavivirus antibodies, of which two subsequently tested positive for WNV-specific IgM antibodies. The follow-up investigation established that both horses had been vaccinated prior to serum samples being drawn, which resulted in an IgM-positive response. All the samples that tested positive by competition ELISA were from horses set to be exported to countries where WNV is endemic. Consequently, the positive results were likely due to previous vaccination. In contrast, 714 samples were seronegative, indicating that the majority of the UK equine population may be susceptible to WNV infection., Conclusions: There was no evidence for cryptic WNV infection in a cohort of horses sampled in England in 2019. All IgM-seropositive cases were due to vaccination; this should be noted for future epidemiological surveys in the event of a disease outbreak, as it is not possible to distinguish vaccinated from infected horses without knowledge of their clinical histories.

In August 2020, as part of a long-term disease surveillance programme, Usutu virus was detected in five Eurasian blackbirds ( Turdus merula ) and one house sparrow ( Passer domesticus ) from Greater London, England. This was initially detected by reverse transcription-PCR and was confirmed by virus isolation and by immunohistochemical detection of flavivirus in tissues. Phylogenetic analysis identified Usutu virus African 3.2 lineage, which is prevalent in the Netherlands and Belgium, suggesting a potential incursion from mainland Europe.

The emergence and spread of tick-borne arboviruses pose an increased challenge to human and animal health. In Europe this is demonstrated by the increasingly wide distribution of tick-borne encephalitis virus (TBEV, Flavivirus, Flaviviridae), which has recently been found in the United Kingdom (UK). However, much less is known about other tick-borne flaviviruses (TBFV), such as the closely related louping ill virus (LIV), an animal pathogen which is endemic to the UK and Ireland, but which has been detected in other parts of Europe including Scandinavia and Russia. The emergence and potential spatial overlap of these viruses necessitates improved understanding of LIV genomic diversity, geographic spread and evolutionary history. We sequenced a virus archive composed of 22 LIV isolates which had been sampled throughout the UK over a period of over 80 years. Combining this dataset with published virus sequences, we detected no sign of recombination and found low diversity and limited evidence for positive selection in the LIV genome. Phylogenetic analysis provided evidence of geographic clustering as well as long-distance movement, including movement events that appear recent. However, despite genomic data and an 80-year time span, we found that the data contained insufficient temporal signal to reliably estimate a molecular clock rate for LIV. Additional analyses revealed that this also applied to TBEV, albeit to a lesser extent, pointing to a general problem with phylogenetic dating for TBFV. The 22 LIV genomes generated during this study provide a more reliable LIV phylogeny, improving our knowledge of the evolution of tick-borne flaviviruses. Our inability to estimate a molecular clock rate for both LIV and TBEV suggests that temporal calibration of tick-borne flavivirus evolution should be interpreted with caution and highlight a unique aspect of these viruses which may be explained by their reliance on tick vectors., Competing Interests: The authors have declared that no competing interests exist.

Background: Bovine babesiosis, commonly known as redwater fever, is a sporadic tick-borne disease in the United Kingdom. Outbreaks occur during the spring, summer and autumn months when ticks are active. This study reports the findings of an investigation of an outbreak of bovine babesiosis during the winter month of February, 2019., Methods: DNA from blood, organ and tick samples taken from affected cattle were tested for the presence of piroplasm and Anaplasma phagocytophilum DNA using PCRs directed to the 18S rRNA gene and msp2 gene respectively. The species of piroplasm was confirmed by sequencing., Results: Babesia divergens DNA was detected in the blood of five cattle displaying clinical signs of babesiosis within a herd of twenty. This parasite was also detected in three of ten ticks removed from one of the affected cattle. In addition, A. phagocytophilum was detected in three cattle tested and two of ten of the ticks., Conclusions: An outbreak of bovine babesiosis during February is unusual as the tick vector, Ixodes ricinus, does not generally become active until temperatures rise later in the year. February of 2019 was unusual as average temperatures during the first week of the month reached over 10 °C, well above historical averages that are typically below 5 °C, and a temperature at which ticks can become active. This unusual weather event is likely to have triggered tick questing, that combined with a co-infection with two tick-borne pathogens caused the severe outbreak of disease.

In mainland Europe, the mosquito species Culex modestus Ficalbi (1890) is a bridge vector for West Nile virus (WNV) from its natural bird-mosquito cycle to mammals. The present study assessed the genetic diversity of Cx. modestus, as well as related Culex species, using the mitochondrial COI DNA barcoding region and compared this with the population structure across Europe. A haplotype network was mapped to determine genealogical relationships among specimens. The intraspecific genetic diversity within individual Culex species was below 2%, whereas the interspecific genetic divergence varied from 2.99% to 13.74%. In total, 76 haplotypes were identified among 198 sequences. A median-joining network determined from 198 COI sequences identified two major lineages that were separated by at least four mutation steps. A high level of intraspecific genetic diversity was not detected in Cx. modestus in samples submitted from different European populations, which indicates that morphologically identified specimens represent a single species and not a species complex. Therefore, it is deduced that different populations of Cx. modestus will show a similar potential to transmit WNV, lending support to concerns that the population present in southeast England represents a risk of transmission to humans., (© 2019 The Royal Entomological Society.)

Vector borne diseases are a continuing global threat to both human and animal health. The ability of vectors such as mosquitos to cover large distances and cross country borders undetected provide an ever-present threat of pathogen spread. Many diseases can infect multiple vector species, such that even if the climate is not hospitable for an invasive species, indigenous species may be susceptible and capable of transmission such that one incursion event could lead to disease establishment in these species. Here we present a consensus modelling methodology to estimate the habitat suitability for presence of mosquito species in the UK deemed competent for Rift Valley fever virus (RVF) and demonstrate its application in an assessment of the relative risk of establishment of RVF virus in the UK livestock population. The consensus model utilises observed UK mosquito surveillance data, along with climatic and geographic prediction variables, to inform six independent species distribution models; the results of which are combined to produce a single prediction map. As a livestock host is needed to transmit RVF, we then combine the consensus model output with existing maps of sheep and cattle density to predict the areas of the UK where disease is most likely to establish in local mosquito populations. The model results suggest areas of high suitability for RVF competent mosquito species across the length and breadth of the UK. Notable areas of high suitability were the South West of England and coastal areas of Wales, the latter of which was subsequently predicted to be at higher risk for establishment of RVF due to higher livestock densities. This study demonstrates the applicability of outputs of species distribution models to help predict hot-spots for risk of disease establishment. While there is still uncertainty associated with the outputs we believe that the predictions are an improvement on just using the raw presence points from a database alone. The outputs can also be used as part of a multidisciplinary approach to inform risk based disease surveillance activities., Competing Interests: The authors have declared that no competing interests exist.

Disease surveillance in wildlife populations presents a logistical challenge, yet is critical in gaining a deeper understanding of the presence and impact of wildlife pathogens. Erinaceus coronavirus (EriCoV), a clade C Betacoronavirus, was first described in Western European hedgehogs (Erinaceus europaeus) in Germany. Here, our objective was to determine whether EriCoV is present, and if it is associated with disease, in Great Britain (GB). An EriCoV-specific BRYT-Green® real-time reverse transcription PCR assay was used to test 351 samples of faeces or distal large intestinal tract contents collected from casualty or dead hedgehogs from a wide area across GB. Viral RNA was detected in 10.8% (38) samples; however, the virus was not detected in any of the 61 samples tested from Scotland. The full genome sequence of the British EriCoV strain was determined using next generation sequencing; it shared 94% identity with a German EriCoV sequence. Multivariate statistical models using hedgehog case history data, faecal specimen descriptions and post-mortem examination findings found no significant associations indicative of disease associated with EriCoV in hedgehogs. These findings indicate that the Western European hedgehog is a reservoir host of EriCoV in the absence of apparent disease.

Background: Usutu virus (USUV) is an emerging zoonotic virus originally from sub-Saharan Africa. It has been introduced into Europe on multiple occasions, causing substantial mortality within the Eurasian blackbird (Turdus merula) population. It is transmitted by the mosquito species Culex pipiens in Europe and Africa. Vector competence studies indicate that European strains of USUV are readily transmitted by indigenous Cx. pipiens. However, there is limited information on the ability of an African strain to infect European mosquitoes., Methods: We evaluated the ability of African strain SAAR-1776 to infect two lines of Cx. pipiens colonised within the United Kingdom (UK). Mosquitoes were fed blood meals containing this virus and maintained at 25 °C for up to 21 days. Individual mosquitoes were tested for the presence of virus in the body, legs and an expectorate saliva sample. Changes to the consensus of the virus genome were monitored in samples derived from infected mosquitoes using amplicon based next generation sequencing., Results: Infection, dissemination and the presence of virus in saliva in one mosquito line was observed, but no evidence for dissemination in the second mosquito line. This suggests a strong barrier to infection in UK Cx. pipiens for this strain of USUV. When comparing the genome of input virus within the blood meal with USUV recovered from an infected mosquito, we observed limited changes in the consensus genome sequence., Conclusions: The evaluation of vector competence of UK populations of Cx. pipiens for Usutu virus suggests a limited susceptibility to infection with USUV strain SAAR-1776 of African origin. However, within a single mosquito there was complete dissemination and expectoration of USUV, indicating that infection, and potentially transmission, is possible. Sequence changes were observed that may represent early adaption to the mosquito host and could reflect the early events of USUV establishment in European mosquito populations.

Background: Rift Valley fever phlebovirus (RVFV) is a mosquito-borne arbovirus causing severe disease in humans and livestock. It is endemic in Africa and spread to the Arabian Peninsula in 2000 raising concerns it could emerge in Europe. The ability of temperate mosquitoes from the United Kingdom (UK) to support replication and transmission of RVFV is unknown., Methods: In this study, two colonised lines of Culex pipiens, wild-caught Aedes detritus and Ae. rusticus from the UK were infected with pathogenic strains of RVFV to assess their vector competence. Mosquitoes were offered artificial blood-meals containing 10 6 or 10 7 plaque forming units (PFU)/ml RVFV, simulating natural peak viraemia in young ruminants, and maintained at 20 °C or 25 °C for up to 21 days. Bodies, legs and saliva were collected and tested for the presence of viral RNA and infectious virus to determine the infection, dissemination and transmission potential., Results: Across temperatures, doses and strains the average infection, dissemination and transmission rates were: 35, 13 and 5% (n = 91) for Cx. pipiens (Caldbeck); 23, 14 and 5% (n = 138) for Cx. pipiens (Brookwood); 36, 28 and 7% (n = 118) for Ae. detritus. However, despite 35% (n = 20) being susceptible to infection, Ae. rusticus did not transmit RVFV. Survival of Aedes species was negatively affected by maintenance at 25 °C compared to the more representative peak average British summer temperature of 20 °C. Increased mortality was also observed with some species infected with 10 7 PFU/ml compared to 10 6 PFU/ml., Conclusions: It can be concluded that temperate mosquito species present in the UK demonstrate a transmission potential for RVFV in the laboratory but, even at high temperatures, this occurred at low efficiency.

Background: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women., Methods: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided., Results: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82)., Conclusions: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.

Background: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered., Methods: We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided., Results: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6))., Conclusions: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.

Introduction: Sex steroids, insulin-like growth factors (IGFs) and prolactin are breast cancer risk factors but whether their effects are mediated through mammographic density, one of the strongest risk factors for breast cancer, is unknown. If such a hormonal basis of mammographic density exists, hormones may underlie ethnic differences in both mammographic density and breast cancer incidence rates., Methods: In a cross-sectional study of 270 postmenopausal Caucasian and Afro-Caribbean women attending a population-based breast screening service in London, UK, we investigated whether plasma biomarkers (oestradiol, oestrone, sex hormone binding globulin (SHBG), testosterone, prolactin, leptin, IGF-I, IGF-II and IGF binding protein 3 (IGFBP3)) were related to and explained ethnic differences in mammographic percent density, dense area and nondense area, measured in Cumulus using the threshold method., Results: Mean levels of oestrogens, leptin and IGF-I:IGFBP3 were higher whereas SHBG and IGF-II:IGFBP3 were lower in Afro-Caribbean women compared with Caucasian women after adjustment for higher mean body mass index (BMI) in the former group (by 3.2 kg/m(2) (95% confidence interval (CI): 1.8, 4.5)). Age-adjusted percent density was lower in Afro-Caribbean compared with Caucasian women by 5.4% (absolute difference), but was attenuated to 2.5% (95% CI: -0.2, 5.1) upon BMI adjustment. Despite ethnic differences in biomarkers and in percent density, strong ethnic-age-adjusted inverse associations of oestradiol, leptin and testosterone with percent density were completely attenuated upon adjustment for BMI. There were no associations of IGF-I, IGF-II or IGFBP3 with percent density or dense area. We found weak evidence that a twofold increase in prolactin and oestrone levels were associated, respectively, with an increase (by 1.7% (95% CI: -0.3, 3.7)) and a decrease (by 2.0% (95% CI: 0, 4.1)) in density after adjustment for BMI., Conclusions: These findings suggest that sex hormone and IGF levels are not associated with BMI-adjusted percent mammographic density in cross-sectional analyses of postmenopausal women and thus do not explain ethnic differences in density. Mammographic density may still, however, be influenced by much higher premenopausal hormone levels.

Background: The allele CHEK2*1100delC doubles the risk of breast cancer in unselected women, but could confer a greater risk in women with a family history of the disease, particularly of bilateral breast cancer. Our aim was to measure the risk of breast cancer in relatives of women with bilateral breast cancer who were carriers of this allele., Methods: A population-based series of 469 bilateral breast cancer cases ascertained through English cancer registries were genotyped for CHEK2*1100delC. Standardised incidence ratios (SIRs) and cumulative risks were calculated for breast cancer, prostate cancer, and all other cancers in the first-degree relatives of carriers and non-carriers., Findings: The relatives of bilateral cases who were wild-type for CHEK2 had three times the population risk of female breast cancer (145 cases: SIR 3.48 (95% CI 2.96-4.09), twice the risk of prostate cancer (34 cases: SIR 2.41, 1.67-3.36) and a large excess of male breast cancer (five cases: SIR 15.06, 4.92-35.36). Relatives of those who were carriers of CHEK2*1100delC had a substantially higher risk of breast cancer (eight cases: SIR 12.11, 5.23-23.88) and possibly prostate cancer (two cases: SIR 9.87, 1.20-35.67)., Interpretation: These data suggest a multiplicative interaction between CHEK2*1100delC and other unknown susceptibility genes. In women with a family history of bilateral disease, CHEK2*1100delC confers a high lifetime risk and might be useful for predictive testing. Bilateral breast cancer cases and their families are likely to provide an efficient basis for identification of additional low-penetrance breast-cancer genes.

This study was undertaken to assess the feasibility of one method of initiating the setting of standards in United Kingdom general practice by the development and selection of criteria for clinical care. Three clinical topics were chosen. An 'academic phase' was used to develop precise criteria, which formed the basis of a draft questionnaire for each of the three topics. A 'consultation phase' followed in which the three questionnaires were sent to a randomly selected sample of general practitioners throughout the UK. Although 53% of the 62 general practitioners invited were willing to be involved in the academic phase only 13% were able to attend a meeting. Of the 262 general practitioners sent one of the questionnaires 63% responded. Using a strict definition of consensus one quarter of the criteria were identified by the respondents to the questionnaire as important or not important; using a less strict definition a further one quarter to one half of the criteria were identified. The study demonstrates that it is possible to develop and select criteria in this way. If this approach were to be developed for performance review, criteria would need to be selected, appropriate target levels of performance set, and suitable methods for their application identified.