Roustide, the Prevacar Group

Invasive meningococcal disease (IMD) is an infrequent yet deadly infection that constitutes a public health emergency. Control requires rapid identification and diagnosis of suspect cases, prompt administration of antibiotic prophylaxis to close contacts, and recognition of epidemiological links among cases. In 2011, the incidence rate of IMD was 0.73 per 100,000 in European Union (EU) countries, as reported by Marcus et al. in their report on a recent cluster of serogroup C Neisseria meningitidis (MenC) in MSM in this edition of Eurosurveillance [1], in the United States (US), it was 0.25 per 100,000 (an all-time low). While outbreaks of IMD in the US and EU are rare, they can be difficult to control, particularly when the primary risk factor is membership in a social network rather than an organisation or institution [2]. In September 2012, a slowly evolving outbreak of IMD was recognised among men who have sex with men (MSM) in New York City (NYC). The NYC Department of Health and Mental Hygiene (DOHMH), in collaboration with community providers, implemented a meningococcal vaccine campaign to prevent further illness and death [3]. IMD cases in MSM have recently also been recognised in Germany, France, and Belgium. In response to these clusters the European Centre for Disease Prevention and Control, with input from leading experts, composed and distributed a rapid risk assessment to help guide medical and public health authorities [4]. The report by Marcus et al. in this issue summarises the German cluster and highlights important issues regarding local and international IMD control [1].

Invasive meningococcal disease (IMD) is an infrequent yet deadly infection that constitutes a public health emergency.Control requires rapid identification and diagnosis of suspect cases, prompt administration of antibiotic prophylaxis to close contacts, and recognition of epidemiological links among cases.In 2011, the incidence rate of IMD was 0.73 per 100,000 in European Union (EU) countries, as reported by Marcus et al. in their report on a recent cluster of serogroup C Neisseria meningitidis (MenC) in MSM in this edition of Eurosurveillance [1], in the United States (US), it was 0.25 per 100,000 (an all-time low).While outbreaks of IMD in the US and EU are rare, they can be difficult to control, particularly when the primary risk factor is membership in a social network rather than an organisation or institution [2].In September 2012, a slowly evolving outbreak of IMD was recognised among men who have sex with men (MSM) in New York City (NYC).The NYC Department of Health and Mental Hygiene (DOHMH), in collaboration with community providers, implemented a meningococcal vaccine campaign to prevent further illness and death [3].IMD cases in MSM have recently also been recognised in Germany, France, and Belgium.In response to these clusters the European Centre for Disease Prevention and Control, with input from leading experts, composed and distributed a rapid risk assessment to help guide medical and public health authorities [4].The report by Marcus et al. in this issue summarises the German cluster and highlights important issues regarding local and international IMD control [1].
The first reported outbreak of IMD in MSM occurred in Toronto in 2001 [5].Subsequently, IMD outbreaks in the MSM community have occurred in Chicago in 2003 [6] and NYC in 2012 and 2013 [3].All three outbreaks were determined to have been caused by MenC, multilocus sequence typing (MLST) sequence type 11 (ST-11), a common invasive strain of Neisseria meningitidis, and prompted public health officials to offer vaccination to people at risk.The IMD strain responsible for the cases in Germany also belongs to the MenC, ST-11 clonal complex, but direct comparisons to the Canadian and US strains have not yet been completed.No links to international travel have been identified between the European and US cases.
Although sexual partners are often elicited during IMD contact investigations, sexual orientation had not previously been incorporated into standardised questionnaires in the US or Europe.MSM may be at higher risk of IMD due to an increased frequency of known risk factors, such as bar patronage and smoking [7][8][9] or through previously unrecognised risk behaviours.Smoking behaviour in NYC among MSM aged 18 to 64 years, however, was not significantly different than among men who have sex only with women (for the years 2009-11: 24% versus 21%, p=0.4) [10].While bar patronage was reported by Marcus et al. in the German cluster, only one of 17 recent MSM cases in NYC reported that they used bars to meet sexual partners.Drug use has appeared infrequently in the literature, but was reported by half of the MSM outbreak cases since 2012 in NYC (crystal methamphetamine, marijuana, cocaine).Whether these factors act through the sharing of cigarettes or drug paraphernalia, direct mucosal damage facilitating bacterial invasion, or via alteration of immune function is not currently known.
The relatively infrequent identification of this particular MenC strain in non-MSM is likely to represent circulation limited to the MSM social network.However, a unique mechanism of transmission or a susceptibility specific to MSM is possible.In the period August 2010 through June 2013, for those cases for whom pulsedfield gel electrophoresis was performed, only two of 16 MenC strain matches to the outbreak strain were not MSM, whereas only one of 15 cases in MSM was due an unrelated MenC strain.NYC is conducting a case-control study of IMD in MSM and performing full genome sequencing of MenC isolates from the past decade to better answer these questions.
The US Centers for Disease Control and Prevention (US CDC) and the German Standing Committee on Vaccination recommend using vaccine to control IMD outbreaks when the attack rate exceeds a threshold suggestive of ongoing transmission [11][12][13].While this recommendation can be readily applied to institutional outbreaks in which the population at risk is easily defined, it is much more difficult to apply to outbreaks in which the only common link is a social network or risk behaviours.In 2005 and 2006, an outbreak of IMD MenC, ST-11, occurred among recovering and current drug users and their close contacts in NYC [14].The outbreak extended over many months without meeting strict US CDC criteria.The DOHMH responded by administering vaccine to 2,700 persons in affected neighbourhoods, utilising locations such as needle exchange sites, methadone clinics, and drug treatment centres [14].
There are many challenges to controlling IMD outbreaks.Contact tracing and antibiotic prophylaxis are the mainstays of public health practice for individual IMD cases.Cases are often unwilling or unable, however, to disclose sexual and drug using contacts.In NYC we have met with good success through the use of serial patient and family interviews and by utilising staff with experience in obtaining sensitive personal information.Vaccination is an attractive option for MenC IMD clusters; however, identifying the population at risk is challenging in community outbreaks.Vaccine campaigns consume substantial human and financial resources and at this time there is no evidence that a single dose of the vaccines available in the US confers either herd or long lasting immunity (personnel communication: Amanda Cohn, US CDC, October 2011).The current NYC vaccine campaign has cost over 1 million US dollars and has not yet ended.Narrowing the vaccine recommendations to target individuals at highest risk must be balanced against the difficulties of reaching cloistered populations and assuring adequate vaccine access for the under-insured.
A common link among MSM IMD cases in NYC has been use of the Internet and smartphone applications to meet sexual partners.The use of social media has recently emerged as a new method for communicating with individuals potentially exposed to an IMD case [15].The DOHMH used email messages and mobile phone and online advertisements to advise the MSM community about the outbreak and need for vaccination.Interestingly, conventional media (major newspapers, network television) coverage sparked the largest uptakes in vaccine administration (Figure 1).In the Toronto and Chicago MSM outbreaks [5,6], vaccination campaigns coincided with the apparent cessation of IMD cases in the affected communities (Figures 1 and  2).We do not have definitive evidence that the vaccine campaigns halted these outbreaks.Nevertheless, it is plausible that vaccination campaigns reduce illness and death when focused on persons at highest risk.Defining that risk when the outbreak is occurring in social networks remains an important challenge for public health officials.Of note, France has issued vaccine recommendations for its MSM community based on the recent European clusters [16], and this is under consideration in Germany [1].
IMD outbreaks among MSM communities in North America and Europe over the past 13 years highlight the common problems faced by public health officials.While the spread of IMD from the NYC MSM community to MSM communities in Europe has not been proven, the timing of cases is suspicious and emphasises the borderless nature of infectious diseases in the 21st century.International spread of IMD is not a new phenomenon [17].After the Hajj pilgrimage in 2000, a serogroup W135 strain resulted in IMD cases in 16 countries [18].The recent cases among MSM on both sides of the Atlantic emphasise the need for constant vigilance in the assessment of risk groups for IMD, and compel public health agencies to add questions about drug use and sexual practices to their routine investigations.
There is also a need to establish relationships and protocols for the sharing of epidemiologic data and microbiological specimens across continents and oceans, as exists for food-borne pathogens [19].In light of the potential for similar outbreaks, routine vaccination of MSM, as well as persons infected with human immunodeficiency virus (HIV), have become important policy questions [20].We are working to determine the costeffectiveness of such a policy and as more is understood about the transmission and behavioural risk factors, how vaccination can be optimised to decrease the morbidity and mortality associated with IMD.
Clinicians should keep IMD in their differential diagnosis when evaluating febrile MSM and public health officials are encouraged to inquire about the sexual partners and social networks of reported IMD cases.

Figure 2
Epidemic curve of invasive meningococcal disease cases among current and former drug users and their close contacts, New York City, 2005-06 (n=24) IMD is a rare but serious disease caused by Neisseria meningitidis, a gram-negative, encapsulated diplococcus.The clinical spectrum of IMD is diverse and may vary from a mild febrile illness to septicaemia and/or meningitis, which may progress to fulminant disease, multi-organ failure and death within hours [1].The proportion of patients who develop severe disease increases with age [2].
In 2006, the German Standing Committee on Vaccination (STIKO) recommended routine MenC vaccination in the second year of life.Catch-up vaccination for all children and adolescents under the age of 18 years on an individual basis is recommended, but a catch-up campaign was not undertaken.In 2010, MenC vaccination coverage at school entry ranged between 53% and 90% in the 16 German federal states [4].In addition to routine childhood vaccination, STIKO recommends vaccination against serogroups A, C, W135 and Y for high-risk individuals independent of their age (i.e.patients with asplenia or immunocompromised individuals including those infected with human immunodeficiency virus (HIV)).However, meningococcal vaccine coverage among HIV patients in Germany is unknown.Vaccines are free of charge in Germany if officially recommended, but can otherwise be individually purchased if prescribed by a physician.

Description of cases
Case 1 was a man in his early 20s.He developed chills, fever and severe abdominal pain in early February, was hospitalised, and died during abdominal surgery within 10 hours after hospital admission.MenC was found in blood culture.The patient had visited several gay venues in Berlin in the days before falling ill.Cases 2 and 3 were both in their mid-20s.They visited a gay nightclub in May and spent the following night together.Two days later, Case 2 developed symptoms (fever, nausea, vomiting, irritability, stiff neck), was hospitalised, and treated in an intensive care unit.He survived, but suffers from irreversible brain damage.Case 3 developed symptoms a day later (irritability, fever, nausea), but did not seek medical care and died at home on the following day.An autopsy revealed death due to septic shock and disseminated intravascular coagulation.MenC was detected in cerebrospinal fluid.
Besides smoking (two cases) and attending gay bars, no other risk factors were reported.None of the three young men had been diagnosed with HIV, and none of the three was vaccinated against MenC.While a common source or direct transmission between Cases 2 and 3 seems likely, no direct link between Case 1 and Cases 2 and 3 was found.No links to men who visited or lived in cities with concurrent or recent IMD outbreaks among MSM (e.g.Paris or New York) could be established [6,7].
Analysis of position 640 of the fumC gene revealed that the strains belonged to a subclone of ST-11 designated electrophoretic type (ET) 15, which has caused a number of small outbreaks in Germany since 1998 [8].The PorA and FetA variants are classically linked to ET-15 and the combination C:P1.5-1,10-8:F3-6 is observed frequently.Therefore, three further typing loci were included, i.e. porB, fHbp, and penA.All three isolates were identical also with regard to these markers: porB allele 2-2, fHbp allele 766, and penA allele 3.This finding supports the hypothesis of a local cluster and link between the three cases.

Retrospective epidemiology
In an analysis of data from the German disease notification system restricted to IMD cases aged 15

Public health response
From October 2012 until the end of June 2013, the incidence of MenC IMD among the MSM community in Berlin was 6.3/100,000 based on five reported cases and an estimated number of 80,000 MSM in the community [9].This is below the threshold of an epidemic situation (defined in Germany as ≥10 cases/100,000 in a given region within three months), but almost 10-fold higher than expected for young male adults in this age group for the entire year (0.65/100,000 with inclusion of all serogroups).
Infectious disease surveillance networks in Germany and healthcare professionals in Berlin were alerted to the detection of this IMD cluster among MSM, which will help to identify additional cases rapidly if they occur.The German AIDS support organisation Deutsche AIDS Hilfe has issued information on the cluster on their website as a first measure to inform the MSM community about symptoms of the disease and the existing recommendation to vaccinate HIVpositive individuals against IMD.According to STIKO, the existing meningococcal vaccination recommendation targeting risk groups (such as HIV patients) can be extended to other population subgroups by the responsible health authorities during regional outbreaks, taking into account the epidemiological and temporal associations between notified cases [10].Since no HIV patients have been identified in the MSM cluster as of today, the state health authority in Berlin is currently considering the option of extending the existing vaccination recommendation to all MSM to prevent further cases.

Rapid communications
Carbapenemase-producing Enterobacteriaceae in Europe: a survey among national experts from 39 countries, February 2013 The spread of carbapenemase-producing Enterobacteriaceae (CPE) is a threat to healthcare delivery, although its extent differs substantially from country to country.In February 2013, national experts from 39 European countries were invited to self-assess the current epidemiological situation of CPE in their country.Information about national management of CPE was also reported.The results highlight the urgent need for a coordinated European effort on early diagnosis, active surveillance, and guidance on infection control measures.
The present report summarises the results from 39 European countries of a self-assessment of the epidemiological stage and the management of carbapenemase-producing Enterobacteriaceae (CPE) at national level.

Background
CPE are an emerging threat to healthcare and are frequently resistant to many other antibiotics than carbapenems [1,2] leaving few treatment options.The extent, to which healthcare systems have already been affected, however, differs substantially from country to country.Following a previous initiative, a group of European experts is implementing the European Survey on CPE (EuSCAPE) in an effort to update assessments of the nature and scale of CPE spread in Europe [3].The current programme receives financial support from the European Centre for Disease Prevention and Control (ECDC).The aim of this study is to obtain a more accurate and timely estimate of CPE prevalence in European countries and to support reference laboratory-capacity building to prevent and control the spread of CPE in Europe.

Development of a questionnaire and collection of information
A Scientific Advisory Board of European experts in the field of carbapenemase-producing bacteria was invited to provide scientific advice in support of the EuSCAPE programme management team.A questionnaire was devised and modified from a 'field-tested' version used during previous similar surveys [3].The questionnaire was divided into two sections.The first section (13 questions) explored the experts' knowledge and awareness of the current occurrence of CPE according to a previously-established epidemiological staging system [1,3].In brief, the system captures seven consecutive stages in the national spread of these organisms.The seven stages are described in Table 1.
The second section (22 questions) collected information about existing requirements, structures and guidance documents for reporting, surveillance, use of reference laboratory services and infection control for CPE.The questionnaire is available from the corresponding author.
In each of the 39 European countries (i.e.27 European Union (EU) Member States, all European Economic Area (EEA)/ European Free Trade Association (ETFA) countries except Lichtenstein, and all EU enlargement countries, as well as Israel), a national expert (NE) with acknowledged laboratory and/or epidemiological experience was identified (for the United Kingdom two NEs participate in this questionnaire survey).The NEs were chosen among European Antimicrobial Resistance Surveillance Network (EARS-Net) contact points, experts from national reference diagnostic laboratories and ECDC-coordinating competent bodies.The list of NEs was validated by ECDC and represents the EuSCAPE Working Group.The NEs were invited to answer the questionnaire online (http://SurveyMonkey. net, SurveyMonkey Corporation, Portland, USA).
Answers from the NEs were compiled and analysed.When necessary, NEs were contacted by e-mail or telephone for clarification, and corrections were made accordingly.The epidemiological stage of some countries was considered as uncertain when (i) the NE reported a lack of awareness about the current epidemiology of CPE in their country, (ii) the answer of the NE indicated considerable underdetection and underreporting of CPE in their country, (iii) the comments made by the NE by e-mail or telephone indicated uncertainty and/or (iv) when frequent introductions into other countries have been described but the NE could not independently support this observation by own sources.In the maps (Figure), this uncertainty was indicated by displaying the respective country as hatched.

Results
All NEs completed the online questionnaire.Thirtyseven NEs declared that they were aware of the current epidemiology of CPE in their country and all rated the occurrence and spread of CPE in their country using the previously established epidemiological staging system (Figure and Table 1).Nevertheless, only 26 NEs could self-assess their current situation with certainty.
Three countries (Iceland, Montenegro and the former Yugoslav Republic of Macedonia) reported no cases of CPE in their country.Sporadic cases, single or sporadic hospital outbreaks were reported by NEs from 22 countries.For 11 countries, regional or national spread was reported, whereas for three countries (Greece, Italy and Malta) NEs reported that CPE are regularly isolated from patients in most hospitals, corresponding to the endemic stage (Table 1).
Among the 31 countries that participated in both the 2010 and 2013 assessments, 17 reported a higher stage by 2013; likewise, by 2013, the number of countries with regional or inter-regional spread or an endemic situation increased from seven to 13 (Table 1).Some countries expressed concerns that underdetection or Sporadic hospital outbreaks Unrelated hospital outbreaks with independent, i.e. epidemiologically unrelated introduction or different strains, no autochthonous inter-institutional transmission reported 2b Regional spread More than one epidemiologically related outbreak confined to hospitals that are part of a regional referral network, suggestive of regional autochthonous inter-institutional transmission 3 Inter-regional spread Multiple epidemiologically related outbreaks occurring in different health districts, suggesting inter-regional autochthonous inter-institutional transmission 4 Endemic situation Most hospitals in a country are repeatedly seeing cases admitted from autochthonous sources 5 The table was reproduced from reference [3].More details on the epidemiological stages are given in the manuscript Table 1.

Figure
In some countries, the epidemiological stage might not represent the true extent of the spread of CPE as it is a subjective judgment by national experts.Uncertainty about the epidemiological stage of a country is indicated by hatching.Results presented here reflect the uncertainty at the time of the survey.For Portugal, case notification and submission of isolates became mandatory on 21 February 2013.Countries that were uncertain about their epidemiological stages had on average 1.9 national management documents regulating surveillance and response structures.In contrast, those who were more certain about their epidemiological stages had on average 4.7 (p-value < 0.001; Wilcoxon Rank Sum Test).

Discussion
The results of this online survey, performed in February 2013, show that, based on the knowledge and judgment of NEs, CPE are continuing to spread in Europe.
Although most countries reported only single hospital outbreaks, the epidemiological situation has deteriorated over the past three years.Among the 31 countries that participated in both 2010 and 2013 assessments, 17 countries were upgraded to a higher epidemiological stage (Table 1).Three countries that reported sporadic occurrence or single hospital outbreaks of CPE in 2010 are now witnessing regional or inter-regional spread, or even an endemic situation.Malta moved from having sporadic cases to an endemic situation, although by nature of its small size, the intermediate epidemiological stages have little relevance.The influx of injured refugees from Libya in 2011, is believed to have contributed to an increase in carbapenem-hydrolysing oxacillinase (OXA)-48-positive Enterobacteriaceae (M.Borg, personal communication, April 2013).In Italy, a sporadic occurrence of Verona integron-encoded metallo-beta-lactamase (VIM)producing Enterobacteriaceae from 2008, accentuated by a single hospital outbreak, has been overtaken by the wide dissemination of KPC-positive K. pneumoniae strains to many healthcare institutions.[4][5][6][7][8][9].The situation in Hungary has evolved in the opposite direction: in 2010, concern centred upon a single clone of KPC-2-positive K. pneumoniae that had attained regional distribution, whereas VIM-4-positive strains were only reported sporadically, but have now spread nationwide [3,10].Overall, KPC-positive Enterobacteriaceae still have the widest distribution among CPE in Europe, but rising numbers of OXA-48-positive isolates are reported, making OXA-48 the most frequently detected carbapenemase in Belgium, France and Malta.Despite the attention that NDM has received when associated with introductions from the Indian subcontinent, the current numbers of reports by European countries are still relatively modest compared to the other carbapenemases [11].The United Kingdom, however, continues to report more NDM-positive isolates than most other European countries [3,12].
The NEs completed the questionnaire to the best of their knowledge, but these were subjective assessments that may have underestimated the true extent of the spread of CPE.Underdetection and underreporting were pointed out by respondents in several countries, leading to uncertainty about the true epidemiological stage (Figure).In particular, this applied to countries from which introductions into other countries have been described but where NEs could not independently assess the extent of CPE spread.Underdetection and underreporting of CPE also coincided with weaker reference laboratory infrastructures and the absence of national recommendations for submission to national reference laboratories and for reporting to health authorities, thus suggesting that the true extent of CPE occurrence in Europe is still underestimated.At the same time, countries with strict screening policies and good surveillance are more likely to report advanced epidemiological stages also affecting the comparability of the assessment.
The keys to success in preventing the establishment of CPE are, firstly, early detection through good diagnostic practices, secondly, containment of spread through patient and contact screening as well as infection control measures.An increasing number of countries have reacted and implemented measures as indicated by the increasing availability of a recommendation or guideline on infection control measures to prevent the spread of CPE [12].Still 18 countries surveyed lacked such guidance and the same number of countries lacked relevant guidance for submission of isolates to national reference laboratories [12].The results of the present report underscore the urgent need for an upgrading of laboratory standards to enable active surveillance and preventive action.To this purpose, the EuSCAPE programme aims to build a laboratory-based network for CPE detection in Europe.

Introduction
Infectious diseases are more prevalent in prison than in the general population, in particular human immunodeficiency virus (HIV) and hepatitis C.This is well documented in the international literature [1][2][3][4][5].In France, foreign nationals represent 18% of admissions to French prisons, and more than half of these entrants originate from countries with a generalised HIV epidemic and from regions with high or medium hepatitis C virus (HCV) endemicity [6].Since 1 January 2009, drug-trafficking offences have accounted for nearly 14% of convicted prisoners.
Implementing epidemiological studies in a prison environment presents more challenges than studies in the community, notably because of ethical considerations [21].National data on HIV and HCV prevalence are however essential to implement prevention interventions and to improve screening and treatment for these two chronic conditions.
In this article, we report the results of a cross-sectional, single-day study based on two-stage sampling of prison establishments and inmates that was conducted in 2010 (Prévacar survey).Estimates of HIV and HCV infection prevalence were produced for the entire prison population, and by sex, age and continent of birth.

Target population
The eligible population for the survey comprised any individual aged over 18 and held in prison on the sampling day (15 May 2010) in metropolitan France and/or in French overseas departments (Antilles, French Guiana and Reunion Island).Prisoners on licence or parole on the sampling day were excluded from the survey.

Sample size calculation
The number of individuals for inclusion in the study was calculated to take into account the proportion of prisoners receiving opiate substitute treatments (estimated at 10%), the absolute level of precision required in the estimates (2%), and the expected design effect produced by the two-stage sampling design employed.The necessary sample size was 1,300 subjects, and 2,154 people were randomly selected in the prison establishments.

Sampling design
The French national prison service has a complete listing of prison establishments in France, and an exhaustive national database of prison inmates which is updated several times per day.Prisoners in the national database are assigned a unique identification number.
To limit the number of prison establishments, we implemented a two-stage sampling design instead of using simple random sampling.Prison establishments and prisoners were selected at the first and second stage, respectively.At the first stage, the exhaustive list of prison establishments was stratified according to ten geographical regions in France, i.e. covering the nation's territory.Within each region, establishments were further stratified to take into account the type of establishment (short, medium or long sentences, female-only or male-only).Establishments were chosen using ordered systematic sampling with unequal probabilities, proportional to the number of prisoners.Establishments for women and in certain priority regions were deliberately oversampled.At the second stage prisoners were selected by simple random sampling using the unique identification number in the national database of people in French prisons on the sampling day.

Data collection
The study did not use biological testing.Instead, for each person sampled, an anonymous individual questionnaire was completed by the Prévacar researchers or by health professionals based in the prison establishments using information in medical records.Proposing HIV and hepatitis C testing for all prisoners on admission to prison is mandatory in France, and French guidelines recommend that this offer be repeated periodically during prison stays.
The questionnaire also collected information on modes of transmission, clinical stage, treatment, viral load, CD4 lymphocyte count, and hepatic fibrosis.Additional information concerning continent of birth, socioeconomic status and employment before imprisonment was collected from the national prisoner database and merged with the questionnaire data using the unique identification number.

Definition of cases
A prison inmate was considered to be HIV infected when their medical record contained one of the following items: a positive ELISA test for HIV infection or a positive Western blot or a CD4 lymphocyte count or HIV viral load.A prison inmate was considered to be HCV infected when their medical record contained one of the following elements: a positive ELISA test for HCV or a positive HCV RNA detection in the previous 12 months.

Ethical considerations
To preserve the anonymity of subjects, a random number (different from the unique prison identification number mentioned above) was assigned to each selected prisoner.Prior to the study, the 2,154 people randomly selected in the prison establishments were informed individually of their selection and information on the study was posted publicly.At this point, prisoner refusal to take part in the survey could be communicated verbally or by returning a reply coupon to the medical team.The survey was approved by an ethics committee (no.909331) and conformed to the principles embodied in the Declaration of Helsinki.

Statistical analysis
Analyses took into account the weighted sample design, i.e. oversampling for size and type of establishment, and estimates were adjusted by post-stratification on the total prison population [22] (n=60,975 on the sampling day) using available prison data (including sex, age group, continent of birth and geographical prison region) recorded for all prisoners in the national prisoner database on the date of sampling.Post-stratification took into account the national distribution of inmates by type of establishment.This means that even for persons whose medical records did not contain a biological test result, i.e. unknown HIV and/or unknown HCV status, the following information was available: sex, age, continent of birth and prison establishment type (short, medium or long term sentences, female-only or male-only).Univariate and multivariate analyses (using logistic regression) were performed to compare sex and age of persons whose medical records contained a biological test result (for HIV or HCV) with those whose records did not contain such a result.All analyses were performed using STATA 11 software.

Results
On the sampling day (15 May 2010), the total number of French prison establishments (for prisoners with short, medium and long sentences) equalled 188 and held 60,975 people.Of these, 27 prisons were randomly selected with specific oversampling conditions, from which 2,154 prison inmates were selected.

Characteristics of the prison population in France on the sampling day
The majority of prisoners were men (97%), and the average age of prison inmates was 34 years (interquartile range: 25-42 years; standard deviation: 0.56).People born in France accounted for 76% of inmates, while those born in north Africa and sub-Saharan Africa accounted for 9% and 5%, respectively.For people born in eastern Europe and western Europe the percentages were 3.4% and 2.7%, respectively.

Study population
Of the 2,154 prisoners included, 57 refused to take part in the survey.Questionnaires completed from medical records numbered 1,876 (87%), one questionnaire per prisoner, and represented 1,607 men and 267 women; sex was unknown for two inmates.Non-completed questionnaires included 221 cases for whom the medical records could no longer be consulted at the time of the survey, because the prisoner's conditions of imprisonment had changed in the period since sampling.
Of the 1,876 questionnaires used, information on HIV and HCV infection status was missing from 28% and 30% of records, respectively.

Comparison of persons with and without biological test result in their medical records
In the univariate and multivariate analysis, prisoners whose medical records did not contain any information on HIV or HCV status were not significantly different from those whose medical records did, in terms of sex, age, and continent of birth (data not shown).However, HIV or HCV test results were two to four times as often absent from medical records of prisoners held in establishments for short and medium length sentences than of those held in prisons for long sentence prisoners.

HIV prevalence and characteristics of HIV-infected persons
HIV prevalence HIV prevalence was estimated at 2.0% (95% confidence interval (CI): 1.0-4.2) (Table ).Prevalence was higher in women than for men, 2.6% (95% CI: 0.7-8.8)and 2.0% (95% CI: 0.9-4.3),respectively, but the difference was not significant.HIV prevalence increased with age up to 50 years from 0% among the 18-21 year-olds to 3.7% among the 41-50 year-olds.HIV prevalence varied according to continent of birth, being highest among individuals born in sub-Saharan Africa (15.4%).Among those born in France, HIV prevalence was 1.1% and was not significantly different from that estimated for people born in North Africa (3.2%) and those born in the Americas (3.5%).No inmate born in Asia or eastern Europe was infected with HIV in our study.
A majority of HIV-positive inmates (75%) were receiving antiretroviral treatment for HIV at the time of the survey.Among inmates with a CD4 count below 350/ mm 3 , the proportion of people receiving antiretroviral treatment was 72%.

HCV prevalence and characteristics of HCV-infected persons
HCV prevalence HCV prevalence was estimated at 4.8% (95% CI: 3.5-6.5)and increased significantly with age up to 50 years, from 0% in the age group 18-21 years to 11.6% in the age group 41-50 years.Prevalence was significantly higher among women than among men, 11.8% (95% CI: 8.5-16.1)and 4.5% (95% CI: 3.3-6.3),respectively (Table ).Prevalence varied by continent of birth, being highest among individuals born in Asia (12.4%) and in eastern Europe (12.3%).Prevalence among people born in France versus north Africa was not significantly different, 5.0% and 5.9%, respectively.Inmates born in sub-Saharan Africa and the Americas were not infected with HCV in our study.
HCV RNA quantification was reported in the medical records of the majority of HCV prisoners (information missing from 6% of records), and was positive for almost half of them (46%; 95% CI: 27.3-66.5).Nearly 2.5% of prison inmates had viraemic HCV.
Among prisoners with chronic hepatitis, i.e. with a persistent positive HCV RNA quantification, approximately half (41%)  had undergone an evaluation for fibrosis by invasive or non-invasive methods in the previous 12 months and 36% were currently receiving treatment.

Discussion
This study is the first to estimate HIV and HCV prevalence among all prison inmates in France and to describe the characteristics of those infected.National HIV prevalence, estimated at 2%, corresponded to 1,233 HIV-infected persons in the total prison population of 60,975 in mainland France and overseas.HCV prevalence, estimated at 4.8%, corresponded to 2,927 HCV-infected persons, in most cases contaminated through drug use.
Our study of prison establishments and prison inmates based on a two-stage sampling design and poststratification adjustment, enabled us to produce HIV and HCV estimates for the entire prison population in French and French overseas prisons i.e. including those not included in the sample.Prevalence estimates were produced for a number of categories, notably sex, age, and continent of birth.Indeed, this methodology could be used to estimate national prevalence in other countries, subject to the availability of a sampling frame comprising an exhaustive list of prison establishments and a list of prison inmates.
A number of limitations of this study need to be noted.Firstly, no biological tests were performed in our study because performing biological tests for research purposes in France requires informed written consent of participants.Currently, ethical committees in France consider that a request for 'informed' consent is incompatible with the status of being a prisoner, i.e. persons who are deprived of their liberty.This position could change in the future.Therefore, the HIV and HCV infection status was obtained from medical records.Although HIV and HCV testing is routinely offered to all prisoners in France, information about the status of these infections was missing from 30% of medical records.The absence of a serological test result from the medical records does not necessarily mean that a test was not performed or offered; a test may have been performed but the result not recorded, or it may have been offered but refused by the prisoner, or performed as part of an anonymous and free medical visit.However, although the proportion not supplying this information was non-negligible, this does not necessarily mean our estimates were biased, since multivariate analysis of inmates without a serological result showed no significant difference in terms of sex, age or continent of birth, variables usually associated with HIV and HCV infection in the literature.Test results were more often lacking in medical records in establishments for short-term and medium-term sentences.This may have occurred because shorter incarceration periods limit the available time for testing.
Secondly, a high proportion of medical records (66%) for HIV infected persons had no information about transmission mode.This is perhaps due to physicians' awareness of the sensitive nature of recording such data in prisons, e.g.homosexuality is still a taboo subject in prisons.Finally, another limitation of the study is the lack of collected variables associated with HIV and/or HCV transmission such as high-risk behaviours, tattooing etc. and the lack of information about the frequency of imprisonment.
HIV and HCV prevalence among prisoners in France is approximately six times higher than in the general population, an observation consistent with those for other countries [3,5,9].In 2009, HIV prevalence in the general French population was estimated at 0.35% [23], while in 2004, the prevalence of anti-HCV antibodies in the population was estimated at 0.8% (95% CI: 0.6-1.1)[24].
HIV prevalence in prisoners of high-income countries range from 0% in prisons in Denmark and Northern Ireland [13,25] to 8-10% in Italy and Portugal [26,27].HIV prevalence among French prison inmates is close to that observed for prisons in North America, ranging from 1% to 2.5% according to the year of the study [1,4,5,8,11,28,29] and higher than the 0.4% reported in the United Kingdom [30,31] and in Australia [32,33].To date, French studies in the published international literature have been based on multi-round surveys conducted in a single prison establishment in Marseille in south-eastern France, with prevalences of 4%-11% depending on the year [9,15,16] and a single-round survey in a single prison establishment in Caen, in northwestern France (prevalence 0%) [19].Therefore, it is not possible to compare results from these surveys, conducted in a single establishment, with our HIV prevalence estimate conducted at a national level.
There is strong consensus in the literature that HIV and HCV prevalence is consistently higher among female prisoners, probably reflecting drug use [3,5,7,11,36].Among the female prisoners in the Prévacar survey, almost one in 10 was infected with HCV.In addition, our study found that HIV and HCV prevalence increased with age, which is also consistent with published literature.Prevalence rates also varied depending on the prisoners' continent of birth, although the small numbers mean that the rates associated with continent of birth were subject to greater inaccuracy (this is reflected by large confidence intervals).HIV prevalence among prisoners born in sub-Saharan Africa was particularly high, over 15%, partly owing to the generalised HIV epidemic in that region.Similarly, HCV prevalence was high, over 12% among prisoners born in Asia, a region with high HCV endemicity, and in eastern Europe, where there is a large-scale epidemic among drug users.
The majority of HIV-infected prisoners in this study had been diagnosed seropositive several years earlier and were at an advanced stage of immunodeficiency: 75% had a CD4 count below 350/mm 3 when the study took place.Among those 75% inmates, three quarters were receiving antiretroviral treatment.Similarly, HCVpositive prisoners had been diagnosed with hepatitis several years before the study took place (on average seven years).Nearly half of them had developed chronic hepatitis.Overall, half of the HCV-infected prisoners had received or were receiving treatment for hepatitis C.These results suggest that treatment for HCV and HIV infections are available for inmates in French prisons, but could be reinforced among inmates with CD4 counts below 350/mm 3 and among those with active HCV infection.
The method developed for this survey enabled us to estimate HIV and HCV prevalences in French prisons at a national level.It could be used for other infectious diseases, in particular tuberculosis and hepatitis B. Nearly 2.5% of prison inmates in France have viraemic HCV, and the risk of HCV transmission to other prisoners is exacerbated by widespread risk behaviours such as tattooing and the sharing of shaving equipment [3,37].It is important that prison establishments maximise efforts to limit the spread of HCV by introducing prevention and harm reduction measures [38,39].The moment of incarceration provides an ideal opportunity for testing and treating HIV and HCV in order to limit the spread of HCV and to improve the prognosis of infected patients.

Introduction
Most emerging infectious diseases are of zoonotic origin [1], and populations at particularly high risk often include individuals with occupational exposure to live animals, such as veterinarians, farmers and those living in close contact with domestic livestock.Q fever, caused by Coxiella burnetii, is a disease of particular concern for pregnant women because infection in pregnancy is suspected to be a potential cause of foetal morbidity and mortality.French case studies have suggested risk of miscarriage, intrauterine growth retardation, oligohydramnion, stillbirth and premature delivery in untreated pregnancies [2][3][4].Recent studies have not found any association between presence of antibodies against C. burnetii and adverse pregnancy outcome, but knowledge on the topic is sparse [5][6][7][8][9].For healthy humans, Q fever infection often has a mild, influenza-like course, but pneumonia is also common.Immunocompromised patients and patients with preexisting valvulopathy or vascular defects are at risk of a more severe course of the infection [10,11].
In small ruminants, infection with C. burnetii is known to cause miscarriage, retained placenta, endometritis and infertility, and placentas of infected animals contain high numbers of bacteria [12,13].Human infection is usually acquired through inhalation of contaminated aerosols from infected animals, which contaminate the environment through excretion of bacteria in large amounts in byproducts during birth, especially placenta [10,11,14].The risk of infection with C. burnetii has been related to particular occupations with close contact to the organism's primary reservoirs, such as domesticated livestock animals.Examples include veterinary practice and farming [15,16].
Q fever is most likely endemic worldwide, but unbiased estimates from relevant populations are scarce because most reports on incidence and prevalence are reported from regions with outbreaks or with particular medical or scientific interest in the infection [2].In Denmark, Q fever has previously been considered a rare and imported disease, but testing for antibodies in livestock animals since 2003 has indicated that the infection is widespread.A recent study found a prevalence of 59% antibody-positive animals from 100 randomly selected dairy herds [17].
When conducting a risk assessment, it is important to quantify the risk of infection in exposed populations.
The aim of the present study was to investigate the prevalence of elevated antibody titres against C. burnetii in Denmark in occupationally and domestically exposed women compared with unexposed women sampled from a population based study of pregnant women.

Study participants
The Danish National Birth Cohort (DNBC), a nationwide cohort of 100,418 pregnant women and their offspring [18], served as base for sampling of the study population.Enrolment in the DNBC took place between 1996 and 2002.All Danish pregnant women were invited for the study in connection with the first antenatal visit to the general practitioner.Information on exposures before and during the early part of pregnancy was collected by means of a computer-assisted telephone interview scheduled to take place in gestational week 12. Interviews included data on reproductive history, age, smoking status, domestic contact to animals and very detailed questions regarding occupational exposure to different animals (interview forms are available at the DNBC website).
Women who confirmed having worked on a farm with live animals during their pregnancy or up to three months before becoming pregnant, were further questioned about the type of animals, the size of the herd, occupation, etc.During pregnancy, two blood samples were collected, one around gestational weeks 6 to 12, the second around gestational week 24; samples were stored in a biobank.A detailed description of the cohort can be found elsewhere [18].
We sampled three groups from the DNBC cohort (Figure 1): • Women with self-reported occupational exposure to livestock (n=195), i.e. veterinarians (n=118) and women who worked on a farm with at least 40 dairy cattle (n=77); • Women with self-reported domestic exposure to livestock (n=202), i.e. cattle (n=180), sheep (n=22) or both (n=13), who were living on a farm and cohabiting with a farmer, but did not have occupational exposure to these animals; • A randomly sampled reference group of women (n=461).Two of these were domestically exposed to animals and were consequently reclassified as such, leaving 459 controls.
It was a prerequisite for all three groups that the women had participated in the interview in early pregnancy and had delivered a blood sample to the biobank.
In order to evaluate a possible association between geographic area and seropositivity, the participants were classified using the nomenclature of territorial units for statistics (NUTS3) [19], which divides the regions of Denmark into 11 areas.These were used in a definition of urban versus rural residence.

Detection of antibodies against C. burnetii
The diagnosis of Q fever relies upon serology.C. burnetii expresses two groups of antigens, phase I and phase II.In acute Q fever, antibodies against phase II antigens are initially elevated, and their titre is higher than that of antibodies against phase I antigens.As with most other infections, IgM antibodies appear first.
In chronically infected individuals, especially antibodies against phase I are elevated.When infected, phase II IgG and IgM antibodies are always elevated, and IgG remain positive for many years.A large study from Australia and England concluded that phase II IgG antibodies persisted after five and 12 years, respectively [20].
To determine antibodies against C. burnetii, we used a two-step approach.Initially, all samples were screened in a commercial enzyme-linked immunosorbent assay (ELISA).The commercial ELISA kit (Panbio, Australia, Coxiella burnetii (Q Fever) IgG and Coxiella burnetii (Q Fever) IgM) were used according to the manufacturer's instructions with minor modifications.Due to small sample size the initial total volume was smaller but same dilution factors were used.
Samples which were positive for either IgG or IgM antibodies in the ELISA were confirmed with an immunofluorescence antibody test (IFA) test.When investigating the association between exposure, Q fever titres and pregnancy outcome, IFA is considered to be the gold standard.The tests (Focus Diagnostics, Q Fever IFA IgG and Q Fever IFA IgM) were performed according to the instructions provided by the manufacturer, with the following minor modifications: due to small sample volume, the 1:10-diluted samples from the ELISA were reused and further diluted as described by the manufacturer.The effect of the initial dilution in the Panbio ELISA buffer was tested on patient samples before the study and did not show any influence on the results (data not shown).
The IFA cut-off suggested by the manufacturer was not used.Since the prevalence of the infection varies between geographic areas, the cut-off suggested by the manufacturer is not necessarily suited for any given area [21].A local cut-off adjusted to the Danish population has been defined, including negative, intermediate and positive titres [22] (Table 1).The intermediate zone was defined in order to address people with an a priori elevated risk of Q fever (such as veterinarians, farmers etc.), with intermediate titres in samples from these high-risk groups considered to be probably positive.When the ELISA-positive samples in our study were reanalysed using IFA, a modified version of this Danish cut-off was used.A sample was considered IFApositive when antibody titres against any of the phases were 1:128 or above.
All serological analyses were performed in a certified laboratory at Statens Serum Institut, Denmark.Laboratory personnel were blinded for exposure status, and samples were always analysed in the same batch of commercial kits.
We have conducted another study assessing pregnancy outcome in women with antibodies to C. burnetii compared to seronegative women [9].This and the present study in part use the same material since the blood samples from the Danish national birth cohort is a precious commodity.However, the studies are independent studies with different study designs and objectives.

Statistical analysis
The strength of the association between exposure and positive IFA serology was expressed as a risk difference as well as a relative risk for occupational and domestic exposure compared to the reference according to the prevalence of antibodies against C. burnetii in pregnancy.We included all veterinarians and women who reported occupational exposure to cattle in the occupationally exposed group.Power calculations were based on the literature and the first Danish data [23] with 11% of 1,613 people tested positive.It was assumed that the prevalence among exposed women would be 10% and 2% in the background population.A sample size of 200 exposed and 200 unexposed would yield an odds ratio of 5 that could be detected by a power of 88% at a two-sided significance level of 0.05.However, as we also wanted to use the sample for another study which required approximately 500 controls, it was decided to use all available blood samples from the reference group in both studies.All analyses were carried out using STATA statistical software, version 11.

Results
Age and distribution of urban or rural residence can be seen in 2).The risk difference between the domestically exposed and unexposed women was 27% (95% CI: 0.2-0.3),and the domestically exposed had a 6.7 times higher risk (95% CI: 4.3-10.6) of being seropositive than the unexposed women (Table 3).
Reporting the IFA results according to the Danish cutoff with intermediate titres classified as negative (Table 1), the trend was the same.Here the proportion of seropositive women was also significantly higher in women with occupational exposure to livestock (19% seropositive; RR: 29; 95% CI: 9.1-93.0).This was also found in women with domestic exposure to livestock (11.0%seropositive; RR: 16.7; 95% CI: 5.0-55.0)when compared with unexposed women (0.7% seropositive).
Figure 3 shows the distribution of positive IgG phase II titres in the three groups and illustrates that unexposed women had mainly titres at the lower end of positivity, whereas the higher titres were primarily found in the two groups of exposed women.

Previous versus recent infection
Among the occupationally exposed women, 89 were phase II IgG-positive, 43 were phase I IgG-positive, and 41 of them were positive in both.Three women's IgM titres against phase II antigens were positive, one of them was also positive for IgG against phase II, and another in IgG against both phases.None was phase I IgM-positive.Among the domestically exposed women, 59 were phase II IgG-positive, 30 were phase I IgGpositive, and 26 of them were positive in both phases.Three were phase II IgM-positive, with one of them also being positive for IgM against phase I, and two for IgG against phase II.One was only phase I IgM-positive.Among the unexposed women, 21 were positive for IgG against phase II, six of them were also phase I IgGpositive.One was positive for IgM against phase I as well as IgG against phase II, and one was phase II IgMpositive but negative in all other phases.Source: [22].
In the present study, a cut-off of 1:128 was used for all phases.Altogether, we mainly found serological evidence of previous infection.

Specific animal contact
Apart from working with live animals, 38 of the 118 veterinarians lived on a farm with animals; none of the veterinarians who lived on a farm had a job without animal contact.
Among the 77 female farmers who all worked on farms with at least 40 dairy cattle, 69 of them lived on cattle farms.Four of them also worked with meat cattle and five worked with sheep.All 202 women domestically exposed were living on a farm and cohabiting with a farmer; 193 of these lived on farms with cattle, 22 on farms with sheep, and 13 on farms where cattle as well as sheep were kept.
Analyses based on specific animal contact according to IFA status showed that 23 of the 31 veterinarians working with cattle were seropositive, and that the risk of being IFA positive were 2.7 times higher in veterinarians who worked with cattle compared to those who did not (RR: 2.7; 95% CI: 1.8-4.0).The positive predictive value of being seropositive being a veterinarian working with cattle was 48.9%.Among the domestically exposed women who were exposed to cattle, 64 (33.2%) were IFA-positive, and the positive predictive value of being seropositive for these women was 98.4%, whereas it was only 9.2% for domestic exposure to sheep.

Urban versus rural area
Among 427 women living in rural areas, 128 (30%) were IFA-positive compared to 48 (11.5%) seropositive among women living in urban areas.The risk of being IFA-positive was 2.6 times higher for women living in rural areas (RR: 2.6; 95% CI: 1.9-3.5).Of the unexposed women, 151 (33%) lived in rural areas.Eleven (7.3 %) of them were seropositive, compared with 11 (3.6 %) seropositive among the unexposed women living in urban areas.

Discussion
We found a high prevalence of antibodies to C. burnetii among pregnant women with occupational or domestic exposure to cattle or sheep compared to the prevalence in randomly selected unexposed pregnant women.The highest predictive values for being seropositive were found among pregnant veterinarians and women with domestic exposure to cattle.
In general, a higher seroprevalence has been found in studies evaluating groups handling livestock, especially veterinarians, than in studies of the background population [24][25][26][27][28][29][30].In one Dutch study on veterinary students, 18.7% were seropositive [31]; in another, 65% of 189 veterinarians and veterinary students were seropositive.Greater number of hours with animal contact per week, greater number of years since  the participants had graduated, living in a rural area, and working as practicing livestock veterinarian were risk factors in that study [32].An American study found antibodies against C. burnetii in 113 (22.2%) of 508 US veterinarians.Compared with veterinarians with a small animal practice, those with a mixed practice for small and large animals and those with a practice for food animals were more likely to be seropositive.Furthermore that study found that having lived on a farm in the past, currently living on a farm, and exposure to ruminants while living on a farm were associated with seropositivity [15].
In Denmark, Q fever became a notifiable disease in animals in 2005.A change in diagnostic practices in cattle and an increasing number of cattle herds testing positive raised the level of awareness among exposed, asymptomatic humans in the period 2006-07.This increased focus on Q fever was thus due to diagnosis and testing rather than to the emergence of a new infection.In the present study, some of the blood samples analysed date back to 1996, and this indicates that C. burnetii is not a newly emerged pathogen in Denmark; most likely it has been common among people with contact to cattle for a long time.
The most recent blood samples from our study dated from 2002; since then, two Danish studies have examined the presence of antibodies to C. burnetii in humans exposed to animals.In a serological analysis of 1,613 people, tested in 2006¬-07 mainly due to relevant exposure to domestic animals, 177 (11 %) were seropositive and 180 had an equivocal result according to the Danish cut-off [33].Another study evaluated blood samples from 2008 from people working with domestic animals and found 39 of 359 (11 %) seropositives, with the highest prevalence of antibodies (36%) among veterinarians [34].Close contact to birth products when performing Caesarean sections and other kinds of veterinary obstetrics is a possible explanation for the higher prevalence of antibodies among veterinarians compared to domestically exposed women found in this study.
According to the authors defining the Danish cut-off [22], high risk groups, such as veterinarians and farmers, with an intermediate titre should be considered probably positive and managed as such (the predictive value of a positive result is likely to be higher in an exposed population than in the general population).Moreover, the Danish cut-off was based on the assumption that blood donors from urban areas of Denmark are not exposed to C. burnetii, but the prevalence of antibodies among women with no animal exposure in our study (4.8%) is rather high compared to, for instance, the seroprevalence of about 2.4% in the general population in the Netherlands before the outbreak in 2007- 10 [35].This may indicate that C. burnetii is generally widespread in Denmark, but could also be an argument in favour of not lowering the cut-off too much and was the rationale behind the cut-off used in this study, which was higher than in other studies [15,25,36,37] .To our knowledge, human outbreaks of Q fever have only been described to originate from small ruminants.In France, goats and sheep have been the source of infection.The Netherlands experienced the world's largest outbreak of Q fever with more than 4,000 humans infected between 2007 and 2010 [38] and here the source of infection was goats [39].
There are different strains of C. burnetii, and, as for other bacteria, and some of the drivers for outbreak potential may be related to the heterogeneity in clinical outcomes, which could arise from differences in virulence and host reservoirs.The presence of strains of different pathogenicity could influence awareness of the disease and therefore partially explain the variation in illness incidence reported from different countries.
In the Dutch outbreak, one genotype was suggested be responsible for the human Q fever epidemic, and this was very similar to one of the genotypes found in goats [39].In comparison to France and the Netherlands, there are few sheep and goats in Denmark; the source of infection here is primarily cattle [40], and as far as we know, Denmark has never experienced a clinically verified Q fever outbreak.
Our study has limitations in that we did not verify positive samples with PCR or culture.But we regard the size of this cohort a major strength of this study.Also, one could argue in favour of testing random negative ELISA samples with IFA, which was not done here.However, the ELISA test was thoroughly investigated before use; the results were published by Kantsø et al [41].
In conclusion, this study found that Danish pregnant women exposed to livestock animals have significantly higher levels of antibodies against C. burnetii when compared to unexposed women, with the highest prevalence of antibodies found among veterinarians who worked with cattle.Our findings confirm that C. burnetii is not a newly emerged pathogen in Denmark and that Q fever is endemic here as probably in most other countries.Our results suggest that contact with livestock is a risk factor for C. burnetii.Keeping in mind the high prevalence of symptomatic human infection during the recent outbreak in the Netherlands, Q fever should be considered as a possible differential diagnosis in people with close contact to domestic animals, especially veterinarians and women domestically exposed to cattle.

Figure 1
Figure 1Invasive meningococcal disease among men who have sex with men and estimated vaccine doses, New York City, January 2012-June 2013

Table 1
Description of the epidemiological stages of carbapenemase-producing Enterobacteriaceae (CPE) Occurrence of carbapenemase-producing Enterobacteriaceae (CPE) in 39 European countries based on self-assessment by respective national experts, 2013 Overall European situation regarding CPE using an epidemiological scale of nationwide expansion B Geographic distribution of CPE by resistance mechanism using the same epidemiological scale KPC: Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae; NDM New Delhi metallo-beta-lactamase; OXA-48: carbapenemhydrolysing oxacillinase-48; VIM: Verona integron-encoded metallo-beta-lactamase.

Table 2
Comparison of epidemiological stages of carbapenemase-producing Enterobacteriaceae (CPE) in 39 European countries, 2010, 2012 and 2013 The epidemiological stage of a country may not reflect the true extent of the spread of CPE, as it is based on the subjective judgment of the responding national expert in 2010 and 2013 and the opinion of the authors of a review in 2012.Some of the countries were not included in the 2010 survey and/or the 2012 review and their epidemiological stage is consequently indicated as 'not available' (NA).For Montenegro and Turkey, discrepancies between results from the 2012 review and the 2013 survey underline the uncertainty of stage designation for these countries.underreporting,or both, could affect the certainty of the stage of their countries (Figure).
a The results were based on data obtained through a Europeanwide consultation during a workshop at the Netherlands's National Institute for Public Health and the Environment (RIVM) on 29 and 30 April 2010 [3].b The results were based on the subjective analyses of the literature available at the time of the publication [1].c This online survey (February 2013).e For France and Poland, discrepancies between results from the 2012 review and the 2013 survey are probably due to the subjective assessment by different experts.f This designation is without prejudice to positions on status, and is in line with United Nations Security Council resolution 1244/99 and the International Court of Justice Opinion on the Kosovo declaration of independence.g

Table 3
National management of carbapenemase-producing Enterobacteriaceae (CPE) in 39 European countries, 2013In the table cells, a dot in signifies 'in place' and the absence of a dot signifies 'absent'.Agreed criteria or policy (including minimum inhibitory concentration (MIC) cut-off, species and resistance confirmation, epidemiological typing) to submit CPE isolates to a national reference laboratory.
a b Voluntary notification to health authorities.c Mandatory notification to health authorities.d Country reporting carbapenem-resistant invasive isolates (Klebsiella pneumoniae and Escherichia coli to the European Antimcirobial resistance Surveillance Network (EARS-Net)).e Only in case of outbreaks.f Only for bacteraemia cases.g This designation is without prejudice to positions on status, and is in line with United Nations Security Council resolution 1244/99 and the International Court of Justice Opinion on the Kosovo declaration of independence.

Table
Estimated number of prison inmates infected with human immunodeficiency virus or hepatitis C virus, and prevalence by sex, age group, and continent of birth, France, May 2010 (n=1,876) CI: confidence interval; HCV: hepatitis C virus; HIV: human immunodeficiency virus.a Number of observations in the sample.b Extrapolated number of inmates, taking into account the weight sampling design and an adjustment by post stratification on the total prison population.c Sex unknown for two inmates.d Age group and continent of birth were unknown for 11 and 18 cases, respectively.

Table 1
Cut-off values immunofluorescence antibody test as applied in Denmark

Table 2
Distribution of selected characteristics among pregnant women sampled from the Danish National Birth Cohort,Denmark,  1996Denmark,   -2002 (n=856)    (n=856) Data on area of residence not available for all participants.