Barry Cookson
email: barry.cookson@hpa.org.uk

Marc J M Bonten

Fiona M Mackenzie

Robert L Skov

Henri A Verbrugh

Evelina Tacconelli

Meticillin-resistant Staphylococcus aureus (MRSA): screening and decolonisation

Keywords:

Meticillin-resistant Staphylococcus aureus (MRSA) infections are of increasing importance to clinicians, public health agencies and governments. Prevention and control strategies must address sources in healthcare settings, the community and livestock. This document presents the conclusions of a European Consensus Conference on the role of screening and decolonisation in the control of MRSA infection. The conference was held in Rome on 5-6 March 2010 and was organised jointly by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC). In an environment

A c c e p t e d M a n u s c r i p t

where MRSA is endemic, universal or targeted screening of patients to detect colonisation was considered to be an essential pillar of any MRSA control programme, along with the option of decolonising carriers dependent on relative risk of infection, either to self or others, in a specific setting. Staff screening may be useful but is problematic as it needs to distinguish between transient carriage and longer-term colonisation. The consequences of identification of MRSA-positive staff may have important effects on morale and the ability to maintain staffing levels. The role of environmental contamination in MRSA infection is unclear, but screening may be helpful as an audit of hygiene procedures. In all situations, screening procedures and decolonisation carry a significant cost burden, the clinical value of which requires careful evaluation. European initiatives designed to provide further information on the cost/benefit value of particular strategies in the control of infection, including those involving MRSA, are in progress.

A c c e p t e d M a n u s c r i p t

Introduction

Whilst the problem of antimicrobial resistance is widespread among common bacterial pathogens, the particular health threat caused by meticillin-resistant Staphylococcus aureus (MRSA) is of increasing concern to clinicians, public health agencies, governments and, last but not least, the general public. This has brought critical attention to bear on the adequacy of current infection prevention and control strategies, which have had to take into account reservoirs of MRSA in healthcare delivery institutions [healthcare-associated MRSA (HCA-MRSA)] and, more recently, the community [community-acquired/associated MRSA (CA-MRSA)] and livestock [livestock-associated (LA-MRSA)] [START_REF] Humphreys | Prevention and control of methicillin-resistant Staphylococcus aureus[END_REF][START_REF] Mackenzie | Report of the Consensus Conference on Antibiotic Resistance; Prevention and Control (ARPAC)[END_REF][START_REF] Struelens | Laboratory tools and strategies for methicillin-resistant Staphylococcus aureus screening, surveillance and typing: state of the art and unmet needs[END_REF][START_REF] Deleo | Community-associated meticillin-resistant Staphylococcus aureus[END_REF][START_REF] Lindsay | Genomic variation and evolution of Staphylococcus aureus[END_REF][START_REF]European Antimicrobial Resistance Surveillance System[END_REF]. For these reasons, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) organised a joint expert meeting to focus on the latest evidence for MRSA prevention and control measures and treatment in Rome, Italy, in March 2010. This review is based on the proceedings of that meeting.

In particular, this document outlines specifically the opinions expressed by experienced clinicians and scientists on the role of screening and decolonisation as useful tools in such management strategies. Low prevalence countries were not considered a major issue: they have very similar screening policies. In our opinion, the target audience for this document should include health policy-makers, infection control teams, and clinicians working in hospitals with endemic MRSA, i.e. a situation where MRSA transmission rates are high and MRSA is constantly being circulated amongst the population present in the hospital and re-introduced by patients previously admitted to the same or other institutes in a locality/region where MRSA is endemic [START_REF]Revised guidelines for the control of epidemic methicillin-resistant Staphylococcus aureus. Report of a combined Working Party of the Hospital Infection Society and British Society for Antimicrobial Chemotherapy[END_REF]. Indications for screening and decolonisation are not necessarily A c c e p t e d M a n u s c r i p t 5 uniformly directed at every hospital within any given country. A recurrent and important feature since MRSA was first reported in the early 1960s has been that hospitals can vary in their MRSA rates, not just between countries but within a country or even in the same city [START_REF] Shanson | Antibiotic-resistant Staphylococcus aureus[END_REF][START_REF] Cookson | Epidemic methicillin-resistant Staphylococcus aureus[END_REF]. However, it is important to harmonise infection prevention and control measures between hospitals to limit MRSA spread between them, and a good example of such harmonisation is to ensure that hospitals inform one another when they transfer MRSA-affected patients between their institutions [START_REF] Murchan | Emergence, spread, and characterization of phage variants of epidemic methicillin-resistant Staphylococcus aureus 16 in England and Wales[END_REF][START_REF] Cookson | Harmony-the International Union of Microbiology Societies' European Staphylococcal Typing Network[END_REF][START_REF] Bootsma | Controlling methicillin-resistant Staphylococcus aureus: quantifying the effects of interventions and rapid diagnostic testing[END_REF].

Screening involving the use of microbiological procedures to detect the carriage of MRSA by individuals without evidence of clinical infection is an essential ‗pillar' of any MRSA control programme [START_REF] Coia | Guidelines for the control and prevention of meticillin-resistant Staphylococcus aureus (MRSA) in healthcare facilities[END_REF][START_REF] Calfee | Strategies to prevent transmission of methicillin-resistant Staphylococcus aureus in acute care hospitals[END_REF][START_REF] Safdar | The risk of infection after nasal colonization with Staphylococcus aureus[END_REF]. Since such procedures carry significant healthcare costs, it follows that any surveillance undertaken be of proven benefit to the overall strategies put in place for the prevention and control of MRSA infections. This is often difficult to ascertain, as such procedures are frequently multifaceted and analysing the contribution of any one component to observed outcomes can, in practice, be extremely difficult [START_REF] Stone | The ORION statement: guidelines for transparent reporting of outbreak reports and intervention studies of nosocomial infection[END_REF].

However, it was stressed that some sort of MRSA screening is essential in order to be successful in MRSA prevention and control. When considering the design of such a screening programme, it is essential to be aware of the context, specifically the MRSA occurrence levels nationally, regionally and locally. It is vital that nationallyagreed guidance is incorporated into local policies and that relevant practices are audited regularly (this is also called process surveillance) to ensure that there is A c c e p t e d M a n u s c r i p t 6 compliance. Policies may need to be modified locally based on the results of these audits so that they remain fit for purpose. This is especially pertinent given the changing landscape in Europe with the emergence of CA-MRSA and LA-MRSA.

Universal and targeted screening

‗Who' should be screened for MRSA as well as ‗where' and ‗when' are still open questions. Several sites are recommended when screening patients. The anterior nares are the ‗headquarters' of S. aureus/MRSA carriage and should always be included, although some data suggest that CA-MRSA may not be carried in the nose as frequently as other MRSA [START_REF] Deleo | Community-associated meticillin-resistant Staphylococcus aureus[END_REF]. Data from community outbreaks suggest that skinto-skin, and to a lesser extent skin-to-fomite, contacts represent common routes of transmission [START_REF] Miller | Clinical practice: colonization, fomites, and virulence: rethinking the pathogenesis of community-associated methicillin-resistant Staphylococcus aureus infection[END_REF]. The throat is also important, especially where relapse following eradication therapy is to be explored (see below). Additional sites are often included but may have diminishing returns. The perineum is more frequently colonised by CAthan by HCA-MRSA strains [START_REF] Lautenbach | Surveillance cultures for detection of methicillin-resistant Staphylococcus aureus: diagnostic yield of anatomic sites and comparison of provider-and patientcollected samples[END_REF]. Other sites include any lesions, manipulated sites (such as intravenous and urinary catheters), the axillae, the fingertips and the hairline. The latter two sites can provide clues that patients are dispersers with an increased risk of transmission to other patients, family members or the wider environment around patient areas or the home [START_REF] Lautenbach | The impact of household transmission on duration of outpatient colonization with methicillinresistant Staphylococcus aureus[END_REF][START_REF] Como-Sabetti | Risk factors for community-associated Staphylococcus aureus infections: results from parallel studies including methicillin-resistant and methicillin-sensitive S. aureus compared to uninfected controls[END_REF]. Pooling swabs from several sampling sites into a single broth culture has long been advocated as a cost-effective screening method where one just wants to know whether, rather than where, subjects are positive [START_REF] Sautter | Selective staphylococcal broth[END_REF].

A c c e p t e d M a n u s c r i p t 7 Both in primary detection and in screening following decolonisation, the use of selective or semiselective broth culture of individual swabs has been shown to increase the sensitivity of detection [START_REF] Sautter | Selective staphylococcal broth[END_REF][START_REF] Böcher | Semi-selective broth improves screening for methicillin-resistant Staphylococcus aureus[END_REF].

In hospitals with endemic MRSA, universal screening of all individuals admitted to the healthcare facility as well as isolation and/or decolonisation of patients screened MRSA-positive are indicated to be the most effective interventions in mathematical models [START_REF] Bootsma | Controlling methicillin-resistant Staphylococcus aureus: quantifying the effects of interventions and rapid diagnostic testing[END_REF] and, in support of this theoretical approach, have been associated with significant reductions in the incidence of MRSA infection in clinical studies [START_REF] Robicsek | Universal surveillance for methicillin-resistant Staphylococcus aureus in 3 affiliated hospitals[END_REF][START_REF] Jog | Impact of preoperative screening for meticillin-resistant Staphylococcus aureus by real-time polymerase chain reaction in patients undergoing cardiac surgery[END_REF]. However, the efficacy and cost effectiveness of universal screening, being strictly related to the local epidemiology of MRSA infections, continues to require clarification [START_REF] Mcginigle | The use of active surveillance cultures in adult intensive care units to reduce methicillin-resistant Staphylococcus aureus-related morbidity, mortality, and costs: a systematic review[END_REF][START_REF] Peterson | To screen or not to screen for methicillin-resistant Staphylococcus aureus[END_REF][START_REF] Wassenberg | Quantifying costeffectiveness of controlling nosocomial spread of antibiotic-resistant bacteria: the case of MRSA[END_REF][START_REF] Weber | Legislative mandates for use of active surveillance cultures to screen for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: position statement from the Joint SHEA and APIC Task Force[END_REF] Screening can also enable closer monitoring of circulating bio/genotypes. Recording typical antimicrobial susceptibility patterns and variants of these can inform the utility for local ‗antibiogram typing' and treatment options. Screening also produces alert organism data, raising possible issues of MRSA occurring in patients without previous hospitalisation, for example livestock exposure in MRSA-positive patients [START_REF] Mulders | Prevalence of livestock-associated MRSA in broiler flocks and risk factors for slaughterhouse personnel in The Netherlands[END_REF][START_REF] Cuny | Nasal colonization of humans with methicillin-resistant Staphylococcus aureus (MRSA) CC398 with and without exposure to pigs[END_REF].

The study that best represents an example of the efficacy of universal screening is that performed by Robicsek et al. [START_REF] Robicsek | Universal surveillance for methicillin-resistant Staphylococcus aureus in 3 affiliated hospitals[END_REF] 70%). However, some limitations of the study need to be emphasised: findings relied on observational data only; and MRSA isolation days and adherence and effectiveness of decolonisation were not monitored.

The alternative to active universal screening is selective (targeted) screening, which takes into account the relative risk to a patient, and others, on the basis of the individual's medical history, the procedure(s) to be undertaken during hospitalisation and the incidence of MRSA colonisation in the community of which they are part [START_REF] Brown | MRSA-laboratory aspects of detection[END_REF].

West et al. [START_REF] West | Effect of targeted surveillance for control of methicillin-resistant Staphylococcus aureus in a community hospital system[END_REF] performed a before-and-after study comparing the rate of MRSA infection before and after the initiation of expanded surveillance in a community hospital system in the USA. Patients considered to be at risk were those who were (a) transferred from another hospital, (b) admitted from long-term care facilities, (c) re-admitted within 30 days after discharge and (d) admitted to a nephrology service.

Cost effectiveness was calculated as the difference between the cost savings associated with preventing nosocomial MRSA bacteraemia and surgical-site infections (SSIs) and the cost of MRSA cultures and contact isolation for patients colonised with MRSA. The mean rate of nosocomial MRSA infection decreased over the study period. Surveillance was cost effective, preventing 13 nosocomial MRSA bacteraemias and 9 SSIs, resulting in a saving of US$1 545 762 [START_REF] West | Effect of targeted surveillance for control of methicillin-resistant Staphylococcus aureus in a community hospital system[END_REF].

A c c e p t e d M a n u s c r i p t 9 Table 1 summarises risk factors to be considered when planning a targeted screening programme. International transfers are becoming a higher priority in many countries with the presence of CA-MRSA and its spread within hospitals causing serious healthcare-associated infections. In some countries, exposure to LA-MRSA is a significant risk, whilst in others it has yet to be described. To improve compliance with MRSA screening policies, we recommended the flagging of MRSA-positive status in the patient's notes or the use of computerised systems that enable one to readily ‗tag' MRSA-positive patients and follow these up accordingly. Such a system was described many years ago but may not be available in many hospitals [START_REF] Cookson | A hospital computer system as a tool for infection control[END_REF].

This selective approach to screening has the undoubted advantage of reduced cost and workload but requires constant vigilance. Over time, changes in those considered to be in at-risk groups may be needed based on monitoring of the incidence of infection in a particular establishment or clinical unit. For example, the National Health Service (NHS) Quality Improvement Scotland Health Technology Assessment (HTA) on the clinical and cost effectiveness of MRSA screening originally recommended screening all overnight admission [START_REF] Ritchie | The clinical and cost effectiveness of screening for meticillin-resistant Staphylococcus aureus (MRSA)[END_REF]. When this strategy was tested, however, the Scottish recommendations were altered to include screening of the majority of elective admissions to acute specialties (excluding paediatrics, obstetrics and psychiatry) and elective admissions to only four specialties (nephrology, vascular surgery, dermatology and care of the elderly) that were identified as having the highest prevalence of MRSA colonisation [START_REF] Reilly | Universal screening for meticillin-resistant Staphylococcus aureus: interim results from the NHS Scotland pathfinder project[END_REF][START_REF]NHS Scotland MRSA Screening Pathfinder Programme Interim Report[END_REF].

Up-scaling selective screening to universal admission screening may be necessary during an outbreak situation in order to differentiate between imported and unrelated The surveillance strategies discussed so far have concentrated on hospital admissions. However, consideration must be also given to cross-transmission of MRSA both by patients and staff. With both groups it is important to distinguish between transient/short-term carriage, longer-term carriage and established colonisation, particularly in the case of staff [START_REF] Cookson | Staff carriage of epidemic methicillin-resistant Staphylococcus aureus[END_REF]. This is often ignored in studies [START_REF] Albrich | Health-care workers: source, vector, or victim of MRSA?[END_REF][START_REF] Vonberg | How often do asymptomatic healthcare workers cause methicillinresistant Staphylococcus aureus outbreaks? A systematic evaluation[END_REF]. In the case of patient transfer screening, two distinct possibilities should be considered: either recognising the risk to patients from a low-dependency medical ward when transferred to high-dependency or surgical wards with an increased chance of auto-infection as a result of invasive procedures; or that of risk to vulnerable patients on these units posed by an incoming carrier of MRSA (crossinfection). Furthermore, even without internal transfer, there is an increased risk of colonisation of patients previously free of MRSA as a result of long-term hospitalisation and antibiotic therapy [START_REF] Tacconelli | Antibiotic usage and risk of colonization and infection with antibiotic-resistant bacteria: a hospital population-based study[END_REF] and, in some situations, regular screening of such patients will be useful. Clearly this strategy would involve significant added workload and cost and, therefore, the definition of long-term stay and the resulting frequency of screening would need to be examined carefully with regard to costbenefit in a particular institution.

Whatever the chosen MRSA screening procedure pursued, which in the case of England and Wales in the UK is mandatory screening of elective surgery patients A c c e p t e d M a n u s c r i p t 11 prior to admission with the imminent addition of emergency admissions, it is implicit in any strategy that it be followed by timely action based on the results as part of agreed infection prevention and control procedures. Furthermore, it is essential that there are continuing audits of compliance with screening procedures, together with assessments of the speed and effectiveness of responses to screening results [START_REF] Harbarth | Universal screening for methicillin-resistant Staphylococcus aureus at hospital admission and nosocomial infection in surgical patients[END_REF].

As already stated, screening for MRSA is pivotal to any strategy for MRSA prevention and control. For example, it enables interpretation of the impact of suppressive, decontamination and isolation strategies. As with healthcare-associated infection surveillance, MRSA screening should provide information for action.

Increasingly in these cost-conscious times, it is vital that we consider the cost effectiveness and cost utility of MRSA screening and the intervention measures it informs. Diverting resources to screening may, for example, have a detrimental effect on patient safety or the quality of patient care.

Screening after hospital discharge

Discharge/follow-up screening and decolonisation of specific patients may be appropriate to break the feedback loop of colonisation/infection that may occur when patients who remain colonised are re-admitted to hospital [START_REF] Spicer | Three strategies in the control of staphylococci including methicillin-resistant Staphylococcus aureus[END_REF][START_REF] Simoens | Search and destroy policy for methicillin-resistant Staphylococcus aureus: cost-benefit analysis[END_REF]. Patients for whom there is considered to be a significant risk of acquiring MRSA during hospitalisation should be screened on discharge, and more so if they are expected to be re-admitted to hospital in the future, especially given that MRSA colonisation can be prolonged for periods of >12 months. Once identified as MRSA-positive, flagging of patient's notes (computerised if possible) may be adequate for some patients. For others, especially where they may be discharged to other care facilities, decolonisation

Isolation and decolonisation

Once MRSA colonisation/infection is detected, contact isolation should be implemented to prevent cross-transmission. Physical isolation of patients found to be colonised with MRSA on admission into a separate unit has two key advantages: it establishes a physical barrier for transmission of MRSA between an MRSA-positive patient and other patients; and it highlights the precautions necessary for healthcare workers (HCWs) and visitors to follow [START_REF] Mackenzie | Report of the Consensus Conference on Antibiotic Resistance; Prevention and Control (ARPAC)[END_REF][START_REF]Revised guidelines for the control of epidemic methicillin-resistant Staphylococcus aureus. Report of a combined Working Party of the Hospital Infection Society and British Society for Antimicrobial Chemotherapy[END_REF]. In an ideal world, all MRSA-positive patients should be isolated with designated nursing staff. However, where there is only limited capacity, a risk assessment undertaken to determine which patients require isolation (with or without their own nursing staff), based on the likelihood of transmission, is necessary. In this regard, patients with underlying skin diseases such as eczema who are more likely to shed large numbers of MRSA into the environment should be given priority. Recent mathematical modelling strongly suggests that both in endemic and epidemic settings of MRSA it is possible to reduce MRSA rates significantly by isolation and that this is cost effective even when the cost of the enhanced diagnostic and control measures is taken into account [START_REF] Shanson | Antibiotic-resistant Staphylococcus aureus[END_REF].

Various criteria for defining clearance exist, although at least three consecutive, weekly negative cultures is advised, assuming a sensitive broth enrichment method is used. In looking at the clinical and cost effectiveness of MRSA screening, the NHS Quality Improvement Scotland HTA recommended that patients identified as MRSApositive (colonised or infected) in a specialty deemed ‗high risk' should be decolonised and isolated, whereas those in specialties considered as ‗low risk'

A c c e p t e d M a n u s c r i p t 13 should be isolated but not decolonised [START_REF] Ritchie | The clinical and cost effectiveness of screening for meticillin-resistant Staphylococcus aureus (MRSA)[END_REF]. However, when attempts were made to implement this strategy within the hospital, patient movement between low-and highrisk specialty wards made selective decolonisation problematic and a decision was taken to decolonise all MRSA-positive patients in Scotland [START_REF] Reilly | Universal screening for meticillin-resistant Staphylococcus aureus: interim results from the NHS Scotland pathfinder project[END_REF][START_REF]NHS Scotland MRSA Screening Pathfinder Programme Interim Report[END_REF].

What regimens are available for consideration when attempting to eradicate MRSA from patients (or staff)? This is a difficult topic, like so many in MRSA epidemiology.

Studies vary in quality of design and there is also no agreement on definitions and methods used, e.g. for how long should follow-up screening be performed, should sensitive broth culture techniques be used? Regimens have been well reviewed and these reviews point out that there were many good studies performed before data abstraction [START_REF] Gemmell | Joint Working Party of the British Society for Antimicrobial Chemotherapy, Hospital Infection Society and Infection Control Nurses Association. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK[END_REF][START_REF] Gould | MRSA Working Party of the British Society for Antimicrobial Chemotherapy. Guidelines (2008) for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the United Kingdom[END_REF].

Neomycin (with chlorhexidine) cream has been used for many years but its effectiveness has been queried and neomycin resistance is a potential problem. It still has a place where mupirocin resistance is an issue. The best evidence for effectiveness exists for mupirocin. Tea tree preparations appear to be more useful at skin sites but have not performed well in nasal MRSA clearance in a double-blind controlled comparison with mupirocin. Eradication of MRSA is far easier where there is just nasal carriage. Where there are skin lesions it is particularly problematic [START_REF] Gould | MRSA Working Party of the British Society for Antimicrobial Chemotherapy. Guidelines (2008) for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the United Kingdom[END_REF][START_REF] Evans | Effect of chlorhexidine whole-body bathing on hospital-acquired infections among trauma patients[END_REF]. Alternatives to mupirocin are needed and their effectiveness needs to be assessed robustly [START_REF] Coates | Nasal decolonization of Staphylococcus aureus with mupirocin: strengths, weaknesses and future prospects[END_REF]. Use of mupirocin in the prevention and control of MRSA needs careful review. Its role in situations where MRSA occurrence is low is less problematic.

A c c e p t e d

M a n u s c r i p t 14 However, frequent use carries a considerable risk of resistance, especially if this use is prolonged and repeated in individuals. Resistant strains can cross-infect and so risks may be particularly large in closed communities, such as healthcare establishments, as opposed to its use following patient discharge. The UK MRSA guidelines recommend its use in ‗especially vulnerable pre-operative patients, such as those undergoing joint replacement, stent placement, vascular and cardiothoracic surgery or for patients in a unit where MRSA has a low prevalence and the intention is to eliminate the risk of spread.' Clearly mupirocin resistance monitoring is important. The UK MRSA guidelines [START_REF] Gemmell | Joint Working Party of the British Society for Antimicrobial Chemotherapy, Hospital Infection Society and Infection Control Nurses Association. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK[END_REF][START_REF] Gould | MRSA Working Party of the British Society for Antimicrobial Chemotherapy. Guidelines (2008) for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the United Kingdom[END_REF] have also reviewed other therapeutic options, including bacitracin, co-trimoxazole, rifampicin, tetracyclines and fusidic acid, which have demonstrated some efficacy (50-75%), but these alternatives were not considered established clinical management. They also recommended that mupirocin should only be used with a systemically active agent in the treatment of patients with carriage, or infection, at extranasal sites. [START_REF] Bode | Preventing surgical-site infections in nasal carriers of Staphylococcus aureus[END_REF] concluded that rapid screening (real-time PCR assay) and immediate initiation of standard mupirocin and chlorhexidine decolonisation reduced the risk of nosocomial S. aureus infections by almost 60%. However, all isolates of S. aureus in this study were susceptible to meticillin and mupirocin, confirming the low endemicity of MRSA in this country. In another recent study, specifically examining MRSA colonisation and infection, using a rapid, multiplex assay for detection, Harbarth et al. [START_REF] Harbarth | Universal screening for methicillin-resistant Staphylococcus aureus at hospital admission and nosocomial infection in surgical patients[END_REF] were unable to demonstrate a decrease in nosocomial infection during the intervention period in a surgical ICU. The authors suggested a number of reasons for the observed outcome, including the fact that the MRSA infection rate at their centre was relatively low in the surgical department (0.36 cases/10 000 patient-days) and was therefore less likely to show a statistically significant effect of the intervention.

Another proposed reason is that more than one-half (57%) of the infected patients were MRSA-free on admission and acquired infection during hospitalisation. This indicated the limited value of admission screening for patients admitted for extended periods into surgical units of institutes where MRSA is endemic that do not perform weekly surveillance cultures. Furthermore, although using a rapid PCR-based test procedure for detection of MRSA, for 31% of patients the result was only available after surgery and 34% of patients with subsequent MRSA SSI did not receive antibiotic prophylaxis covering MRSA. To underline further the low level of available evidence, a recent systematic review and meta-analysis of the effect of MRSA detection by rapid screening tests on hospital-acquired MRSA infections and A c c e p t e d M a n u s c r i p t 16 acquisition rates showed that screening using rapid molecular methods was not associated with a significant decrease in MRSA SSIs [START_REF] Tacconelli | Rapid screening tests for meticillin-resistant Staphylococcus aureus at hospital admission: systematic review and meta-analysis[END_REF]. These conflicting reports add to the controversy regarding the clinical and cost-benefit of universal admission screening, as opposed to selective screening, and emphasise the need for more carefully designed and executed clinical studies to address these issues [START_REF] Albrich | Health-care workers: source, vector, or victim of MRSA?[END_REF][START_REF] Harbarth | Universal screening for methicillin-resistant Staphylococcus aureus at hospital admission and nosocomial infection in surgical patients[END_REF][START_REF] Wernitz | Effectiveness of a hospital-wide selective screening programme for methicillinresistant Staphylococcus aureus (MRSA) carriers at hospital admission to prevent hospital-acquired MRSA infections[END_REF][START_REF] Strausbaugh | Preventing transmission of multidrug-resistant bacteria in health care settings: a tale of 2 guidelines[END_REF][START_REF] Farr | Political versus epidemiological correctness[END_REF][START_REF] Diekema | Look before you leap: active surveillance for multidrug-resistant organisms[END_REF][START_REF] Van Rijen | Kluytmans Intranasal mupirocin for reduction of Staphylococcus aureus infections in surgical patients with nasal carriage: a systematic review[END_REF]. New studies in areas of high MRSA endemicity, or outbreaks, would provide invaluable data enabling evidence-based decision-making [START_REF] Jog | Impact of preoperative screening for meticillin-resistant Staphylococcus aureus by real-time polymerase chain reaction in patients undergoing cardiac surgery[END_REF].

Before attempting patient (and staff) decolonisation, careful evaluation of the extent of carriage sites is required. Decolonisation is unlikely to succeed, or at least its success may be reduced considerably, if, for example, there are open wounds/lesions, intubation, external bone fixation, skin conditions such as colonised or infected eczema or burns, or affected urinary or intravascular catheters. For these patients it is necessary to consider the likelihood of recolonisation on wards where MRSA is endemic. Where relapse has occurred following attempted decolonisation, one needs to re-assess the patient. Typing isolates collected before and after decolonisation will assist on occasions when fresh acquisition is being considered. However, if there is insignificant variation in local epidemic MRSA, even by fine genetic typing, this will not help.

Another issue to be considered when planning a screening strategy is the development of mupirocin resistance. Higher risk has been reported to be related to age, throat carriage and the number of colonised sites [START_REF] Harbarth | Risk factors for persistent carriage of methicillin-resistant Staphylococcus aureus[END_REF]. However, in a recent systematic review the occurrence of resistance during treatment appeared to be extremely low [START_REF] Ammerlaan | Eradication of methicillin-resistant Staphylococcus aureus carriage: a systematic review[END_REF].

A c c e p t e d M a n u s c r i p t

Staff screening

Staff screening is a complex consideration both microbiologically and in terms of employee care. There are various categories of screening that have been considered, including: anonymous staff screening whilst on duty to encourage improved hand hygiene or to increase awareness [START_REF]Revised guidelines for the control of methicillin-resistant Staphylococcus aureus infections in hospitals. British Society for Antimicrobial Chemotherapy, Hospital Infection Society and the Infection Control Nurses Association[END_REF]; pre-employment and agency staff screening; screening to plan eradication regimen design; and screening to confirm MRSA eradication. Although potentially contentious, there is also ad hoc screening of staff whilst on duty. If new MRSA cases are discovered from clinical specimens, or the patient screening strategies mentioned above, then amongst the possible causes one must consider staff-associated transmission. However, to be labelled as a carrier of MRSA will undoubtedly affect personnel morale and cooperation. In addition, temporary removal of staff from duty during decolonisation will result in difficulty in maintaining adequate staffing levels. Therefore, it is recommended to involve staff representative organisations in establishing screening and eradication procedures for doctors, nurses and others with close patient contacts. Despite these difficulties, a number of advantages of staff screening have been recognised both for patients and staff [START_REF] Albrich | Health-care workers: source, vector, or victim of MRSA?[END_REF].

We recommend that HCWs are questioned regarding any infected or potentially contaminated skin lesions and to send such staff to occupational health departments for screening and case review. In such cases, and indeed whenever HCWs are to be screened, it is very important that they are screened at the commencement of duty, not during or at the end of duty. Such screening should be undertaken at least 12 h (and ideally at least 1 day) after a period of duty. This will reduce the chances of [START_REF] Cookson | Staff carriage of epidemic methicillin-resistant Staphylococcus aureus[END_REF]. Once MRSA is detected in a HCW, repeat screening of the individual needs to be undertaken, again at least a day after being on duty. Typing of strains can be valuable for testing epidemiological hypotheses and to validate the success of intervention measures. Whilst the value of general staff screening remains to be determined by controlled studies, the contribution of such procedures to an infection control investigation of unexpected infection in a unit is likely to be positive, if isolated strains are fully typed.

Whether or not similar screening should be undertaken routinely in nursing homes or other long-term care facilities remains unclear. In the case of nursing homes in particular, the contribution of MRSA carriage and infection by companion animals also needs to be assessed, as many of the patients will have pressure sores or varicose ulcers requiring long-term wound management, often on a daily basis [START_REF] Enoch | MRSA carriage in a pet therapy dog[END_REF][START_REF] Lefebvre | Contamination of pet therapy dogs with MRSA and Clostridium difficile[END_REF].

Environmental decolonisation

It has been demonstrated that the immediate environment around patients is often positive for MRSA. This is especially important in ICUs where much of the equipment will become contaminated with MRSA [START_REF] Boyce | Environmental contamination makes an important contribution to hospital infection[END_REF]. Routine disinfection of such equipment and potentially contaminated surfaces is therefore part of the MRSA control bundle of measures. Yet the importance of environmental cleaning as a single measure within an infection control programme has never been quantified. Environmental sources of nosocomial pathogens have also been taken account of in the ‗five moments for hand hygiene' described by the World Health Organization September 2010) [START_REF] Sax | ‗My five moments for hand hygiene': a user-centred design approach to understand, train, monitor and report hand hygiene[END_REF] Screening is rarely required unless there is continuing transmission to previously MRSA-negative patients despite interventions including ensuring there is good compliance with environmental cleaning and hand hygiene for patient-related procedures. Screening of the environment should be informed by epidemiological clues, such as suspected spread via common bronchoscope usage amongst newly MRSA-positive patients. It is important not to focus only on the environment in these situations. There may be infected or persistently MRSA-colonised staff for example, including those working at night or from agencies. There may also have been observed breakdowns in decontamination, e.g. terminal cleaning, sharing of stethoscopes or pens between patients. Data from screening of these instruments can be used to inform the importance of staff compliance with procedures. Airborne spread is uncommon but has been documented, e.g. on dermatological wards and burns units; if there doubts about the effectiveness of the ventilation of patient single rooms, then screening may be advised by the infection control team.

Ongoing European projects

Conclusions

As concluded in an earlier publication of a consensus statement by experienced practitioners in the field of prevention and control of healthcare-associated infections, including MRSA, -success in preventing and controlling MRSA is dependent on the appropriate attitude and high standards of professionalism among all who deliver healthcare‖. To do this, appropriate evidence-based strategies are axiomatic.

Standard precautions, especially hand hygiene, together with isolation/cohorting, Edited Table 1

  at a three-hospital organisation in the USA with ca. 40 000 annual admissions. The authors performed an interventional study comparing rates of MRSA clinical disease during and after hospital admission in three consecutive periods: (i) baseline (12 months); (ii) MRSA screening of all

  Intensive Care Unit (ICU) (12 months); and (iii) universal MRSA screening of all hospital admissions, with contact isolation and decolonisation of MRSA-positive cases (21 months). During the last universal screening period, the prevalence of MRSA infections decreased significantly compared with the baseline (-

  A c c e p t e d M a n u s c r i p t 10 cases [positive culture/polymerase chain reaction (PCR) 48 h of admission] and new cases of hospital-acquired colonisation or infection that are part of the outbreak (first positive culture/PCR >48 h after admission). This differentiation is essential for monitoring the effect of infection control measures.

A

  c c e p t e d M a n u s c r i p t 12 following an assessment of the likelihood of its success is the best course of action[START_REF] Mackenzie | Report of the Consensus Conference on Antibiotic Resistance; Prevention and Control (ARPAC)[END_REF].

  The value of decolonisation of either MRSA-positive patients or HCWs remains in need of further clarification. The purpose of decolonisation can be considered either as the prevention of infection or the prevention of transmission. Although these two goals are closely linked, they comprise two different situations where the evidence for the net benefit of decolonisation is not yet established conclusively. Various potentially confounding issues have been identified. Patient lengths of stay are often very short and these pose challenges as post-discharge screening is required to confirm or refute the effectiveness of decontamination measures. This process can be facilitated to an extent by computerised, or patient note, flagging so that readmitted patients can be identified more readily and admission screening performed.

A c c e p t e d M a n u s c r i p t 15 Prevention

 15 of post-surgical infection in patients with colonised with MRSA deserves special attention. Recently, from the results of a randomised, double-blind, placebocontrolled study of 6771 surgical patients in five hospitals in The Netherlands, Bode et al.

A c c e p t e d M a n u s c r i p t 18 detecting

 18 HCWs who are transient carriers of MRSA and categorising them as colonised staff requiring decolonisation

A c c e p t e d M a n u s c r i p t 19 (

 19 http://www.who.int/gpsc/5may/background/5moments/en/index.html; accessed 27

  MOSAR (Mastering Hospital AntimicrobialResistance in Europe), a Europe-wide research network co-ordinated by INSERM (the French National Institute of Health and Medical Research) and supported by the European Commission, was established in 2007 and will examine factors determining the dynamics of spread of antimicrobial-resistant bacteria within healthcare facilities and the relative efficacy and medicoeconomic impact of control strategies. Currently, the MOSAR network A c c e p t e d M a n u s c r i p t 20 has three clinical trials in progress in ICUs, surgical units and rehabilitation centres (http://www.mosar-sic.org; accessed 27 September 2010). The SATURN project, a multicentre European project supported by the European Commission, was established in January 2010 (http://www.ec.europa.eu/research/health/infectious-diseases/antimicrobial-drugresistance/index_en.html; accessed 27 September 2010). The network aims to study the impact of antibiotic exposure on the evolution of antimicrobial-resistant bacteria, mainly MRSA and extended-spectrum -lactamase-producing Gram-negative bacteria. The overarching rationale of SATURN is to improve methodological standards and to conduct research that will help to understand better the impact of antimicrobial use on acquisition, selection and transmission of antimicrobial-resistant bacteria in different environments, by combining analyses of molecular, individual patient-level and ecological data. The European Centre for Disease Prevention and Control (ECDC) (http://www.ecdc.europa.eu; accessed 27 September 2010) has also contracted groups to produce MRSA guidelines and an assessment of MRSA typing methodologies.

  decolonisation in selected situations, are key to the control and prevention of MRSA infection[START_REF] Mackenzie | Report of the Consensus Conference on Antibiotic Resistance; Prevention and Control (ARPAC)[END_REF]. We now agree and propose that universal or riskbased screening for potential sources of MRSA, whether in the guise of MRSA carriers among patients and HCWs or of MRSA-contaminated surfaces in the health care environment, is an indispensable part of an effective MRSA control strategy in healthcare institutes where MRSA is endemic. The strategy adopted for a screening programme must be established with the active participation of infectious disease physicians, clinical microbiologists, public health officials and economists for a particular country or region.



  Risk factors for colonisation with meticillin-resistant Staphylococcus aureus (MRSA) at hospital admission HCA-MRSA infection CA-MRSA infection  Previously colonised or infected, or their close contacts Previous therapy with quinolones, cephalosporins or carbapenems  Previous hospitalisation (especially in a hospital known to have high incidence of MRSA), surgery or healthcare contact  Previous MRSA colonisation or infection  Dialysis Indwelling bladder or vascular device at home  Underlying chronic illness  i.v. drug abuse  Residency in LTCFs or NHs, i.v. therapy, or specialised nursing at home  Open wounds (pressure sores, varicose ulcers)  International or interhospital transfers from high-risk location an endemic area such as North America

Acknowledgments

The meeting was sponsored by the following companies, which gave unrestricted education grants: Astellas Pharma; Becton Dickinson; bioMérieux; Cepheid; Novartis; and Wyeth. This review is based on the proceedings of an expert panel meeting jointly held by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC), 5-6 March 2010, Rome, Italy.

Funding

None.

Competing interests

None declared.

Ethical approval


MD Christophe Hézode
email: christophe.hezode@hmn.aphp.fr

Boceprevir and telaprevir for the treatment of chronic hepatitis C: Safety management in clinical practice

Keywords: AEs, adverse events DAAs, direct-acting antivirals PEG-IFN, pegylatedinterferon RBV, ribavirin hepatitis C, direct acting antiviral, protease inhibitor, anemia, rash, safety

Effective management of adverse events (AEs) is important to prevent treatment discontinuation and optimize hepatitis C virus (HCV) infection eradication rates. The addition of direct-acting antiviral agents (DAA), telaprevir (TVR) or boceprevir (BOC) to pegylated interferon (PEG-IFN) and ribavirin (RBV) represents a new era of therapy associated with an improvement in treatment response rates and an impairment of the safety profile compared to PEG-IFN/RBV. An increase in the frequency and severity of anemia was reported in clinical trials for both drugs, and skin disorders including rash and pruritus occurred more frequently with the TVR-based regimen. These AEs are generally manageable and do not lead to early discontinuation. The management of anemia has not been clearly established and the impact of RBV dose reductions anderythropoietin alpha (EPO) use on treatment efficacy and safety must be clarified. The management of rashes, which were mild and moderate in more than 90% of the cases, is well planned, does not require TVR discontinuation and can be treated using emollients and topical corticosteroids. However, approximately 5% of rashes were severe and a few cases were classified as severe cutaneous adverse reactions (SCAR) leading to treatment discontinuation.

Introduction:

Because of the consequences of treatment failure in patients with chronichepatitis C virus (HCV) infection, optimizing treatment efficacy and safety is essential to prevent the development of morbidities and increase survival rates [START_REF] Shepard | Global epidemiology of hepatitis C virus infections[END_REF][START_REF] Poynard | Impact of peylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C[END_REF][START_REF] Shiratori | Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival[END_REF]. Managing adverse events (AEs) during antiviral treatment plays an important role in improving adherence and reducing premature treatment discontinuation. In addition, interactions among different drugs in the regimen may affect the efficacy and/or safety of therapy and must be managed appropriately in each patient. While AEs and drug-drug interactions are generally well established for standard peginterferon (PEG-IFN)/ribavirin (RBV) therapy [START_REF] Fried | Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection[END_REF][START_REF] Mchutchison | Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection[END_REF][START_REF]EASL Clinical Practice Guidelines: Management of hepatitis C virus infection[END_REF], the addition of direct-acting antiviral agents (DAAs) to PEG-IFN/RBV as part of a triple therapy regimen will change the factors to be taken into account in patient management. The oral DAA, telaprevir (TVR) and boceprevir (BOC), in combination with PEG-IFN/RBV have led to a significant improvement in sustained virologic response (SVR) in HCV genotype 1 patients, buthave been associated with an increase in several AEs compared to PEG-IFN/RBV alone. In clinical practice, the effective management of safety and drug-drug interactions will be essential to optimize the benefits provided by these agents for patients infected with HCV genotype 1.

Managing safety and tolerance to triple combination therapy

In placebo-controlled phase II/III studies, the most common AEs that occurred more frequently with TVR than with placebo (>5% difference) included pruritus, rash, anemia and gastrointestinal disorders (anorectal symptoms, nausea and diarrhea), which were generally manageable and did not lead to premature discontinuation [START_REF] Jacobson | Telaprevir for previously untreated chronic hepatitis c virus infection[END_REF][START_REF] Zeuzem | Telaprevir for retreatment of HCV infection[END_REF][START_REF]Telaprevir EU Summary of Product Characteristics[END_REF]. In both BOC phase III studies, the main AEs were an increase in the occurrence of fatigue, anemia, nausea, diarrhea, dysgeusia (taste alteration), and neutropenia [START_REF] Bacon | Boceprevir for previously treated chronic HCV genotype 1 infection[END_REF][START_REF] Poordad | Boceprevir for untreated chronic HCV genotype 1 infection[END_REF][START_REF]Boceprevir EU Summary of Product Characteristics[END_REF].

Anemia

Anemia is a well known RBV-related event which is exacerbated by the addition of TVR and BOC. The mechanism of anemia with both DAA was not due to hemolysis but was thought to be the result of a bone-marrow suppressive effect. In clinical trials, triple therapy with TVR or BOC was associated with an increase in the incidence (approximately 20%) and severity of anemia compared to PEG-IFN/RBV alone (Table 1). The frequency of anemia, defined as hemoglobin levelsbelow 10 g/dL, was about 50% for triple therapy with BOC and 40% with TVR. Hemoglobin values gradually improved after the end of TVR dosing at Week 12, and were similar to those with PEG-IFN/RBV alone by week 20. The impact of anemia on the SVR rate was different for the two drugs. Anemia had no effect on efficacy outcomes in treatment-naïve patients [START_REF] Sulkowski | Anemia had no effect on efficacy outcomes in treatment-naïve patients who received telaprevir-based regimen in the advance and illuminate phase 3 studies[END_REF] with TVR (Figure 1). In contrast, for BOC the SVR rate was more frequently achieved in patients with anemia than in those withoutin treatment-naïve and -experienced patients (14) (Figure 2). Premature discontinuation of antiviral treatment because of anemia remained rare (Table 1). The management of anemia in TVR and BOC clinical trials is summarized in Table 1. In BOC trials, 43% of patients received erythropoietin alpha (EPO) for the management of anemia, de facto using a quadruple combination therapy [START_REF] Bacon | Boceprevir for previously treated chronic HCV genotype 1 infection[END_REF][START_REF] Poordad | Boceprevir for untreated chronic HCV genotype 1 infection[END_REF][START_REF]Boceprevir EU Summary of Product Characteristics[END_REF]. This may be problematic in clinical practice, as BOC will have to be administered for was used in 1% of patients only [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF]. Blood transfusion was required in lessthan 5% of the patients for both drugs. A similar proportion of patients underwent RBV dose reductions to manage anemia, approximately 22 to 26% (Table 1) [START_REF] Jacobson | Telaprevir for previously untreated chronic hepatitis c virus infection[END_REF][START_REF] Zeuzem | Telaprevir for retreatment of HCV infection[END_REF][START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF] Bacon | Boceprevir for previously treated chronic HCV genotype 1 infection[END_REF][START_REF] Poordad | Boceprevir for untreated chronic HCV genotype 1 infection[END_REF][START_REF]Boceprevir EU Summary of Product Characteristics[END_REF]. The retrospective analysis of phase III clinical trials with BOC and TVR showed that RBV dose reduction did not seem to have a negative impact on SVR (Figure1, 2) [START_REF] Sulkowski | Anemia had no effect on efficacy outcomes in treatment-naïve patients who received telaprevir-based regimen in the advance and illuminate phase 3 studies[END_REF][START_REF] Sulkowski | Anemia during treatment with peginterferon alfa-2b/ribavirin with or without boceprevir is associated with higher SVR rates: analysis of previously untreated and previous-treatment-failure patients[END_REF]. In addition, the use of EPO did not seem to have a positive impact on SVR ratein BOC studies. These initial analyses must be discussed in relation to the results of large retrospective studies of patients treated with PEG-IFN/RBV. These studies have shown that a dose reduction of RBV only has a negative effect on the efficacy of outcomes when the cumulative dose is less than 60% of the initially planned dose. If the dose reduction of RBV occurs when HCV RNA is undetectable, the impact on SVR seems to be reduced [START_REF] Reddy | Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment[END_REF]. When EPO is used, the full dose of RBV can often be maintained and the quality of life is improved [START_REF] Afdhal | Epoetinalfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study[END_REF]. In a post hoc analysis of a controlled study involving more than 3,000 patients, it has been shown that patients who developed anemia during a course of PEG-IFN/RBV had higher SVR rates than those who did not develop anemia [START_REF] Sulkowski | Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response rate[END_REF]. In this study, EPO increased the chance of eradicating HCV when it was administered in the first 8 weeks, probably when HCV RNA was still detectable. After the eighth week of treatment, EPO had no beneficial effect on the SVR rate. If these results are extrapolated to triple therapy, it may be necessary to maintain the full dose of RBV until HCV RNA becomes undetectable. Thus, EPO could be used according to the local regulations of each country. If anemia occurs when HCV RNA is undetectable, the RBV dose could be reduced bystagesof 200 mg daily. The value of administering EPO or reducing the dose of RBV in patients with hemoglobin levelsbelow 10 g/dL is under investigation in a prospective clinical trial with BOC. The results of this important study will be available in 2012. The initial dose of protease inhibitors must be maintained in all cases. Finally, a few patients with cirrhosis were included in phase III clinical trialswith BOC and TVR [START_REF] Jacobson | Telaprevir for previously untreated chronic hepatitis c virus infection[END_REF][START_REF] Zeuzem | Telaprevir for retreatment of HCV infection[END_REF][START_REF] Bacon | Boceprevir for previously treated chronic HCV genotype 1 infection[END_REF][START_REF] Poordad | Boceprevir for untreated chronic HCV genotype 1 infection[END_REF]. The first safety report of the CUPIC cohort, related to the French early access program andincluding a large number of treatment experienced patients with cirrhosis treated with triple therapy showed a poor safety profile. BOC or TVR in combination with PEG-IFN/RBV was associated with high rates of serious adverse events (40% to 57%) with a median treatment period of 84 to 89 days. EPO was used in 41% to 45% of patients and blood transfusions were required in 4% to 17% of patients, suggesting that triple therapy must be administered cautiously with intensive safety monitoring, including anemia, in patients with cirrhosis [START_REF] Hézode | Safety of telaprevir or boceprevir in combination with peginterferonalfa/ribavirin, in cirrhotic non responders. First results of the French early access program (ANRS CO20-CUPIC) in real-life setting[END_REF].

Dermatological adverse events

Dermatological reactions with PEG-IFN/RBV are well established and tend to be a uniform entity of dermatitis: generalized pruritus and skin xerosis, with eczematiform lesions accentuated by erythematous papules and microvesicles that are often excoriated, predominantly located on the extremities and on truncal skin sites exposed to friction [START_REF] Lübbe | Clinical and immunological features of hepatitis C treatment-associated dermatitis in 36 prospective cases[END_REF].These eruptions can be managedusing the same approach as for chronic eczema (topical corticosteroids, gradually replaced by emollients), and there is usually no need todiscontinue antiviral treatment [START_REF] Lübbe | Dermatological side effects[END_REF] . The new treatment era with DAA is accompanied by additional patient management considerations for HCV-treating physicians. In particular skin disorders are expected to be more frequent and more severe with triple combination regimens than with PEG-IFN/RBV alone.

In clinical trials, dermatological AEs have been reported at higher frequencies with TVRbased and sometimes with BOC-based therapy, compared to PEG-IFN/RBV alone [START_REF] Jacobson | Telaprevir for previously untreated chronic hepatitis c virus infection[END_REF][START_REF] Zeuzem | Telaprevir for retreatment of HCV infection[END_REF][START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF] Bacon | Boceprevir for previously treated chronic HCV genotype 1 infection[END_REF][START_REF] Poordad | Boceprevir for untreated chronic HCV genotype 1 infection[END_REF][START_REF]Boceprevir EU Summary of Product Characteristics[END_REF]. In placebo-controlled TVR Phase II/III studies, in which 2012 patients received at least one dose of TVR and 764 patients received at least one dose of placebo, 55% of TVR-treated patients developed a rash compared to 33% of patients treated with PEG-IFN/RBV alone [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF].

Although it was more extensive and severe, the typical rash in people who received a TVRbased regimen was virtually indistinguishable from the PEG-IFN/RBV rash visually and on histopathology.Rashes were primarily pruritic and eczematous, although some had an additional maculopapular component, which is not consistent with a typical hypersensivity.

Histologically, the rash appeared to be a spongiform dermatitis, with predominantly lymphatic or eosinophilic perivascular infiltration. Most (>90%) rashes were mild or moderate (grade 1 and 2), involving less than 30% of the body surface area (BSA), and progression to more severe rash was infrequent (<10%) [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF] Cacoub | Dermatological side effects of hepatitis C and its treatment: patient management in the era of direc-acting antivirals[END_REF]. Approximately 50% of rashesdeveloped within the first 4 weeks of treatment, with the remaining 50% starting between 5-12weeks and the median time to onset of rash (any grade) was 25 days (range 1-350) [START_REF] Cacoub | Dermatological side effects of hepatitis C and its treatment: patient management in the era of direc-acting antivirals[END_REF]. Therefore, skin eruptions can occur at any time during TVR treatment. Following the end of TVR treatment at week 12, all patients continued to receive PEG-IFN/RBV, and the incidence of rash was similarbetween TVR and placebo-treated patients.

Overall, the incidence of severe or grade 3 rash (primarily eczematous, pruritic and involving more than 50% of BSA) was 4.8% versus 0.4% with PEG-IFN/RBV alone [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF]. Rash led to premature discontinuation of TVR alone in 5.8% of patients and of TVR combination therapy in 2.6% of patients compared to none of those receiving PEG-IFN/RBV. Following the end of TVR treatment or discontinuation, symptomsimprovedand usually resolved, although rashes may take several weeks to resolve.

A few cases of rash were classified as severe cutaneous adverse reactions (SCAR), which can be life-threatening if unrecognized or unmanaged, and require immediate discontinuation of antiviral treatment. In placebo-controlled Phase II and III trials, 11 patients (0.4%) were recorded as having drug reactions with eosinophilliaand systemic symptoms (DRESS) and three patients (<0.1%) had suspected Stevens-Johnson Syndrome (SJS) [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF] Cacoub | Dermatological side effects of hepatitis C and its treatment: patient management in the era of direc-acting antivirals[END_REF]. Among the 11 reported cases of DRESS, three were confirmed by a systematic retrospective assessment by expert dermatologists.One of these cases has been reported separately [START_REF] Montaudié | Drug rash with eosinophillia and systemic symptoms due to telaprevir[END_REF].Among the three SJS cases, one occurred 11 weeks after TVR was discontinued and was not considered to be related to TVR. Of the two cases of suspected SJS that occurred during the TVR treatment phase, one was considered to be possible SJS by expert dermatologists, and the other probable SJS. All of these severe reactions resolved when treatment was discontinued [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF] Cacoub | Dermatological side effects of hepatitis C and its treatment: patient management in the era of direc-acting antivirals[END_REF]. Finally, the mechanism of TVR-related rash remains unknown and no predictors have been identified.

The second dermatological AEs that wasfrequently reported with TVR was pruritus.This event was generally reported when rash was present, but could also be seen without it.

Pruritus may be invalidating and cause rare treatment discontinuations.

Guidance for managing rashes

The goal of physicians should be togive patients the best chance of eradicating HCV, i.e. to continue antiviral therapy when possible in accordance with treatment and rash management protocols. However, to avoid exposing patients to the risk of severe drug-induced cutaneous reactions, physicians treating HCV should be able to easily distinguish between dermatitis and SCAR.The recommendations for grading and monitoring of dermatological reactions, and for discontinuation of TVR, PEG-IFN, and RBV because of such events are summarized in Table 2 [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF]. Figure 3 provides a guide to estimate body surface area as an indicator of the severity of a dermatological reaction [START_REF] Hettiaratchy | Initial management of a major burn: IIassessment and resuscitation[END_REF]. A number of clinical and biological criteria should help physicians to distinguish between TVR-related dermatitis and potential SCAR. If drug rash with eosinophilia and systemic symptoms (DRESS) alert criteria are present, including an onset between 5 -10 weeks after the first dose of TVR that rapidly progresses to exanthema with a prolonged fever (> 38.5°C) that is not related to the PEG-IFN injection and facial oedema, the following confirmation criteria should be assessed: enlarged lymph nodes (at least 2 sites), eosiniphilia (≥ 700/µL or ≥ 10%), atypical lymphocytes, internal organ involvement (liver and kidney) [START_REF] Cacoub | Dermatological side effects of hepatitis C and its treatment: patient management in the era of direc-acting antivirals[END_REF]. Patients presenting with rapidly progressing exanthema, skin pain, atypical or typical target lesions, mucosal involvement in at least 2 sites, or with blisters or epidermal detachment should be suspected of having Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) [START_REF] Cacoub | Dermatological side effects of hepatitis C and its treatment: patient management in the era of direc-acting antivirals[END_REF].

In the case of Grade 1 or 2 rash, patients can benefit from guidance on optimal skin care techniques that may limit symptoms and allow optimal antiviral therapy to be continued for as long as possible. Emollient cream, rather than lotions or ointments may be effective in relieving eczematous reactions. Cream should be applied for at least 15 minutes, beginning with areas around the joints, and progressing with broad strokes across the rest of the skin. This should be begun 15 minutes after showering or bathing, and should be applied daily.

Rashes can be primarily treated with topical corticosteroids. Permitted systemic antihistaminic drugs may also be used for the treatment of pruritus. Regular follow up is important, and the patient should be advised to limit exposure to sun/heat. Baking soda or oatmeal baths and loose-fitting clothes can be suggested.If grade 3 rashis present TVRmust be discontinued immediately and can be managed with topical corticosteroids without antiviral treatment (PEG-IFN/RBV) discontinuation.In case of SCAR, all antiviral treatment must be discontinued immediately and the patient must be hospitalized in an appropriate department.

Anorectal disorders

In placebo-controlled TVR Phase II/III trials, anorectal adverse events occurred more frequently in TVR arms than in control arms: 26.2% versus 5.4%, respectively [START_REF] Jacobson | Telaprevir for previously untreated chronic hepatitis c virus infection[END_REF][START_REF] Zeuzem | Telaprevir for retreatment of HCV infection[END_REF][START_REF]Telaprevir EU Summary of Product Characteristics[END_REF]. Events usually developed within the first 2 weeks of treatment.Reported events includedhemorrhoids, anal pruritus, anal discomfort or rectal burning. Most of these events were mild to moderate, very few led to treatment discontinuation, and they resolved after completion of TVR dosing.

The mechanism is unknown and no evident association was found with either generalized pruritus or skin rash. An anal examination should be performed to exclude lesions that could explain the symptoms, especially hemorrhoids, fissure nor fistula. Generally, an anal examination shows non specific erythema secondary to itching. Standard symptomatic care may be considered for managing anorectal disorders, including short-term use of non-specific topical ± including local anesthetic in case of rectal burning. Topical corticosteroids and allowed systemic antihistaminic drugs may also be used for the treatment of pruritus.

Managing drug-drug interactions

Drug-drug interactions that lower antiviral or concomitant medication drug levels to below therapeutic ranges can result in a loss of efficacy, with suboptimal drug pressure potentially leading to drug resistance [START_REF] Seden | Antiretroviral drug interactions:often unrecognized, frequently unavoidable, sometimes unmanageable[END_REF]. In contrast, drug-drug interactions that elevate drug levels and exposure can increase the risk of AEs [START_REF] Seden | Antiretroviral drug interactions:often unrecognized, frequently unavoidable, sometimes unmanageable[END_REF]. Both of these effects may reduce the chances of treatment success, but with effective management they can be lessened.

The mechanisms of drug-drug interactions include absorption, gastrointestinal metabolism or transport, and hepatic metabolism ortransport. For example, liver enzymes such as cytochrome P450 (CYP) 3A and transporters such as P-glycoprotein (P-gp) may affect plasma drug concentrations. Ultimately, whether an interaction takes place is dependent upon characteristics of both the drug and the patient. Table 3 summarizes the key pharmacological characteristics of TVR and BOC that need to be accounted for when considering the risk of drug-drug interactions [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF]Boceprevir EU Summary of Product Characteristics[END_REF].

As a result of these characteristics, TVR and BOC are contraindicated with a number of drugs, in particular those that are highly dependent on CYP 3A (TVR) or CYP 3A4/5 (BOC) for clearance and for which elevated plasma concentrations are associated with serious of lifethreatening events. Concomitant administration of TVR with active substances that strongly induce CYP 3A, and thus may lead to lower exposure and loss of efficacy of TVR, is also contraindicated (Table 4) [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF]Boceprevir EU Summary of Product Characteristics[END_REF] In summary, it is important to review all medications prior to initiation of triple combination therapy. Once this information has been collected, a key source of information and recommendations regarding co-administration with different compounds is the drug product label [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF]Boceprevir EU Summary of Product Characteristics[END_REF]. As with HIV, online tools are now also becoming available to help healthcare professionals predict, avoid and manage drug interactions in HCV.

Conclusion

The addition of DAA (TVR or BOC) to PEG-IFN/RBV therapy will change the spectrum of elements to be taken into consideration for patient management compared toPEG-IFN/RBV alone [START_REF] Asselah | New direct-acting antivirals' combination for the treatment of chronic hepatitis C[END_REF]. The main adverse events reported in clinical trials evaluating the efficacy and safety of TVR or BOC in combination with PEG-IFN/RBV were generally manageable and did not lead to premature discontinuation, although an increase in the frequency and severity of anemia and skin disorders relative to PEG-IFN/RBV alone were noted. In clinical practice, monitoring and effective management of AEs and drug-drug interactions will be essentialto optimize treatment with TVR and BOC, and improve cure rates across different patient populations. Table 1 Incidence and management of anemia with TVR and BOC in triple combination compared to PEG-IFN/RBV alone in controlled clinical trials [START_REF] Jacobson | Telaprevir for previously untreated chronic hepatitis c virus infection[END_REF][START_REF] Zeuzem | Telaprevir for retreatment of HCV infection[END_REF][START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF] Bacon | Boceprevir for previously treated chronic HCV genotype 1 infection[END_REF][START_REF] Poordad | Boceprevir for untreated chronic HCV genotype 1 infection[END_REF][START_REF]Boceprevir EU Summary of Product Characteristics[END_REF]. TVR phase II/III placebo-controlled trials [START_REF] Jacobson | Telaprevir for previously untreated chronic hepatitis c virus infection[END_REF][START_REF] Zeuzem | Telaprevir for retreatment of HCV infection[END_REF][START_REF]Telaprevir EU Summary of Product Characteristics[END_REF] BOC phase III clinical trials ( Grading and recommendations for managing dermatological reactions with TVR-based triple combination therapy [START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF] Cacoub | Dermatological side effects of hepatitis C and its treatment: patient management in the era of direc-acting antivirals[END_REF]. -Monitor for progression or systemic symptoms until the rash is resolved.

Figureslegends

Moderate rash (grade 2)

Diffuse rash <50% of BSA -Monitor for progression or systemic symptoms until the rash is resolved.

-Consider consultation with a dermatologist.

-For moderate rash that progresses, permanent discontinuation of TVR should be considered. If the rash does not improve within 7 days following TVR discontinuation, RBV should be interrupted. Interruption of RBV may be required sooner if the rash worsens despite discontinuation of TVR. PEG-IFN may be continued unless interruption is medically indicated.

-For moderate rash that progresses to severe, permanently discontinue TVR (see below).

Severe rash (grade 3)

Extent of rash > 50% of BSA or associated with significant systemic symptoms, mucous membrane ulceration, target lesions, epidermal detachment.

-Permanently discontinue TVR immediately.

-Consultation with a dermatologist.

-Monitor for progression or systemic symptoms until the rash is resolved.

-PEG-IFN and RBV may be continued.

Figure 1 :

 1 Figure 1:Impact of anemia and RBV reduction dose on SVR rate in treatment-naïve patients

Figure 2 :

 2 Figure 2: Impact of anemia and management of anemia RBV on SVR rate in treatment-naïve

Figure 3 :

 3 Figure 3: Estimating body surface area (23).

1 )

 1 Localized skin eruption and/or a skin eruption with a limited distribution (up to several isolated sites on the body)

Table 2

 2

	10-12)

Table 3

 3 Summary of key pharmacological characteristics of TVR and BOC[START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF]Boceprevir EU Summary of Product Characteristics[END_REF][START_REF] Carg | Low-dose RTV and the pharmacokinetics of the investigational HCV protease inhibitor TVR in Healthy volunteers[END_REF][START_REF] Kassera | Clinical pharmacology of BOC:metabolism, excretion, and drug-drug interactions[END_REF].

	If improvement is not observed

Table 4

 4 Contraindications to TVR and BOC[START_REF]Telaprevir EU Summary of Product Characteristics[END_REF][START_REF]Boceprevir EU Summary of Product Characteristics[END_REF].

	Class	Agent	TVR (9)	BOC (12)
	Alpha-1receptor antagonists	Alfuzosin	Contraindicated	No recommendation
	Antiarrhythmics	Amiodarone, bepridil,	Contraindicated	Bepridil contraindicated.
		quinidine	(contraindicated with	Caution with
			class Ia/III, except	amiodarone/quinidine
			IVlidocaine
	Anticonvulsants	Carbamazepine,	Contraindicated	No data available
		Phenobarbital, phenytoin		not recommended
	Antihistamines	Astemizole, terfenadine	Contraindicated	No recommendation
	Antimalarials	Lumefantrine, halofantrine	No recommendation	Contraindicated
	Antimycobacterials	Rifampicin	Contraindicated	No data available
				not recommended
	Antipsychotics	Pimozide	Contraindicated	No data available
				not recommended
	Benzodiazepines	Oral midazolam, oral	contraindicated	contraindicated
		triazolam
	Digestive motility stimulants	Cisapride	Contraindicated	No recommendation
	Ergot rye derivatives	Dihydroergotamine,	Contraindicated	Contraindicated
		ergonovine, ergotamine,
		methylergonovine
	Herbal products	St John's wort	Contraindicated	No recommendation
		(Hypericumperforatum)
	HMG-CoA reductase	Atorvastatin, simvastatin,	Contraindicated	No data available. Therapeutic
	inhibitors	lovastatin		monitoring recommended
				(atorvastatin, simvastatin)
	PDES inhibitors	Sildenafil, tadalafil	Contraindicated	No recommendation
	Tyrosine Kinase inhibitors	Not specified	No recommendation	Contraindicated


Hervé Locteau
email: herve.locteau@univ-rouen.fr

Sébastien Adam

Éric Trupin

Jacques Labiche

Pierre Héroux

Symbol Spotting using Full Visibility Graph Representation

Keywords: perceptual grouping, visibility graph, segmentation, symbol spotting, symbol recognition, cyclic string edit distance

In this paper, a method for matching symbols in line-drawings is presented. Facing both segmentation and recognition of symbols is a difficult challenge. Starting from the results of a vectorization procedure, a visibility graph is built to enhance the main geometric constraints which were specified during the construction of the initial document. The cliques detection, which correspond to a perceptual grouping of primitives, is used in the system to detect regions of particular interest. Both opened and perceptually closed curves are identified from aggregation of cliques. Finally, the recognition stage uses an attributed edit distance technique to match approximated curves within the host attributed relation graph and the ones from a collection of symbols.

Introduction

Symbol recognition deals with identification of a given object but objects have also to be extracted in the input data. In specific cases, symbol localization can be triggered from the localization of the main white connected component (pixel based approaches) or the main minimal cycle within the junction graph (skeleton based approaches) leading to a framing window that enables the identification or rejection of the symbol. Aiming to achieve both localization and recognition of a priori known classes of symbols in a document requires to make those processes interacting. As an alternative to this proposal, particular patterns from a junction within the junction graph permit to dynamically define a region of interest from which a vectorial signature is extracted in [START_REF] Rusiñol | Symbol spotting in technical drawings using vectorial signatures[END_REF]. This spotting technique postpone the recognition step restricting significantly the regions that have to be classified or rejected. It is both relevant for symbols built from a cycle and the ones that have no cycle in the junction graph. No matter localization and recognition are synchronized or not, although structural methods are generally sensitive to noise, they represent an appealing framework capturing the spatial and topological relationship between graphical primitives.

In this study, we investigate the use of visibility graphs for symbol representation as they look close to the perceptual grouping human vision may achieves. The relevancy of the final representation is twofold : it is suitable for (i.) symbols with or without any closed curve and (ii.) symbols built from disconnected components. This type of graph is introduced in the section 2. We present in section 3 how cliques within the visibility graph can be aggregated to build (nearly) closed curves that can then be indexed to provide regions of interest. Finally, our matching process based on an attributed edit distance is depicted in section 4.

Visibility Graph

Visibility representations are of particular interest in computer science such as graphics, VLSI layout, motion planning and computational geometry [START_REF] O'rourke | Computational geometry column 18[END_REF]. In this work, a visibility graph is defined from a set of n vectorial primitives such that each primitive is mapped to a node while edges represent visibilities between couples of primitives (u, v). The visibility relation used throughout between u and v corresponds to the existence of a point on u and a point on v defining a line segment that does not intersect any other primitive [START_REF] Wismath | Computing the full visibility graph of a set of line segments[END_REF]. Such a relation has been called weak visibilty in some works and leads to a full visibility graph, FVG for short. As an example, we report the FVG build from a set of segments in the figure 1. for all i ∈ [0, n] do for all P e ∈ {Begin(i) = Bi, End(i) = Ei} do computes polar coordinates of extremities P k of primitives j with respect to P e sort the (θ(P k ), ρ(P k )) according to θ(), then to ρ() end for computes the visibility polygon of Pe (see §2.1) extends the visibilities of primitives j around Pe (see §2.2) end for

The algorithm used to extract the FVG of a segments' set is summarized in (Alg. 1). For a given primitive j, let S j and F j stand respectively for the first and the second, counterclockwise endpoint, thus :

if it is hardly connected to primitive i (i.e. B j = P e or E j = P e), the junction point's angle is set to the opposite one of P e (the other endpoint of the primitive i), -since

S j P e F j < π, if θ(F j ) < θ(S j ), θ(F j ) = θ(F j ) + 2π.
The procedures corresponding to the extraction of the visibility polygon of a point P e and its use to extend the visibility of primitives around this point are both based on line sweep algorithms.

Computing the visibility polygon of a point

Following the Wismath's idea, we first computes the visibility polygon of a point. The primitives are sorted within a stack by their distance between a reference point and the intersection point of a ray sweeping the plane. The algorithm (Alg.

2) permits to build the visibility polygon V P oly(P e) of a point P e. Dealing with (i.) colinear points and (ii.) common points are taken into account when we update the stack (insertion and deletion) and when we evaluate whether a point is visible or not. Obviously, a first series of visibilities involving the primitive i can be directly extracted from V P oly(P e). Nevertheless, it is also necessary to seek for particular configurations within V P oly(P e) in order to specify a second series of visibilities involving primitives both referenced in V P oly(P e).

Extending the visibility of primitives around a point

From the visibility polygon's building procedure of a point P e, we can note that visibilities between a couple of primitive (i, j) are extracted from at least an endpoint of either the primitive i or the primitive j. In order to detect visibilities involving banal points (points distinct from endpoints) both for a primitive u and a primitive v, further works should be done.

From a series of observations, Wismath highligthed in [START_REF] Wismath | Computing the full visibility graph of a set of line segments[END_REF] the configuration around P e from V P oly(P e) which permits to fully define the set's visibility graph of n non-intersecting line segments.

Given three points of V P oly(P e), saying q u , q a , q b such as q u P e q a < π and q u P e q b > π. If points q a and q b have a corresponding primitive v, then we can report the primitive u, corresponding to q u , and v are visible around P e. Indeed a perception can be issued from q u from either q a q u P e or P e q u q b , no matter the position of P e (the other endpoint of the primitive i). Such case is illustrated by the figure 2.

However, due to the management of colinear and equal points, the procedure should include a verification step. We have to check that no radial primitive hides the perception issued from q u . For example, if a primitive whom extremities are Similar approaches are reported in the litterature ( [START_REF] Saund | Finding perceptually closed paths in sketches and drawings[END_REF][START_REF] Zuwala | Une méthode de localisation et de reconnaissance de symboles sans connaissance a priori[END_REF]) from a junction graph whose nodes are the segments and edges specify the connexity (which may be inexact in some cases). The goodness measure to be optimized is based on a compactness measure, and possibly, on other criteria that figure the endpoint distance or the degree to which one end of the curve extends beyond the other. Regarding the compactness measure, this property is estimated from a ratio of area of the region bounded by the curve to the area of an approximated shape of the curve, the bounding box in [START_REF] Zuwala | Une méthode de localisation et de reconnaissance de symboles sans connaissance a priori[END_REF], the convex hull in [START_REF] Saund | Finding perceptually closed paths in sketches and drawings[END_REF]. Nervertheless, the curves defining a symbol are not strictly compact and may contain concavities.

Here, we adopt a measure of goodness issued from the visibility relations extracted beforehand. Let s be a seed curve, c a clique to be merged and L the operator that enumerates the primitives collected in a set. If L(s) ∩ L(c) = ∅ then the measure of goodness is defined as follows :

goodness(s ∪ c) = 1 - i∈Conf (s,c) length(i) i∈L(s)∩L(c) length(i) (1)
where Conf (s, c) enumerates the primitive of L(s) ∩ L(c) that are conflicting, i.e. a primitive both viewing a primitive l at the left hand side in s [respectively in c] and a primitive r at the right hand side in c [respectively in s].

As an example, we report in the figure 3 the measures of goodness for 3 candidate fusions. The third one is clearly discarded since the primitive shared by the seed curve and the clique is conflictive. On the other hand, the impact of the conflictive primitives for the two other fusions is null. Thus, the fusion's measure of goodness tends to 0 if primitives shared by the seed curve and the clique are in conflicting uses; tends to 1 otherwise. 4 Symbol detection

Region of interest

Symbol spotting consists in localizing possible symbols in complex drawings without necessarily recognizing the symbols themselves, and especially, segmenting them. Such an approach aims to select regions of interest from a similarity measure of two descriptors, and to a certain extend, restrict the possible classes of symbols. Then, a more computational expensive process can be considered for the recognition. Without any a priori knowledge on the orientation and size of the objects to be found, dynamic framing windows are constructed in [START_REF] Rusiñol | Symbol spotting in technical drawings using vectorial signatures[END_REF] from vector data to get a vectorial signature.

Here, we investigate an indexing procedure of the curves issued from the visibility graph's analysis. In [START_REF] Huet | Line pattern retrieval using relational histograms[END_REF], a compact shape representation is presented for retrieving line-patterns from large databases. A relational histograms is built from edges of a neighborhood graph. The resulting descriptor includes relative angle and length ratio attributes. Once a curve within the host VFG is found to be similar to ones of the VFG of at least one symbol's model, the recognition process of such symbol(s) is triggered.

Extending partial matching

Template matching techniques are rarely used for symbol recognition when dealing with unsegmented and distorted symbols. In [START_REF] Parker | Vector templates for symbol recognition[END_REF][START_REF] Valveny | Hand-drawn symbol recognition in graphic documents using deformable template matching and a bayesian framework[END_REF], the efficiency of such a technique is reported regarding identification from flexible frameworks based on symbols' vector representation.

Given a template as an hypothesis and an estimated affine transformation, the template made of vectorial primitives is fitted to the data. Various measures, e.g. distance transform in [START_REF] Parker | Vector templates for symbol recognition[END_REF], can then be considered to characterize the accuracy of the involved sumbol's class. In [START_REF] Valveny | Hand-drawn symbol recognition in graphic documents using deformable template matching and a bayesian framework[END_REF], the template can also be distorted during matching, adapting iterately the component's local parameters of the template trough the EM algorithm.

In [START_REF] Lladós | Symbol recognition by error-tolerant subgraph matching between region adjacency graphs[END_REF], an error-tolerant subgraph isomorphism algorithm has been proposed for symbol recognition. The underlying representation during the matching process is an attributed cyclic string corresponding to the external polygonalized boundaries of a region adjacency (sub)graph. A branch and bound approach is driven by boundaries substrings' attributes specified within the model graphs. This growing string approach is suitable for region adjacency graph but the latter is not enough expressive as (i.) it does not permit to model multi-component symbols and (ii.) it only relies on boundaries of loops.

Edit distance is very effective for string, tree and graph based representations provided that the edit operation costs can be determined [START_REF] Neuhaus | Self-organizing maps for learning the edit costs in graph matching[END_REF]. Edit operations usually concern substitution, insertion and deletion but can be extended to merging or splitting to handle distortions.

Our basic idea to extend the growing string matching proposed by Lladós et al. is to let the algorithm searching for any closed curve (a region) or nearly closed curve which is visible to curves that belong to the partial matching. Nevertheless, cyclic string are initially employed by Lladós et al to solve the problem of the starting symbol of a closed boundary and to obtain a representation that is invariant under rotation. Managing both closed and nearly closed curves, the use of such an approach make us introduce some virtual segments to fill the gaps of fragmented curves. We always get closed boundaries which can be represented by cyclic strings. Moreover, the full visibility graph of curves falls into a region adjacency graph and the growing string is fully relevant.

The string matching has been also reformulated to take into account both line segments and circular arcs issued from the vectorization process. Indeed, despite the full visibility graph extraction process is described for a segments' set, we can use the arcs of circle initially found during the vectorisation step replacing the list of connected segments by the corresponding arcs. Figure 4 illustrates the alignement of two strings, namely a segment s and an arc a. The initial substitution cost c(s → a) is thus modified to introduce a repulsive part that is proportional to the inscribed angle. Two facts that motivate our approach should be noticed. First, we do not work on the junction graph since the seek for nearly closed curve cannot safely be achieved while working on it: junction can be missing, leading to a single fragment instead of a junction involving three fragments for example. Moreover, we do not use a distance based approach to define the relation between couple of primitives since it suggests to introduce a priori some thresholds which is a tedious task and even impractical for heterogeneous document images. Finally, the perceptually closed curves should be relevant enough to spot symbols within complex document. There, the indexing procedure allows to quickly find similar curves' couple and to trigger error-tolerant subgraph isomorphism detection. We are not able to evaluate the performance of this system either for identification or localization since this paper describes a work in process. Such elements will be provided during the workshop.

Fig. 1 .Algorithm 1

 11 Fig. 1. Set of primitives and its Full Visibility Graph. Segments are separated from each other for clarity.

Fig. 2 .

 2 Fig. 2. Visibility polygon of the point Pe -from qu, the primitive corresponding to qa and q b is visible due to the absence of any radial primitive such as [Pe q5] (see text).

Fig. 3 .

 3 Fig. 3. (a): seed curve (fragmented) ; (b), (c) and (d): Possible fusions and their measure of goodness. A red segment denotes a conflictive primitive contrary to blue segment.

Fig. 4 .

 4 Fig. 4. Alignement of a line segment s and a circular arc a during attributed string edit distance (and the obtained mean primitive)

q 5 and P e is added to the initial set of primitives, visibility must not be created from the tuple (q u , q a , q b ) = (q 2 , q 8 , q 9 ) considering the notations of the figure 2.

Identifying perceptually closed curves

The Gestalt laws of perception (e.g. proximity, smooth continuation, closure) seem to depict the perceptual phenomena exploited by the human vision system. As the Saund's paper ( [START_REF] Saund | Finding perceptually closed paths in sketches and drawings[END_REF]) reads, a visual system will take advantage of a detection of closed or nearly closed curves. Coherent objects, such as the symbols used in technical drawing domains, tend to be spatially compact and relatively uniform in surface appearence with respect to the surrounding background.

In this work, we adopt the famous framework that consists in starting from seed curve fragments and trying to extend it by tracing from one clique to another with which it is associated by at least one shared primitive. The key problem is to determine whether a new clique can be merged or not since primitives have not beforehand been clustered within a single partition.


Anne-Lise Fevre-Gautier

Antoine Beylot

Stéphane Vaxelaire

teaching and research institutions in France or abroad, or from public or private research centers.

Developments in Social Life Cycle Assessment (S-LCA) for Life Cycle Sustainability Assessment (LCSA)application to the construction and demolition sector in France

Anne-Lise Gautier 1 , Antoine Beylot 1 , Stéphane Vaxelaire A sustainabilityLCA framework was designed, built on environmental and social LCA methodologies to assess the environmental and social efficiency of such construction projects. It wasapplied to the case study to compare its global performance with a similar case which would have been conducted in "business as usual" conditions.An environmental LCA was conducted,based on existing international standards. At the same time,a S-LCA methodology was developedon the basis of UNEP-SETAC Guidelines and applied to the French sector of building and construction, to assess social impacts supported by the system's stakeholders.

Results showeda high contribution of natural mineral resources use in the total environmental impact, due to extraction and transportation. It was also demonstrated that the energy necessary forasphalt production was much higher than the one for itsimplementation. Environmental impacts are thus highly dependent on asphalt production and natural mineral resources' quantities and origin. Regarding social impacts, specific impacts categories, indicators and data were searched for and an impacts screening was conducted. Based on sectorial data, itfocuseson two stakeholders' categories:workers and local communities. Final results highlight the fact that S-LCA needs strong methodological developments to address intraEurope comparative case-studies and to produce methodologies for system definition, data inventory, impacts characterization, reference databases and indicators.

  Troyes, the Industrial Ecology Club (guild) of Aube and Eiffage (French public works firm).The projectis based on a specific case-study concerning the construction of a part of the ring road of Troyes city (Aube, France) where alternative construction materials and techniques,such as secondary raw materials and local natural resources,have been used.

	1
	1 BRGM, 3 av. C. Guillemin, 45060 Orleans, France
	E-mail contact: al.gautier@brgm.fr
	The results of a project aiming at developing a methodology for sustainability analysis dedicated
	toinfrastructures and buildings construction projects will be presented.Thisresearch project was carried
	outin collaboration with ADEME (French agency of environment and energy control), University of
	technology of