PhD, MPH Maria Lahuerta

MD, MPH Meritxell Sabidó

Federica Giardina

BSc Gabriela Hernández

MD Juan Fernando Palacios

MD Rudy Ortiz

Victor Hugo Fernández

MD Jordi Casabona

The Uale

Bmath

Meng

Bec Victor Hugo Fernández

Comparison of users of an HIV/syphilis screening community-based mobile van and traditional voluntary counselling and testing sites in Guatemala

Keywords: mobile van, Guatemala, HIV, syphilis, rapid tests

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Early identification of HIV and sexually transmitted infections (STI) not only results in earlier treatment initiation and reduced morbidity but also decreases further infection transmission. Most voluntary, counselling and testing (VCT) services are usually offered by traditional publicly funded HIV/STI clinics and community-based services. However, outreach programmes such as mobile vans (MV) clinics for HIV/STI screening have proven to be an effective service in reaching at-risk populations, including female sex workers (FSWs), men who have sex with men (MSM) and injection drug users (IDUs) [START_REF] Difranceisco | HIV seropositivity rates in outreach-based counseling and testing services: program evaluation[END_REF][START_REF] Ellen | Comparison of clients of a mobile health van and a traditional STD clinic[END_REF][START_REF] Reisner | Differential HIV risk behavior among men who have sex with men seeking health-related mobile van services at diverse gay-specific venues[END_REF], offering them VCT in convenient locations. In addition, the uptake of HIV testing increases four-fold when VCT is provided in community-based settings, highlighting the potential to reduce testing barriers such as stigma [START_REF] Arlington | NIMH Project Accept/HPTN 043: a Phase III randomized controlled trial of community mobilization, mobile testing, same-day results and post-test support for HIV in sub-Saharan Africa and Thailand[END_REF][START_REF] Khumalo-Sakutukwa | Project Accept (HPTN 043): a community-based intervention to reduce HIV incidence in populations at risk for HIV in sub-Saharan Africa and Thailand[END_REF][START_REF] Samayoa | Does HIV VCT Reduce Risk Behaviors? An Observational Study in Guatemala City[END_REF]. Furthermore, recent evidence has shown that the use of rapid tests might enhance the effectiveness of MV clinics, increasing significantly the proportion of patients receiving their results and post-counselling [START_REF] Benzaken | Field evaluation of the performance and testing costs of a rapid point-of-care test for syphilis in a red-light district of Manaus, Brazil[END_REF][START_REF] De La Fuente | Increasing Early Diagnosis of HIV through Rapid Testing in a Street Outreach Program in Spain[END_REF][START_REF] Guenter | Rapid point-of-care HIV testing in community-based anonymous testing program: a valuable alternative to conventional testing[END_REF][START_REF] Liang | Rapid HIV testing of clients of a mobile STD/HIV clinic[END_REF].

Several studies have found differences in demographic, behavioural and clinical characteristics between clients seen in traditional HIV/STI clinics and those seen at a MV HIV/STI clinic [START_REF] Difranceisco | HIV seropositivity rates in outreach-based counseling and testing services: program evaluation[END_REF][START_REF] Ellen | Comparison of clients of a mobile health van and a traditional STD clinic[END_REF][START_REF] Reisner | Differential HIV risk behavior among men who have sex with men seeking health-related mobile van services at diverse gay-specific venues[END_REF]. Studies conducted in urban populations of the United States have observed that mobile clinic clients were more likely to be diagnosed with HIV [START_REF] Ellen | Comparison of clients of a mobile health van and a traditional STD clinic[END_REF] and that "high-risk" clients (including MSM and IDUs) were more likely to seek care in non-traditional outreach settings (1). Reisner et al. observed that MSM accessing MV services in Massachusetts, USA had higher HIVrelated risk behaviours [START_REF] Reisner | Differential HIV risk behavior among men who have sex with men seeking health-related mobile van services at diverse gay-specific venues[END_REF]. However, there is little information on the effectiveness of MV HIV/STI clinics in identifying HIV and STIs among at-risk population in developing countries, in particular in Central America.

Guatemala currently has a concentrated HIV epidemic, with less than 1% in the general population and high HIV prevalence in at-risk groups [START_REF]AIDS epidemic update[END_REF]. In the past years, efforts have been made to expand VCT services across the country, with the number of facilities providing HIV counselling and testing increasing from 41 in 2007 to 183 at the end of 2008 [START_REF]Towards Universal Access: Scaling Up Priority HIV/AIDS Interventions in the Health Sector[END_REF]. Despite this, HIV testing is still conducted largely in client-initiated testing sites and outreach programmes are still scarce [START_REF] Cohen | HIV/AIDS: Latin America & Caribbean. Guatemala: struggling to deliver on promises and assess HIV's spread[END_REF], resulting in missed HIV/STI prevention opportunities, especially for hard-to-reach populations such as FSW and MSM that might not seek care at traditional VCT clinics. A study about reproductive healthcare perceptions and needs among FSWs in Guatemala found that most of them were reluctant to attend public health care centres due to the stigmatizing nature of service provision and the discriminatory attitudes of the health personnel [START_REF] Porras | Reproductive health and healthcare among sex workers in Escuintla, Guatemala[END_REF].

To address the effectiveness of MV services in identifying cases of HIV and STIs and contribute to infection control efforts, we aimed to compare HIV and syphilis prevalence and risk behaviour characteristics between subjects tested at the MV and those tested at the traditional VCT service offered at 3 STI clinics in Escuintla, Guatemala.

METHODS

Study setting and population

In 2005 the Fundació Sida i Societat, a non-profit organization that specializes in providing STI and HIV prevention and care services in resource-constrained settings, in collaboration with the Ministry of Health of Guatemala implemented the UALE Project (UALE means 'be in health' in Latin), a multilevel intervention whose overall aim is to prevent and control HIV/STI particularly among vulnerable groups in Guatemala [START_REF] Sabidó | The UALE Project: decline in the incidence of HIV and sexually transmitted infections and increase in the use of condoms among sex workers in Guatemala[END_REF]. The UALE project includes 3 STI clinics located within the community health care centers of 3 municipalities of the Escuintla province (Escuintla provincial capital, Santa Lucia Cotzumalguapa, and Puerto de San José), which has one of the highest HIV prevalence of Guatemalan provinces [START_REF]Plan Estratégico Nacional ITS/VIH/SIDA 2006-2010[END_REF]. This might be related to elevated population mobility through the Pacific Road, the traffic of irregular migrants and illegal drugs, as well as the widespread sex work. All 3 clinics offer HIV and syphilis counselling and testing on a voluntary and anonymous basis from 8:30 to 16:00, uninterrupted.

In 2006, a community-based MV offering a VCT service with HIV and syphilis rapid tests was implemented to target hard-to-reach population in the municipalities where the STI clinics were located and in 10 other municipalities characterized by a high number of commercial sex venues.

To establish the operational frame of the MV, we used the community mapping of commercial sex venues and sites frequented by MSM and transgenders (TG) already completed by the UALE project in each municipality. Experienced health educators visited bars, brothels, MSM hair salons, and streets where sex workers met clients to obtain the permission of their owners/managers. None of them refused the MV service provision. The MV offered the VCT service once every two weeks in a different site of each municipality. Subjects were recruited from February 2006 to May 2009. We defined FSW as women who reported having sex in exchange for money during the last 12 months. The MSM/TG group was defined as men who self-identified as homosexuals or who reported having sex with penetration with a same sex partner during the last 12 months, including male sex workers (MSW). Those who did not meet any of the previous criteria were considered people who do not report being a member of a risk group, from now on referred to as the "not-reporting" (NR) group.

Counselling and testing

The procedures were similar in both settings. After obtaining written informed consent from participants, trained health educators conducted pre-test HIV counselling and collected data on sociodemographic characteristics, personal risk behaviours, HIV testing history and reasons for testing by means of a structure questionnaire. Educational material on HIV/STI and condoms were available in both settings.

Samples were collected by a practitioner nurse, who also performed both the HIV and syphilis testing by fingerprick. HIV testing was done using the Determine HIV-1/2 rapid test (Abbott Laboratories, Tokyo, Japan) and participants received their results within 15 minutes. Venipuncture blood was drawn from participants with a reactive HIV rapid test result, who were post-test counselled as preliminary positive, and were asked to return to the STI clinic or to the MV testing place after 7 days to receive their confirmatory test result and counselling by the same heath educator. All reactive samples were confirmed by enzyme-linked immuno-sorbent assay (ELISA) using Bioelisa HIV-1+2 (Biokit, Lliçà d'Amunt, Spain). Those participants with a positive Determine HIV-1/2 rapid test that did not return for their results were actively traced. Subjects with a positive confirmatory test were referred and accompanied by a community health worker to the HIV referral hospital for enrolment into the care and treatment programme.

Syphilis testing was performed using the Determine Syphilis rapid test (Abbott Laboratories, Tokyo, Japan). Participants with a reactive syphilis rapid test were referred to the STI clinic for confirmatory testing using Treponema pallidum hemagglutination test (Immutrep TPHA; Omega Diagnostics Ltd, Ontario, Canada) and the Venereal Infections Research Laboratory test (VDRL; Murex Biotech Limited, Dartford, United Kingdom). Due to the high probability of syphilis reinfection, treatment was administered when the rapid treponema test was reactive to minimize loss of follow-up as well as to stop the transmission chain.

Data analysis

The analysis was restricted to participants who were at least 15 years old and to the baseline visit, regardless of the testing site. Data was analyzed using STATA version 10.0 (StataCorp, College Station, TX) and described using frequencies, medians and interquartile ranges (IQR).

Sociodemographic and behavioural characteristics and HIV/syphilis prevalence of each subpopulation between the STI clinics and the MV were compared using the Chi-square test or Fisher's exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. Within each sub-group, the prevalence of HIV over time was determined using the Mantel-Haenszel test for trend. This analysis was included in the general IRB of the UALE project, that was approved by the Hospital Germans Trias i Pujol Ethics Review Committee, and had the support of the Guatemalan Ministry of Health and the Escuintla Department of Health.

RESULTS

Subjects' Characteristics

From February 2006 to May 2009, 2,874 subjects (≥15 years old) were tested for HIV and syphilis (MV: 1,336 (46%) vs. STI clinics: 1,538 (54%)). Only 125 (4%) had more than one visit and subsequent visits were excluded from the analysis. A mean of 80 subjects received VCT per month (43 people at the clinics and 37 at the mobile van).

The socio-demographic characteristics of subjects included in the analysis are described in Table 1. The median age of the NR tested at the MV was slightly older than those tested in the traditional clinics (29.6 vs. 28.3 years, p-value=0.007), and the proportion of females tested in the MV was also significantly higher (MV:62% vs. STI clinics:55%, p-value=0.005). The MSM/TG group included 28 (5%) transgenders and 123 (23%) male sex workers (which included 9 transgenders). Among NR, subjects tested in the MV were significantly more likely to report that they took the test to know their health status (MV:98% vs. STI clinics:94%, p-value<0.001), although less likely to report that the partner asked them to take the test (MV:1% vs. STI clinics:3%, p-value=0.001). Overall, 1,136 (40%) had ever been tested for HIV. MSM/TG (including male sex workers) seen at the MV clinic were significantly less likely to have had a prior HIV test in the past than MSM/TG seen at the STI clinics (21% vs. 41%, p-value<0.001).

Almost 24% of FSW were from a country other than Guatemala (mainly from El Salvador and Honduras), and this proportion was similar in both settings.

HIV and syphilis prevalence

The MV screened 29% (513/1,746) of the NR, 73% (385/529) of the MSM/TG and 73% (438/599) of the FSW, and detected 19% (27/140) of HIV and 69% (25/36) of syphilis cases (Table 2). HIV prevalence was significantly higher at the STI clinics for NR (MV:1% vs. STI clinics:7%, p-value<0.001) and MSM/TG (MV:1% vs. STI clinics:8%, p-value<0.001). Among MSM/TG, the HIV prevalence was similar in the three subgroups (MSM:3% , TG:4%, MSW:3%) (data not shown). Syphilis prevalence was similar between the MV and the clinics for NR and MSM/TG. The 2 cases of syphilis in the MSM/TG were MSM who were not TG nor MSW.

Although not significant, syphilis rates among FSW tested in MV tended to be slightly higher (MV: 5% vs. STI clinics:2%, p-value=0.128). Five participants were co-infected with HIV and syphilis.

The proportion of patients with a reactive HIV rapid test who returned for their confirmatory results was lower in the MV than in the STI clinics (MV:42% vs. STI clinics:65%, p-value<0.001).

Nevertheless, all of them were post-counselled as preliminary positive the day they undertook the rapid HIV test and those who did not come back for their confirmatory result were actively traced.

From 2006 to 2008, HIV prevalence at the clinics reduced significantly for NR and MSM/TG (NR: 18% vs. 6%, p-value<0.001, test for linear trend); MSM/TG: 25% vs. 5%, p-value=0.06, test for linear trend), while no statistically significant difference was observed across time in the MV (data not shown).

Risk behaviours

HIV-related risk behaviours are displayed in Table 2. NR tested at the MV were less likely to report having had sex with a FSW (MV:11% vs. STI:17%, p-value=0.009) or with multiple partners (MV:5% vs. STI:12%, p-value<0.001). MSM/TG tested at the MV were more likely to report having sex with a bisexual partner (MV:53% vs. STI:34%, p-value<0.001), although the proportion reporting other risk behaviours were similar in both groups. A substantial proportion of MSM/TG reported having had sex in exchange of money or drugs in the past 12 months (MV:25% vs. STI:19%, p-value=0.134), although the HIV and syphilis prevalence of this subgroup were similar to the overall MSM/TG group (data not shown). Finally, FSWs tested in the MV were more likely to report having had sex with multiple partners (MV:47% vs. STI:33%, p-value=0.003), as well as more likely to have used a condom at their last sexual intercourse (MV:78% vs. STI:68%, p-value=0.021).

DISCUSSION

Our findings confirm significant differences in HIV and syphilis prevalence and risk behaviour characteristics between mobile clinic users and traditional STI clinic users in Escuintla, Guatemala. Contrary to our initial hypothesis, HIV prevalence was statistically significantly higher in the STI clinics for both the NR and MSM/TG, suggesting that the traditional VCT did effectively identified high-risk subjects. Nonetheless, the MV was successful in diagnosing new cases of HIV and syphilis and increasing access to at-risk populations such as MSM/TG and FSW. Our results are contrary to those found by Ellen et al. [START_REF] Ellen | Comparison of clients of a mobile health van and a traditional STD clinic[END_REF] in Baltimore, USA, although the context of our study was considerably different and they did not stratify by population group. In fact, their MV group had a higher percentage of at-risk subjects (FSWs and IDUs), which could explain the higher prevalence of HIV in this group. The higher HIV rates observed in the STI clinics among people who do not report being a member of a risk group could be explained in part by high-risk subjects seeking HIV screening earlier than others, as suggests the higher proportion of men attending the clinics who have sex with sex workers and who had multiple sexual partners during the last 12 months. Because seeking HIV testing is a voluntary decision, data from the VCT service located in the STI clinic is particularly prone to participation bias, and therefore HIV prevalence in the STI clinic will result in an overestimation of the prevalence in this group. Although Escuintla province has one of the highest HIV prevalence in Guatemala, ( 16), the overall HIV prevalence in people who do not report any risk behaviours is much higher than expected (5% compared to the national estimate of 0.8% ( 18)).

With regards to MSM/TG, our findings are consistent with those observed by Bailey et al. [START_REF] Bailey | Community HIV testing for men who have sex with men: results of a pilot project and comparison of service users with those testing in genitourinary medicine clinics[END_REF], where HIV prevalence was higher at the STI clinics. Despite the low level of risk behaviours reported by MSM tested in the STI clinics, they showed higher HIV rates, reported lower condom use and were twice as likely to have had a prior HIV test than those tested in the MV, which suggests they might perceive themselves at risk of infection. Moreover, a salient proportion of MSM/TG in our study performed sex work, but their HIV and syphilis prevalence were similar to those who did not. The overall HIV prevalence for MSM was 5.5%, much lower than the 12% that Soto et al. found in Guatemala City [START_REF] Soto | Sentinel surveillance of sexually transmitted infections/HIV and risk behaviors in vulnerable populations in 5 Central American countries[END_REF]. The MV provided HIV testing and counselling services to a group of MSM/TG who continue to face obstacles in accessing essential VIH prevention, treatment, and care services, since 80% of those seen at the MV were being tested for HIV for the first time. In fact, most of the MSM/TG were tested at the MV, indicating that MV does indeed increase access and choice for this population seeking tested for HIV and syphilis as previously described [START_REF] Bailey | Community HIV testing for men who have sex with men: results of a pilot project and comparison of service users with those testing in genitourinary medicine clinics[END_REF]. No significant differences in HIV prevalence were observed among FSWs and the overall 4% prevalence was similar to what has been described elsewhere [START_REF]Report on the Global AIDS Epidemic[END_REF][START_REF] Soto | Sentinel surveillance of sexually transmitted infections/HIV and risk behaviors in vulnerable populations in 5 Central American countries[END_REF]. FSWs tested in the MV reported higher HIV-related risk behaviour but significantly higher proportion of condom use during the last sexual intercourse. Overall, condom use for FSWs was considerably high (68%).

Whether the high condom use among FSW in this study is related to the UALE project needs further evaluation but the project has shown a significant reduction of the STI and HIV incidence among FSWs attending the STI clinic as well as an increase in condom use with clients [START_REF] Sabidó | The UALE Project: decline in the incidence of HIV and sexually transmitted infections and increase in the use of condoms among sex workers in Guatemala[END_REF].

In Latin American and Caribbean countries, the proportion of FSWs and MSM who know their HIV status from a recent test is 66% and 34% respectively [START_REF]Towards Universal Access: Scaling Up Priority HIV/AIDS Interventions in the Health Sector[END_REF], which is similar to the percentage observed in our study. In the three populations, the main reason for testing was to know their health status while the proportion that tested because they perceived themselves to be at risk for HIV/STI was considerably low. Taking into account the low proportion of subjects that used a condom at their last sexual intercourse (especially NR and MSM/TG), the low risk-perception reported in this study provides evidence of one of the main barriers to behavioural change that would lead to safer conducts and lower HIV/STI prevalence.

A unique aspect of the mobile van is that it allows HIV/STI control programmes to be spatially and temporally targeted. The MV service identified more than two-thirds of the new syphilis cases (mostly in FSWs), suggesting the potential of this innovative service. The high prevalence of syphilis in the FSW group tested in the MV could be due to a higher proportion of street-based FSW in the MV compared to the traditional clinic. Contrary to off-street FSWs, street-based FSWs are not required to visit the health clinic periodically to obtain a health stamp in their health card (which includes a medical examination and HIV/STI testing) [START_REF] Sabidó | The UALE Project: decline in the incidence of HIV and sexually transmitted infections and increase in the use of condoms among sex workers in Guatemala[END_REF], and are more reluctant to attend the health centre for examination of STIs [START_REF] Porras | Reproductive health and healthcare among sex workers in Escuintla, Guatemala[END_REF]. One of the limitations was possible misclassification of high-risk subjects, which could have led to include MSM who do not self-identify as homosexuals or did not disclose their sexual orientation in the NR group. To minimize this bias, the health workers had extensive experience working with vulnerable groups and ensured high levels of confidentiality. A second limitation was the need to confirm the reactive rapid tests, which might have led to loss of follow-up. In fact, one of the limitations of outreach programmes is the difficulty of ensuring that HIV-positive patients actually access the health system. In our study, all patients with a reactive HIV rapid test were post-counselled as preliminary positive and an active case finding programme was implemented for those confirmed HIV-positive patients that did not return for their results. Finally, the cost of the MV was reasonable and affordable for resource-constraint budgets but studies about its costeffectiveness are still scarce [START_REF] Shrestha | Cost-effectiveness of finding new HIV diagnoses using rapid HIV testing in community-based organizations[END_REF].

The high HIV prevalence observed in the three groups combined with reported low condom use and low perception risk highlight the need to expand current HIV prevention and treatment programmes in the country. Our findings provide evidence of the success of STI clinics in identifying new cases of HIV among at risk population as well as emphasizing the benefits of using innovative approaches such as MV that contribute to increasing access to hard-to-reach groups.

KEY MESSAGES

• HIV prevalence was statistically significantly higher in the STI clinics for both NR and MSM/TG, suggesting that the traditional VCT did effectively identified high-risk subjects.

• The mobile van was successful in diagnosing new cases of HIV and syphilis and increasing access to at-risk populations such as MSM/TG and FSW.

• People who do not report being member of a risk group had higher than expected HIV prevalence and any other BMJPGL products and sub-licences such use and exploit all subsidiary rights, as set out in our licence http://sti.bmjjournals.com/ifora/licence.pdf).

Table 1.

Comparison of sociodemographic characteristics and reason for testing between 1,336 mobile van users and 1,538 traditional clinic users by type of population (people who do not report being a member of a risk group, men that have sex with men and female sex workers) in the province of Escuintla, Guatemala.

People

who do not report being

		member of a risk group (NR) N=1,746	a	Men who have sex with men and transgenders (MSM/TG) N=529	Female sex workers (FSW) N=599
		Mobile van	Traditional			Mobile van	Traditional		Mobile van	Traditional
		clinic	clinic	p-value	clinic	clinic	p-value	clinic	Clinic	p-value
		N=513	N=1,233			N=385	N=144		N=438	N=161
		(29%)	(71%)			(73%)	(27%)		(73%)	(27%)
	Age (median [IQR])	29.6 [23.4-38.4]	28.3 [22.2-36.5]	0.007 a *	23.8 [20.0-29.7]	22.4 [19.7-30.0]	0.236 a	28.5 [22.4-34.3]	28.8 [23.6-35.3]	0.366 a
	Sex
	Male	194 (37.8)	556 (45.1)	0.005*	362 (94.0)	139 (96.5)	0.253	-	-	0.294 b
	Female	319 (62.2)	677 (54.9)			-	-		438 (100)	161 (100)
	Transexual	0 (0)	0 (0)			23 (6.0)	5 (3.5)		-	-
	Country of origin other than Guatemala c	5 (1.0)	25 (2.0)	0.123	8 (2.1)	7 (4.9)	0.086	103 (23.5)	38 (23.6)	0.950
	Ethnic group indigenous	27 (5.3)	48 (3.9)	0.198	11 (2.9)	6 (4.2)	0.447	18 (4.1)	9 (5.6)	0.429
	Reasons for testing
	Perceive themselves at risk for HIV	5 (1.0)	23 (1.9)	0.213 b	16 (4.2)	6 (4.2)	0.996	3 (0.7)	1 (0.6)	1.000 b
	To know their health status	504 (98.3)	1,153 (93.5)	<0.001*	373 (96.9)	139 (96.5)	0.837	388 (88.7)	138 (85.7)	0.326
	Partner asked them to take the test	3 (0.6)	37 (3.0)	0.001 b*	6 (1.6)	3 (2.1)	0.710 b	0 (0)	0 (0)	_
	Report symptoms	0 (0)	26 (2.1)	-		0 (0)	1 (0.7)	0.272 b	0 (0)	0 (0)	_
	Reported prior HIV test in the past	166 (32.4)	389 (31.6)	0.741	81 (21.0)	61 (42.4)	<0.001*	322 (73.5)	117 (72.7)	0.889
	Values are n(%) and p-value is from Chi-square test unless otherwise indicated.
	a: p-value from the Wilcoxon test

b: p-value from the Fisher's exact test c: El Salvador, Honduras and other Central American countries * p-value <0.05

Table 2 .

 2 Comparison of HIV/syphilis prevalence and risk behaviors between 1,336 mobile van users and 1,538 traditional clinic users by type of population (people who do not report being a member of a risk group, men that have sex with men and female sex workers) in the province of Escuintla, Guatemala.Values are n(%). P-value is from Chi-square test unless otherwise indicated. a: P-value from the Fisher's exact test. b: Operational definition of client of a sex worker. c: Bisexual partner defined as those who engage in sexual relationships with both men and women. * p-value <0.05

			People who do not report being a member of a risk group (NR) N=1,746	Men who have sex with men and transgenders (MSM/TG) N=529	Female sex workers (FSW) N=599
			Mobile	Traditional		Mobile van	Traditional		Mobile	Traditional
			van clinic	clinic	p-value	clinic	clinic	p-value	van clinic	Clinic	p-value
			N=513	N=1,233		N=385	N=144		N=438	N=161
			(29%)	(71%)		(73%)	(27%)		(73%)	(27%)
	Test results
	HIV prevalence		6 (1.2)	91 (7.4)	<0.001*	3 (0.8)	12 (8.4)	<0.001*	17 (3.9)	10 (6.3)	0.265
	Syphilis prevalence		4 (0.8)	7 (0.6)	0.743 a	0 (0)	2 (1.4)	-	20 (4.6)	2 (1.3)	0.128 a
	Sexual risk behaviors, last 12 months
	Sex with a sex worker	b	50 (11.2)	146 (16.6)	0.009*	31 (12.7)	24 (19.4)	0.091	NA	NA
	Sex with multiple partners	24 (5.4)	107 (12.3)	<0.001*	108 (38.9)	49 (39.5)	0.899	184 (47.1)	49 (32.7)	0.003*
	Sex in exchange of money or drugs	4 (0.8)	12 (1.0)	1.000 a	96 (25.0)	27 (18.8)	0.134	438 (100)	161 (100)	-
	Sex with bisexual partner c	2 (0.5)	5 (0.6)	1.000 a	163 (52.6)	42 (33.9)	<0.001*	30 (8.5)	5 (3.4)	0.053 a
	Sex with injection drug user	1 (0.2)	1 (0.1)	1.000 a	9 (3.9)	3 (2.4)	0.553 a	16 (4.6)	4 (2.7)	0.338 a
	Condom use at last sexual intercourse	84 (18.9)	151 (17.4)	0.496	122 (47.3)	45 (38.1)	0.097	314 (77.7)	96 (67.6)	0.021*

ACKNOWLEDGMENTS

We would like to thank Asamblea por la Paz, the Centro de Medicina Tropical del Instituto de Salud Carlos III and the Centre d'Estudis Epidemiològics sobre les ITS/HIV/SIDA de Catalunya (CEEISCAT), Institut Català d'Oncologia/Departament de Salut, Generalitat de Catalunya. This project was funded by the Agència Catalana de Cooperació al Desenvolupament, the Agencia Española de Cooperación Internacional al Desarrollo, and the Global Fund to Fight AIDS, Tuberculosis and Malaria.

FUNDING

The project was supported by the Catalan Agency for Cooperation Development, the Spanish Agency for International Development Cooperation, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and Fundació Sida i Societat. The funding agency had no role in the design, conduct, or performance of the study; the analysis or reporting of the data; or the preparation, review, or acceptance of the article.

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in STI

COMPETING INTERESTS

None declared.

CONTRIBUTIONS OF EACH AUTHOR TO THE PROJECT

All authors reviewed and approved the final contents of the manuscripts. In addition, M.L analyzed data and was the main writer of the manuscript; M.S. designed and supervised the overall study and assisted in writing the manuscript; F.G. supervised the analysis and interpretation of the data; G.H supervised sample collection and was responsible for laboratory test for HIV and syphilis; R.O supervised data collection and active case finding.; J.F.P., V.H.F. and J.C provided institutional support for subject recruitment and data collection.

APPENDIX

The UALE Project includes the following: director: Jordi Casabona; executive director: Jaume Font; Ministry of Health in Guatemala: Bianca Rosa Guevara, María Isabel Pedroza, Laura Figueroa; local coordinators: Victor Hugo Fernández, José Ernesto Monzón; medical doctors: Rudy Ortiz, Otoniel Barrios; nurses: Elva Orellana, Irma Mazariegos, Isabel Barrientos, and Leticia Roldan; health educators: Estuardo Cabrera, Kristian Villavicencio, Miguel Meléndez; psicologist: Karla Guzman; microbiologists: Gabriela Hernández, Olga Gálvez, Cristina Cu, Samuel Churuc, Amelia Gerónimo, Xavier Vallès, Victoria González, Christian Alvarez; Statisticians: Federica Giardina; I.T: Mikhail Nikiforov; epidemiologists: Meritxell Sabidó; National AIDS Programme: Mariel Castro; primary health care centre: Maribel Godoy (Santa Lucía Cotzumalguapa), Lucía Gallardo (Puerto de San José), Karina Sazo (Escuintla); data entry: Hugo Felipe; technical support: Fabiola Llanos, Chus Sanz, Mirian Guadalupe Brañas.


Anupma Kumar

Jayashree N Sahni
email: jayashreesahni@yahoo.co.uk

Alexandros N Stangos

Claudio Campa

Simon P Harding

Mrs J Sahni

Consultant Ophthalmologist

Effectiveness of Ranibizumab for Neovascular Age-related Macular Degeneration using Clinician Determined Retreatment Strategy

Keywords:

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Age-related macular degeneration (AMD) is a major cause of visual disability in the developed world. [START_REF] Klein | Prevalence of age-related maculopathy: the Beaver Dam Eye Study[END_REF][START_REF] Vingerling | The prevalence of age-related maculopathy in the Rotterdam study[END_REF] The prevalence of AMD increases significantly with age, with neovascular (nAMD) having the slightly higher prevalence compared to geographic AMD. [START_REF] Bressler | Age-related macular degeneration[END_REF] Each year in the United Kingdom (UK) there are an estimated 26,000 new cases of nAMD. [START_REF]Macular degeneration (age-related)ranibizumab and pegaptanib[END_REF] The introduction of Ranibizumab, [START_REF] Ferrara | Development of Ranibizumab, an antivascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration[END_REF] a recombinant humanised monoclonal antibody fragment that binds and effectively neutralises all active forms of vascular endothelial growth factor (VEGF), has heralded the introduction of a novel treatment of nAMD. However, treatment with anti-VEGF drugs requires regular intravitreal injections, which inevitably results in an increase on the demands of AMD services. The landmark randomised controlled trials, Minimally Classic/Occult Trial of the Anti-Vascular Endothelial Growth Factor Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR), have reported high rates of stabilisation of vision and, for the first time, moderate rates of improvementt irrespective of lesion type. [START_REF] Rosenfeld | Ranibizumab for neovascular agerelated macular degeneration[END_REF][START_REF] Brown | Ranibizumab versus verteporfin for neovascular age-related macular degeneration[END_REF] A subsequent small open label, single centre non-randomised study, the Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with intraOcular Ranibizumab (PrONTO) also showed similar results with fewer number of injections compared to the landmark studies. [START_REF] Fung | An OCT guided, variable dosing regimen with intravitreal Ranibizumab (Lucentis) for neovascular age-related macular degeneration[END_REF] Since its introduction there have been a small number of studies of Ranibizumab in routine clinical practice reporting the efficacy of different dosing regimes of Ranibizumab. [START_REF] Dadgostar | Evaluation of injection frequency and visual acuity outcomes for Ranibizumab monotherapy in exudative agerelated macular degeneration[END_REF][START_REF] Cohen | Results of one-year's treatment with Ranibizumab for exudative age-related macular degeneration in a clinical setting[END_REF][START_REF] Rothenbuehler | Effects of Ranibizumab in patients with subfoveal choroidal neovascularization attributable to age-related macular degeneration[END_REF][START_REF] Michalova | Ranibizumab treatment for neovascular age-related macular degeneration; from randomized trials to clinical practice[END_REF] In the UK, the National Institute for Clinical Excellence (NICE) approved the use of Ranibizumab as treatment for nAMD providing patients met the following criteria: visual acuity 6/12 to 6/96, lesion size ≤12 disc diameter, recent disease progression and recommended treatment to be continued in those who demonstrate adequate response. [START_REF]Macular degeneration (age-related)ranibizumab and pegaptanib[END_REF] Patients with permanent structural damage are excluded. Based on the drug dosing regime presented by the manufacturer to the European Medicines Agency (EMEA) the NICE committee recommended that the majority of patients would require a mean of 8 injections in the first year and 6 injections in the second year in order to maintain vision. Eyes should receive an initial 3 dose initiation phases followed by clinician determined retreatment on a pro re nata (PRN) basis. [START_REF]Lucentis summary for the public: EMEA/H/C/715[END_REF] The aim of our study was to determine if the results achieved in the randomised clinical trials (RCTs), could be translated into routine clinical practice applying the NICE recommendation. We present our 12 months clinical efficacy data of Ranibizumab from a single centre, evaluating best corrected visual acuity (BCVA), contract sensitivity (CS) and optical coherence tomography (OCT) mean central foveal thickness (CFT).

Patient and methods

We prospectively studied consecutive patients with treatment naïve nAMD commencing intravitreal Ranibizumab. Lesion components included were: classic OCT scans were evaluated at every visit for presence or absence of intra-retinal fluid (IRF) and SRF. CFT was noted from the central reading on the map generated by the fast macular thickness protocol of the Stratus OCT (Zeiss, Germany). We evaluated the percentage of patients with CFT > 200 μm at each time point since previous data on healthy eyes using the Stratus OCT (OCT3) has shown the CFT to be approximately 180±20μm. [START_REF] Chan | Normal macular thickness measurements in healthy eyes using stratus optical coherence tomography[END_REF] At these visits patients also had CS measurement on a Pelli-Robson chart at 1 meter with standardised illumination, fluorescein angiography (FA) and slit lamp fundus examination. In the interim visits BCVA, CFT and slit lamp examination were performed. For the purposes of this study we analysed data from baseline, months 3, 6, 9 and 12. Data were collected on number of intravitreal injections and complications. Baseline FAs were reviewed by externally accredited masked graders (Liverpool Reading Centre) to establish lesion characteristics for the purpose of analysis. CNV subtypes were categorised as classic with no occult, predominantly classic with occult, minimally classic without occult, minimally classic with occult, occult no classic and the presence of RAP lesion was also determined.

All patients were treated with monthly intravitreal 0.5mg Ranibizumab for the first 3 months. A set of crtieria were used to inform the retreatment decision making, but these were not prescriptive and the eventual decision to retreat was based on individual clinicans judgement (Table 1). Retreatment with Ranibizumab was considered if there was any deterioration in the signs and symptoms including drop in BCVA (5 to 19 letters from baseline), worsening of intra retinal or subretinal fluid, fresh haemorrhage or extension of lesion on FA. It was recommended that retreatment be avoided if there was no improvement in BCVA, there was persistent unresolving intraretinal and subretinal fluid, evidence of structural damage on OCT or there was an adverse event such as drop in BCVA by >20 letters. CFT reduced from baseline by -100.1µm (± 111.9) (p<0.001).

In this cohort of patients we had one adverse event of raised intraocular pressure which was treated with intravenous acetazolamide and resolved with no secondary vascular occlusion or impact on vision.

Discussion

In this study we have presented our one year data of Ranibizumab for treatment naïve CNV secondary to AMD and RAP lesions from a single tertiary centre.

Mean BCVA improved by 3. to our study but the use of stricter inclusion and re-treatment criteria may have influenced their results. Some of the differences in the re-treatment guidelines between our studies were a) use of sub-RPE fluid on OCT and b) using metamorphopsia on the Amsler grid as indicators for re-treatment, whereas we stopped treatment if there was evidence of persistent IRF or SRF unresponsive to treatment. [START_REF] Rothenbuehler | Effects of Ranibizumab in patients with subfoveal choroidal neovascularization attributable to age-related macular degeneration[END_REF] In comparison to Cohen et al. our favourable result may be partially attributed to the monthly follow-up visits at our centre which effectively results in the better monitoring of disease activity. In other clinical studies visual outcome data has been reported using different vision charts and the use of conversion techniques limit comparison of. [START_REF] Dadgostar | Evaluation of injection frequency and visual acuity outcomes for Ranibizumab monotherapy in exudative agerelated macular degeneration[END_REF][START_REF] Michalova | Ranibizumab treatment for neovascular age-related macular degeneration; from randomized trials to clinical practice[END_REF] In the PrONTO study the mean CFT was 394μm at baseline and 216μm at 12 months. In our cohort mean CFT reduced from 347 (±102) μm to 246 (±107) μm at 12 months. The maximum drop was at the 3 month visit. There was no statistically significant correlation between CFT and BCVA. However, there was a slight increase in the number of patients with CFT >200μm at the 9 month visit corresponding to the drop in vision. CFT was noted from the fast macular thickness map on the Stratus OCT. Errors of retinal boundary and thickness measurements are frequent with the OCT analysis and segmentation algorithms were reported in 92% of eyes in a previous study by Sadda et al. and others. [START_REF] Sadda | Errors in retinal thickness measurements obtained by optical coherence tomography[END_REF] This could have influenced the readings in our study. The scans were reviewed for the presence of IRF, SRF and PED to inform our decision to retreat. This may have resulted in under treatment of the patients at the interim visits when the decision to retreat was based on OCT parameters. OCT scans cannot be used in isolation as predictor of disease activity. As noted in a recent study the resolution of fluid is not always correlated with improvement in vision. [START_REF] Dadgostar | Evaluation of injection frequency and visual acuity outcomes for Ranibizumab monotherapy in exudative agerelated macular degeneration[END_REF] Previous studies have also suggested that leakage on FA may not collect as fluid on OCT

(especially Stratus OCT).[17]

There are some limitations to our study. Presence of co-existing ocular pathology or time to treatment from first diagnosis has not been taken into consideration and may have contributed to our results.

[18] Strict inclusion and exclusion criteria utilised in RCTs cannot be adhered to in routine clinical practise. This inevitably results in differences between the study populations, which may affect the final outcome and limit translation of results achieved in RCTs. However we believe that our results give a good estimate of the efficacy of the protocol we used applicable to routine clinical care as defined in at least one national guideline.

In conclusion, our results show that a 3 monthly treatment initiation phase followed by PRN treatment was associated with rates of stabilisation and maintenance of vision as good as the landmark RCTs. However, this regime achieved in our hands only half of the rates of improvement in vision by 3 lines or more seen in the RCTs. Statistically significant improvements in retinal morphology and improvement in CS were also seen. Guidelines for retreating patients outside RCTs need to be established and further data is required to determine a treatment regime, which provides clinical, economic and practical effectiveness.

  and occult choroidal neovascularisation (CNV), RAP, blood, pigment epithelial detachment (PED), elevated blocked fluorescence, subretinal fluid (SRF). Inclusion criteria were: age > 50 years; baseline best corrected VA ≥ 25 letters; nAMD lesions any component of which extended to within 200µm of the foveal centre ; signs of presumed recent disease progression in cases with occult or minimally classic lesions, as defined by recent loss of vision, new haemorhage and or an increase in lesion size on fluorescein angiography. Ethical approval for the research of clinical effectiveness of Ranibizumab in nAMD was obtained from the Liverpool Research Ethics Committee (LREC ref 02/051). Full refraction protocol BCVA assessment was performed by externally accredited optometrists using the Early Treatment Diabetic Retinopathy Study (EDTRS) chart. BCVA was scored based on the total number of correct letters identified at 2 m plus 15. If the patient read fewer than 20 letters at 2 m, the patient was tested on the top 3 lines at 1 m and the score was the total number of letters read at 2 m plus the total number of letters read at 1 m and recorded at baseline, months 3, 6, 9 and 12.

Table 1 .

 1 Criteria used to guide clinician in re-treatment decision making.

		Consider re-treatment Consider no treatment
	Patient symptoms	Worse	• Better / no change
	BCVA	Between 5 to 19 letter	• < 5 letter loss from
		loss from previous visit	previous visit
		Or
			• ≥ 30 letters lost from
			baseline
	Fresh haemorrhage	Present
	Subretinal fluid	Present	• absent
			• persistent but
			unresponsive to
			previous treatments
	Intraretinal fluid	Present and worsening	• absent
		with drop in BCVA
	Structural damage on		• present
	OCT

In patients with clinical evidence of irreversible damage with no potential benefit from continuing treatment a decision was taken to suspend further intervention.

Statistical analysis of the data was performed using SPSS for Windows version 12.0 (SPSS INC, Chicago, IL, USA). Data analysis was performed using descriptive statistics and paired sample t-test. respectively. Mean BCVA (letters ± SD) baseline for predominantly classic lesion was 52.13 ± 13.02 and 50 ± 12.7 for and minimally classic or occult lesions.


Michael Samarkos
email: msamarkos@gmail.com

Charis Giannopoulou

Eleni Karantoni

Vassileios Papastamopoulos

Ioannis G Baraboutis

Athanassios Skoutelis

Keywords: HIV infections, AIDS, Syphilis, Periostitis

published or not. The documents may come

Syphilitic periostitis in an HIV positive patient

• Syphilitic periostitis usually involves long bones but it can involve the skull as well. There is pain and localized tenderness over the affected bones.

• Syphilitic periostitis can cause diagnostic dilemmas or be confused with other manifestations of syphilis, eg skull periostitis with syphilitic meningitis.

• As the incidence of syphilis is increasing, especially among HIV(+) patients, physicians should have a high index of suspicion to recognize its protean manifestations.

CASE REPORT

A 25 year old Caucasian male presented to the emergency department with a temporalfrontal bilateral headache lasting for a week. His past medical history was unremarkable and he was not taking any medication. The patient was alert, oriented, with normal level of consciousness and vital signs. There was no fever, vomiting or focal neurological signs.

Physical examination revealed a few maculopapular lesions on the soles. Cerebrospinal fluid (CSF) examination at the emergency department revealed mild pleocytosis (30 cells/μl, predominantly lymphocytes), increased protein (100 mg/dl, normal range<50 mg/dl) and normal glucose. Gram and acid-fast stains showed no bacteria, and latex tests for Cryptococcus sp. and Streptococcus pneumoniae were also negative. He was admitted with a working diagnosis of viral meningitis. Complete blood count and serum chemistries were within normal limits. Further testing revealed that the patient was HIV(+) with a CD4 count of 340/μL and a viral load of 44500 copies/ml. Serum non-treponemal and treponemal tests were positive (VDRL=1/8, FTA-ABS=+++), while CSF VDRL was negative. Cerebrospinal fluid PCR for Coxsakie and Echo viruses was negative. Head MRI was unremarkable.

Six months earlier the patient had tested negative for HIV. He could not recall any symptoms or signs suggestive of acute HIV infection or any genital or mouth ulcers in the past few months. However, he reported a high risk sexual contact, approximately six weeks before headache started.

One day after his admission the patient complained of pain on the left hemithorax. On examination there was only tenderness on palpation on the anterior part of the 8th rib.

Chest radiograph was normal. Bone scan however showed increased 99m Tc-MDP uptake , suggestive of periostitis, in the skull and the anterolateral arche of the 7th, 8th and 10th left ribs (Figure 1). Skull plain films were normal. On further questioning the patient reported that he felt that the headache was getting worst by pressure on the skull bones.

We diagnosed secondary syphilis with cutaneous and bone involvement based on the rash, the positive serology and the bone scan findings. Because of the positive serology and the abnormal CSF, neurosyphilis could not be ruled out, therefore intravenous penicillin G, 18 million units daily, was initiated. Five days after initiation of treatment the patient was asymptomatic and he started antiretroviral therapy with abacavir, lamivudine, lopinavir and ritonavir. A follow-up bone scan 3 months after therapy revealed resolution of the rib lesions but persistently abnormal uptake in the skull (Figure 2 -Web only).

DISCUSSION

Skeletal involvement is unusual in early acquired syphilis. It can present as periostitis, arthritis, osteitis or osteomyelitis. Syphilitic periostitis was originally described in 1887 by J.

Hutchinson, as quoted by Roy et al [START_REF] Roy | Acute periostitis in early acquired syphilis[END_REF] . Periostitis in particular is rarely reported. It was reported in only 2 out of 854 patients in an earlier study [START_REF] Mindel | Primary and secondary syphilis, 20 years' experience. 2. Clinical features[END_REF] . Literature on syphilitic periostitis is limited to case reports [START_REF] Coyne | Syphilitic periostitis in a newly diagnosed HIV-positive man[END_REF][START_REF] Denes | Syphilitic periostitis[END_REF] .

During early syphilis spirochetes can hematogenously spread to the periosteoum, Haversian canals and medulary spaces, resulting in periostitis, osteitis or osteomyelitis [START_REF] Ehrlich | Radiographic findings in early acquired syphilis: case report and cirtical review[END_REF] .

Long bones in both arms and legs are usually involved, while skull periostitis is less frequent.

Clinically, there is tenderness over the involved bones, which is sharply localized and may be accompanied by local pitting edema [START_REF] Roy | Acute periostitis in early acquired syphilis[END_REF] . Pain is aggravated during the night 6 and on exposure to heat [START_REF] Roy | Acute periostitis in early acquired syphilis[END_REF] .

In most cases of syphilitic periostitis radiological changes are minimal. When radiologically detectable, periosteal reaction is usually laminated or solid, but can be perpendicular suggesting osteosarcoma. In the skull, soft tissue swelling and wavy periosteal reaction can be found [START_REF] Ehrlich | Radiographic findings in early acquired syphilis: case report and cirtical review[END_REF] . In our patient both plain radiographs as well as MRI of the head were normal. Bone scintigraphy is more sensitive than radiography in early detection of secondary syphilis skeletal lesions, such as syphilitic periostitis and can be useful in the determination of disease extent, in biopsy guiding and in patients' follow up [START_REF] Thakore | Role of bone scintigraphy in the detection of periostitis in secondary syphilis[END_REF] . In our patient the follow-up scan showed that although rib lesions had cleared, skull lesions persisted. A possible explanation for that is that skull lesions were more severe and they would need more time to resolve. Although MRI in our patient did not reveal bone changes, there are reports that MRI can aid to the diagnosis of syphilitic periostitis [START_REF] Naraghi | Magnetic resonance imaging features of osseous manifestations of early acquired syphilis[END_REF] .

The diagnosis of syphilitic periostitis can be difficult if other manifestations of early syphilis, such as genital ulcers and rash, go unnoticed. One of the reasons why syphilitic bone involvement of the skull (e.g. periostitis) can go undiagnosed is because headaches may be attributed to meningeal involvement [START_REF] Davidson | Bone invasion in secondary syphilis[END_REF] . In our patient the presence of skull syphilitic periostitis and HIV seropositivity created a diagnostic dilemma since headache could be attributed to any of syphilitic periostitis of the skull, syphilitic meningitis or HIV associated aseptic meningitis [START_REF] Ghanem | Neurosyphilis in a clinical cohort of HIV-1infected patients[END_REF] .

As the incidence of syphilis is increasing, especially among HIV(+) patients, it is expected that some patients present with unusual manifestations [START_REF] Zetola | Syphilis and HIV infection: an update[END_REF] . Physicians, therefore, should have a high index of suspicion in order to diagnose early these patients.

Figure 1 :

 1 Figure 1: 99m Tc Bone scan showing increased uptake in the skull (panels A and B) and ribs (panel C).

Figure 2 (

 2 Figure 2 (Web only): 99m Tc Bone scan showing increased uptake in the skull but not in the ribs (panels A and B) three months after therapy.

AUTHORS' CONTRIBUTIONS:

M. Samarkos: writing of the manuscript, C. Giannopoulou: imaging studies and literature review, E. Karantoni, care of the patient and literature review, V. Papastamopoulos: care of the patient, manuscript review, I. Baraboutis: writing of the manuscript, A. Skoutelis: Reviewing the manuscript.

COMPETING INTERESTS: None declared.

LICENCE STATEMENT

"The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in STI and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence http://group.bmj.com/products/journals/instructions-for-authors/licence-forms."


Simon Tamayo
email: simon.tamayo@univ-metz.fr

Thibaud Monteiro
email: thibaud.monteiro@loria.fr

Nathalie Sauer
email: nathalie.sauer@univ-metz.fr

Lgipm Ea

DELIVERIES OPTIMIZATION BY EXPLOITING PRODUCTION TRACEABILITY INFORMATION

Keywords: Food traceability, Raw material dispersion, Genetic algorithms, Artificial neural networks, Expert systems, Optimization. 1 0 , max

The recent product traceability requirements, particularly in food production chains, demonstrate an industrial need to improve traceability systems. Having real-time access to traceability information allows its exploitation, which is the aim of this work. In this paper the problem of minimizing the cost of products recall is treated. First the raw material dispersion problem is analyzed, in order to determine a risk level criterion or "production criticality". This criterion is used subsequently to optimize deliveries dispatch with the purpose of minimizing the number of batch recalls in case of crisis. This is achieved by implementing decision-making aid tools based on operational research and artificial intelligence.

INTRODUCTION

Worldwide, recent legislation requirements have appeared concerning food traceability, which now must be established at all stages of production. Therefore traceability solutions have reached an important stage of development. This research is held within the project of designing a deliveries optimization unit, to be adapted to traceability software. The aim of this work is the reduction of the products recall cost, in case of a certain crisis by minimizing the quantity of products to be recalled. The presented work was carried out as a PhD research project in agreement with a software provider company working in the industrial traceability field.

The traceability system in the farming and food supply chain can be described as the documented identification of the operations which leads to the production and sale of a product [START_REF] Bertolini | FMECA approach to product traceability in the food industry[END_REF]. I.e. traceability refers to the capability to trace goods along the distribution chain on a batch number or series number basis. Traceability makes recalls possible, which contributes to food safety in the food industry, it links the information and material flow. The opportunity to connect traceability with the whole documentation and control system represents an effective means of boosting the consumer's perception of food safety and quality [START_REF] Moe | Perspectives on food manufacture[END_REF].

The traceability information treatment assumes great quantity of data as well as an increasing information diversity, which can be translated as a need for computerization in addition to the implementation of some other functions like inventory control, production planning, material output register and deliveries management. Computerized traceability solutions already exist, but as these solutions do not represent any kind of advantage to producers, they remain doing paper traceability, which is useless during a recall procedure. Although, traceability information can be used to improve the production and logistic fields, in order to obtain a supplementary benefit. [START_REF] Wang | Optimisation of traceability and operations planning: an integrated model for perishable food production[END_REF] propose a MILP model (Mixed Integer Linear Programming) in order to optimize lot sizing for perishable food production. This optimization takes into account in the same analysis traceability and economic criteria.

In this paper, the main objective is to find a way of delivering in order to recall a minimum number of final products in case of crisis; this problems becomes complex in the case the raw materials cutting and assembling recipes optimization. The works around this matter have been deployed in relation with a software provider of the sector. Consequently a final product deliveries optimization is proposed using traceability information. Hence one not only traces the products in order to perform recalls possible, but also to achieve a better production and logistic management, reducing risk and cost in food recalls. That is to say, take into account the real production's characteristics, given by the traceability information in order to assign the deliveries in a smarter way looking forward for a reduction of the recall size in case of crisis. A very important criterion to take into account is the "raw materials disperision" (wich will be formally presented in section 4).

The paper is organized as follows: after outlining the background and the problem statement, section 3 details the approach and shows the retained decision process. In section 4, the first step of our approach is detailed. After having defined the optimizing criterion (the raw materials dispersion in the final products), a model is proposed in order to solve it by a genetic algorithm. Then the production's sanitary risk level (defined as criticality) is assigned for all production batches (section 5). This determination is made with a neural network which models the expertise of the logistic manager. In section 6, a solution to final product delivery optimization is proposed. This solution is compared with the FIFO strategy, generally used for delivery decision. Finally, conclusions and prospects are suggested in section 7.

PROBLEM STATEMENT

The risk impact and the ontological requirements of a traceability system have been studied in the past years [START_REF] Borst | Engineering Ontologies[END_REF]. The relevance of product tracing in both the external supply chain and inside the production system has been considered by [START_REF] Ramesh | Requirements traceability: Theory and practice[END_REF]. The need for traceability computerization introduced previously has been studied by numerous authors like [START_REF] Sahin | Performance evaluation of a traceability system[END_REF], who judge Information Technology to be the fundamental tool in the traceability of manufactured products. Several models of managing traceability information have been considered [START_REF] Jansen-Vullers | Managing traceability information in manufacture[END_REF] as well as a general framework and a statement of experimental evidence [START_REF] Regattieri | Traceability of food products: General framework and experimental evidence[END_REF] which have considered all the technological solutions in the traceability market.

Most of this scientific literature is focused on general factors such as identification technologies (tools and hardware solutions such as RFID, 2D Code, Processing board, etc.) and potential advantages. The problem of optimization in production was also considered from the traceability point of view, specifically regarding the raw material dispersion problem, to our knowledge this problem has first been formalized on the case of a sausage factory [START_REF] Dupuy | Batch dispersion model to optimize traceability in food industry[END_REF], the dispersion problem concept comes from this sausage manufacturing process. Pork meat industry is particularly interested in improving its traceability [START_REF] Liddell | Market opportunities and threats to the U.S. pork industry posed by traceability systems[END_REF]. In order to produce sausages, this company cuts pork meat in components like ham, belly, loin, trimmings… Further in the production process, these meat components are minced and mixed to create minced meat batches. These minced meat batches will be used to produce different types of sausages. Each type of raw material gives components in fixed proportions. This is the disassembling (or cutting) bill of material. A component can also come from different raw material types. The finished products (sausages) are composed of several components in given proportions. This is the assembling (or mixing) bill of material. During a working day, the company receives several batches of different types of raw material (ham, side of pork, shoulder…). So, many batches of components will be created and also many finished product batches. The purpose of the company is to minimize the cost due to a food safety crisis. If the food safety problem comes from a raw material batch, the company will identify (tracing) and recall all products which contain the raw material. If it concerns a finished product, the company will identify (tracking) the raw material batches and then recall all the corresponding finished products. So, in order to minimize the cost of a food safety crisis, the company has to minimize the number of recalled products. In the case of sausage production, batch size should be reduced but also batch mixing. The more raw material batches are mixed in finished product batches, the more important the recall and the cost. Dupuy's works (2004) finally leads us to the purpose of this paper which does take advantage of traceability information in order to obtain a benefit in other fields of production and management.

In order to achieve this aim, this paper presents a methodological approach to the problem, starting with an activity analysis which enables the definition of the main work axis. Thus, three principal subjects are defined as follows: dispersion evaluation and optimization, criticality determination and final product delivery optimization. As a matter of fact, this approach allows the producer to identify the failures on its production recipe, the most critical elements within its production chain, and therefore improve the performance of delivery allocation. Moreover, this final optimization can be measured as a reasonable decrease in the recall size, hence a significant economic stake.

To achieve the final purpose of reducing the recall size and cost one must perform an intelligent delivery allocation. Therefore, this supposes a previous knowledge of the production in terms of "recall risk", which depends on several production factors, chiefly on the raw material dispersion. Consequently, this dispersion value needs to be modelled and optimized. To that end, the initial section consists of raw material dispersion optimization, a criterion used subsequently for the determination of the criticality index of production batches. From which we get to finally develop an optimization of the manufacturing product delivery in order to reduce the number of batch recalls in case of a crisis.

GLOBAL APPROACH

This paper focuses on the integration of several manufacturing parameters into a raw material dispersion diagnosis, inside the internal production chain. Thus, it aims at optimizing packing and distribution criteria, considering possible critical situations. It is imperative to know the "risk" to send a potentially perilous production to an important customer, or to the big distribution market (which supposes a dispersion increase over the external chain). Therefore, one would like to assign in an optimal way the production outgoing batches to the delivery orders.

Globally, the traceability information regarding the initial product cutting and mixing leads to a dispersion evaluation and optimization of the fabrication recipe. Therefore, this dispersion and some other traceability indicators are computed to obtain a criticality value of the production. Lastly, this criticality allows an optimization of the delivery order allocation. In the SADT activity diagram [START_REF] Marca | IDEF0 and SADT: A Modeler's Guide[END_REF], shown in Figure 1, a logical order to solve the earlier mentioned problems is exposed, according to the sequence of information. The need to find solutions to evaluate dispersion should be noted because these dispersion values will be fundamental for production criticality determination and thus the ulterior delivery assignment.

DISPERSION OPTIMIZATION

The developed tool is presented to face the dispersion optimization problem. In the methodology summarised in the Figure 1, a genetic algoritm has been selected for the resolution of the mentioned problem. It is shown that the optimization of the raw material input allocation towards the fabrication products is NP-hard; this is why a meta-heuristic method is selected for its resolution.

Definition of dispersion (Dupuy et al., 2002)

The descending dispersion of a raw material batch is the number of batches of finished products which contain a part of this raw material. The ascending dispersion of a finished product batch is the number of raw material batches used in this finished product. The total dispersion of a system, as is shown in Figure 2, is equal to the summation of the descending dispersions of all raw material batches and the ascending dispersions of all finished products.

To decrease this dispersion, we must determine the way of distributing raw materials throughout production, as well as the way of assembling finished products from sub-products in a multistage production configuration. [START_REF] Dupuy | Batch dispersion model to optimize traceability in food industry[END_REF] proposed a mathematical model based on MILP programming to optimize dispersion in food industry. Optimization is made with LINGO 6.0 software. This approach can only be used for small problems. With real industrial problems, computing time using deterministic algorithms widely increases. Indeed, we prove that this decision problem belongs to the NP-complete problems (see Theorem 1). A calculation of complexity shows that the total number of possible combinations C is:

Problem's complexity

∑ = = = =       * = RM B j j Q i i n j i Q E C Theorem 1. The dispersion optimization is NP-hard.
Proof. We prove the hardness of the dispersion optimization by showing that its decision version has the same form as the one from the "graph coloring problem". In fact, the total number of possible combinations for the dispersion optimizing problem, given by formula (1), is the same as the "graphs coloring problem" [START_REF] Wegener | Complexity Theory: Exploring the Limits of Efficient Algorithms[END_REF]. As the latter problem is NP-hard, it allows concluding that the complexity of the dispersion optimizing problem is NP-hard.

With a NP-complete problem, the existence of a solution algorithm of polynomial complexity remains unknown [START_REF] Palekar | A branch and bound method for the fixed charge transportation problem[END_REF]. As a result, when the problem size is important and the response time requierements are limited, meta-heuristic methods are considered. A genetic algorithm is presented in the following section.

The genetic algorithm (GA)

Genetic algorithms belong to a class of stochastic search methods that work iteratively on a population of candidate solutions to the problem (individuals), performing a search guided by the "fitness" (i.e. the value of the objective function) of each solution [START_REF] Holland | Adaptation In Natural And Artificial Systems[END_REF] and (Goldberg, 1994). In particular, the higher the fitness, the more the genes of a solution are likely to be propagated to the next iterations [START_REF] Naso | Genetic algorithms for supply-chain scheduling: A case study in the distribution of ready-mixed concrete[END_REF]. This Darwinian principle is emulated with specific crossover, mutation and selection operators, which are applied with stochastic mechanisms that make the GA explore solutions with increasing fitness. Thus, their flexibility is geared towards the characteristics of the objective function; the GA fits perfectly to the dispersion optimizing problem, as they do not rely on specific a priori hypotheses (e.g. continuity and convexity).

In the following section, the different stages of GA are presented according to this plan:

• Initial population • Evaluation • Selection • Crossing • Mutation • Parameters setting

Initial population creation

The algorithm starts with numerous alternative solutions to the optimization problem, which are considered individuals in a population. In order to create a population adapted to our raw-material distribution problem, a function was developed, defining the problem's initial conditions, that is to say, the configuration and characteristics of the production to be optimized. Thereafter, random matrices, called participation matrices, were created, containing the assignment allocations of rawmaterials vs. fabrication products (Figure 3A). A matrix is created each time products are cut or composed, i.e. for each choice of outgoing material.

There will be as many solution matrices as production stages minus one. These solutions are arbitrarily created, using random generating tools in an orderly manner, this trying to ensure coverage of all space solutions.

0 0 1 1 0 0 RM4 1 0 1 0 1 1 RM3 0 0 1 1 1 0 RM2 1 0 0 1 0 1 RM1 SP6 SP5 SP4 SP3 SP2 SP1 0 0 1 1 0 0 RM4 1 0 1 0 1 1 RM3 0 0 1 1 1 0 RM2 1 0 0 1 0 1 RM1 SP6 SP5 SP4 SP3 SP2 SP1 0 0 Q 44 Q 43 0 0 RM4 Q 36 0 Q 34 0 Q 32 Q 31 RM3 0 0 Q 24 Q 23 Q 22 0 RM2 Q 16 0 0 Q 13 0 Q 11 RM1 SP6 SP5 SP4 SP3 SP2 SP1 0 0 Q 44 Q 43 0 0 RM4 Q 36 0 Q 34 0 Q 32 Q 31 RM3 0 0 Q 24 Q 23 Q 22 0 RM2 Q 16 0 0 Q 13 0 Q 11 RM1 SP6 SP5 SP4 SP3 SP2 SP1
A) Participation matrix (raw materials -sub products) B) Quantities assignment (raw materials -sub products)

Evaluation

Once the population is created, its behavior must be evaluated. Thus, one must count each individual's total dispersion value which corresponds to its fitness. Afterwards a classification of the population is performed. For every individual, one determines the adaptation value which is conversely proportional to its classification. According to each individual's adaptation a number of reproductions is assigned (for the next generation). The more the adaptation value is important, the more the individual is used for the reproduction. Therefore every individual has an adaptation value, a dispersion value and a number of reproductions for the next generation.

Selection and elitism

Before making the population's "natural selection" by fitness, the best individuals of the preceding generation are added to the next generation, which enable the GA not to lose the best solutions through the evolution. Therefore, the best individuals of this hybrid generation are stored in a new generation list. This elitism is necessary for the convergence of the method. The size of the elite selection can variate as a parameter depending on the problem. An example of those selection rules and meta-heuristics can be found in [START_REF] Siarry | Advances in Metaheuristics for Hard Optimization[END_REF] and [START_REF] Talbi | Parallel Combinatorial Optimization[END_REF].

Crossing

To carry out the reproduction of the population's individuals, random reproduction couples are assigned, while respecting the numbers of reproductions indicated in the evaluation. Once the list of couples is established, each one is taken (father and mother) to create an individual child who inherits from each of its parents half of the solution (as shown in Figure 4). This is carried out in order to be able to respect nomenclature constraints automatically, without needing to correct the children's composition after each reproduction. So, this crossing solution is chosen to gain computational time. Other crossing operators could be used to gain efficiency [START_REF] Holger | Stochastic Local Search-Foundations and Applications[END_REF] and (Talbi, 1999), but require to repair new children.

Mutation

To mutate the individuals of a generation, the procedure used consists in performing random changes in the quantities distribution of each individual (the result of these changes can be degradation in terms of dispersion).

After the initial matrix composition, the coherence between the solution's parts is verified. If in a stage of production, raw material is assigned to a product, then the solution of the following stage must respect this constraint. If it is not in case, an adaptation step has to be used.

Thereafter, random quantities are assigned while observing the problem's limiting conditions by the quantities and the nomenclatures defined previously. As a result, a group of matrices, called assignment matrices, is obtained; each one contains the raw material distribution for all production stages, indicating for each option of assignment, the quantity to be sent, or zero, if the choice of assignment is not made (Figure 3B). If the arising problem contains sub-products coming from external suppliers (which are not manufactured from the materials contained in the preceding production stage), parallel participation and assignment matrices are created. Finally all the quantities assignment matrices toghether correspond to an individual of the population.

0 0 Q 1 44 Q 1 43 0 0 RM4 Q 1 36 0 Q 1 34 0 Q 1 32 Q 1 31 RM3 0 0 Q 1 24 Q 1 23 Q 1 0 RM2 Q 1 16 0 0 Q 1 13 0 Q 1 11 RM1 SP6 SP5 SP4 SP3 SP2 SP1 0 0 Q 1 44 Q 1 43 0 0 RM4 Q 1 36 0 Q 1 34 0 Q 1 32 Q 1 31 RM3 0 0 Q 1 24 Q 1 23 Q 1 0 RM2 Q 1 16 0 0 Q 1 13 0 Q 1 11 RM1 SP6 SP5 SP4 SP3 SP2 SP1 1 st production level Q 2 46 0 0 Q 2 43 0 0 FP4 Q 2 36 0 0 Q 2 33 0 Q 2 31 FP3 0 0 Q 2 24 0 Q 2 22 0 FP2 0 0 Q 2 14 0 0 0 FP1 SP6 SP5 SP4 SP3 SP2 SP1 Q 2 46 0 0 Q 2 43 0 0 FP4 Q 2 36 0 0 Q 2 33 0 Q 2 31 FP3 0 0 Q 2 24 0 Q 2 22 0 FP2 0 0 Q 2 14 0 0 0 FP1 SP6 SP5 SP4 SP3 SP2 SP1 2 nd production level 0 0 Q 1 44 Q 1 43 0 0 RM4 Q 1 36 0 Q 1 34 0 Q 1 32 Q 1 31 RM3 0 0 Q 1 24 Q 1 23 Q 1 0 RM2 Q 1 16 0 0 0 0 Q m1 11 RM1 SP6 SP5 SP4 SP3 SP2 SP1 0 0 Q 1 44 Q 1 43 0 0 RM4 Q 1 36 0 Q 1 34 0 Q 1 32 Q 1 31 RM3 0 0 Q 1 24 Q 1 23 Q 1 0 RM2 Q 1 16 0 0 0 0 Q m1 11 RM1 SP6 SP5 SP4 SP3 SP2 SP1
1 st production level after mutation

Q m2 46 0 0 0 Q m2 42 0 FP4 Q m2 36 0 0 Q m2 33 0 Q m2 31 FP3 0 0 Q 2 24 0 0 0 FP2 0 0 Q 2 14 0 0 Q m2 11 FP1 SP6 SP5 SP4 SP3 SP2 SP1 Q m2 46 0 0 0 Q m2 42 0 FP4 Q m2 36 0 0 Q m2 33 0 Q m2 31 FP3 0 0 Q 2 24 0 0 0 FP2 0 0 Q 2 14 0 0 Q m2 11 FP1 SP6 SP5 SP4 SP3 SP2 SP1
2 nd production level after mutation Figure 5. Mutation example After performing the mutation, individuals must be checked because it is quite frequent that when assignment quantities are changed, the solution disrespects the problem's constraints. Thereafter, the transferred individual is adapted to the respect of the constraints as seen in Figure 5.

Algorithm's parameter setting

Parameters definition determines the GA's performance and its adaptation capacity to a specific problem (Bourda et al., 1997). Thus, the "size of the population", "pre selection quantity", "elitism rate", "reproduction rate", "mutation probability", and maximum "number of generations" are defined. In order to determine these parameters, an iterative procedure must be developed so an evaluation of the results can be made to all the possible combinations of the parameters' variations; eventually obtaining the best parameter configuration to the specific case of study considered.

Evaluation of the algorithm and results

In order to evaluate the performance of the GA, the numerical example of the AOSTE sausages fabrication, ssuggested by Dupuy is considered [START_REF] Dupuy | Analyse et conception d'outils pour la traçabilité de produits agroalimentaires afin d'optimiser la dispersion des lots de fabrication[END_REF]. This problem presents 4 batches of raw materials divided into 2 types, 6 batches of components divided into 2 types, 2 batches of bought components (one of each type) and 4 batches of finished products divided into 2 types. The material quantities and names are shown in Figure 6 (the quantities are specified inside each batch). The goal is to find the quantities (marked as "?") corresponding to the sub product batches, to obtain the lowest possible raw materials dispersion according to the cutting and assembling nomenclatures (Figure 7).

Results

Initially, one tried to solve this problem by an exact method with the "LP_solve" solver. After three days of computing, an optimum has not been determined. However, the best solution obtained by this solver is used as reference to evaluate the performances of the developed Meta heuristic.

The genetic algorithm sorts a total dispersion value equal to 12, in 1.3 seconds. A very good performance is noticed, as well as the possibility of having data with optimal dispersion values in real production time, which enables the analyzer to give objective notes of dispersion to the production batches. By obtaining these results, one defines the most adapted parameters on this example after an evaluation of the algorithm's behavior through the changing of its parameters. Figure 8 illustrates the solution given by the GA, containing the dispersion value and the quantity assignment for the allocations of "raw materials vs. sub-products", of "sub-products vs. finished products" and of "bought sub-products vs. finished products".

A fast convergence into a very acceptable solution is noticed. In this convergence graph (Figure 9) the evolution of the population towards the optimum is shown, as well as the disturbances caused by the mutations, which frequently exit the solutions from local optimums, allowing the population to reach the global optimum easily.

It is possible to have very fast convergence due to the fact that the population procreates a "great individual". This one being too often chosen, the population tends to converge on its genome. In that specific case "the diversity of the genetic pool is then too reduced so that AG can progress" [START_REF] Rennard | Handbook of Research on Nature Inspired Computing for Economics and Management[END_REF].

CRITICALITY DETERMINATION

In the activities decomposition presented at the beginning, the use of an artificial neural network was considered in order to determine criticality associated to production. Neural networks are non-linear statistical data modeling tools which can be used to model complex relationships between inputs and outputs or to find patterns in data [START_REF] Rich | Artficial Intelligence 2nd edition[END_REF].

Definition of criticality

In this application "criticality" is defined as an index associated to production or to a batch of production which represents quantitatively its state of current risk. Criticality makes it possible to take into account simultaneously several parameters of manufacture in only one value exposing the potential danger. The goal is to obtain coherent criticality values by exploiting traceability information. Therefore, it is a question of making a multi-criteria decision and of assigning a criticality value to a list of entries as shown in Figure 10 Production markers This application seeks to develop an artificial neural network that allows producers to consider all possible types of indicators. Indeed, neural network models can be used to infer a function from observations even if the complexity of the data or task makes formal design of such a function difficult [START_REF] Najafi | An intelligent dynamic reconstruction filter for audio signal reconstruction using neural networks[END_REF], [START_REF] Yu | Adaptive neural model-based fault tolerant control for multi-variable processes[END_REF]. To determine the criticality value, much traceability information has to be taken into account. This information could be qualitative (example: quality of suppliers) and quantitative (example: dispersion note). The criticality value depends on the industrial context and has to be adapted to each situation. So it is difficult to make a formal design of criticality function.

Traceability Information

Criticality determination

Criticality value

Batch

Nevertheless, a production process expert can give an evaluation of this criticality value without being able to formalize the inference process. Neural networks, as systems capable of learning, operate the principle of "induction", i.e. acquiring training by experiencing. So, they are fully successful to solve the determination problem of the criticality value. Furthermore, this determination is a statistical problem of filter type with possibly noisy data input. It is a problem for which the neural networks have shown their effectiveness [START_REF] Shin | A neural architecture applied to the enhancement of noisy binary images[END_REF] and [START_REF] Martin | Neural Networks for Control[END_REF].

The problem was solved by using a neural network of the linear filter type and by a supervised training of it. The developed tool can be exploited in several fields. Once the network is designed, a simple reset and training will enable it to be exploited in a different field of production with other incoming parameters.

Creation of a training database

Before using the artificial neural network, a training database containing the list of examples must be formalized. The parameters establishing the production criticality must be defined initially. The following criteria were considered (Figure 11): • A dispersion note coming from the previously developed module; this note represents the ratio between the production's real dispersion and the optimal dispersion that the production could have had. It varies from 1 to 10 (1 being a bad dispersion and 10 an optimal dispersion).

• A general supplier's note, including raw material suppliers and dry material suppliers (plastic and paper). It is an average note of the suppliers group associated to the current production. It varies from 1 to 10, 1 being the equivalent to very bad suppliers and 10 to the optimal suppliers. In the food industry there is a real presence high and low quality suppliers, manufacturers must adapt their production to the demand forecasts with the available raw materials which means in certain cases, the use of low quality raw materials.

•

The number of production stops. This value varies from 0 to 3, 0 being a production without stops (optimal lifecycle in the production) and 3 being the maximum possible stops. Hence, an increase in production time and a lifecycle less appropriate. It is important to consider the number of stops in production because the life cycle of food products is particularly sensitive to changes in state and temperature. For example, frozen meat must remain on the machines blenders a specific time, and a production stop during the mixing process can represent a significant change in the BBD (best before date) or in the product's sanitary risk level.

• Response Number of remaining days. This value takes into account the expiration date of the raw materials while assigning the nearest expiration date of the raw materials involved to the finished products. This value varies from 0 to 30 days, 0 being a catastrophic value, and 30 days an optimal value).

Considering the presented criteria, a set of examples was manually generated by means of an expert in the food production domain.

Creation of the artificial neural network

The programming strategy is supported by MATLAB's "Neural Network Toolbox". The program initially loads all the training examples, which can be constantly modified or enriched. The construction procedure starts by assigning the initial weights and biases of the network. First, all the weights and biases are set to zero. Then the network is modified according to the loaded examples by adapting the weights and biases to them. In order to ensure an optimal effectiveness, the training is carried out. A number of training iterations is limited in order to have a stop criterion. Subsequently, the network is trained until it is ready to make its own criticality decisions. However, if it needs to be adapted to special evaluation situations, it would have to receive extra training, considering new inputs.

Evaluation of the artificial neural network

To evaluate the application, a network was generated and then a simulation of its behavior was carried out by entering a set of random inputs and by watching the criticity output, after having rounded up this value to the nearest integer.

Results

Table 2 shows the criticity results for a random set of input parameter values. Table 2. ANN evaluation results

These results were reasonable. The artificial neural network developed gives a very logical set of results containing criticity values, which could be exploited as production re-engineering criteria. These results confirm the good choice of the type of network and open new horizons to continue the development towards future optimizations.

FINAL PRODUCTS DELIVERIES OPTIMIZATION

The aim of this final section is to reduce potential product recall costs. The risks of recall vary significantly. Therefore, it is important to consider the necessary indicators, in order to properly diagnose and assign the production of outgoing batches to the delivery orders. The last part of the work presents real-time decisions and actions, which stand for the benefit to be obtained from information that has been collected and analyzed.

Actual deliveries priority criteria and constraints must be considered. The most representative criteria are summarized in Table 3 FIFO Criterion (first in -first out). 6

Maximum reception date (given by the client). 5 The tool to be developed must be able to operate as an expert, while making delivery choices after reasoning facts and known criteria. This is why using an expert system seems to be the best choice for this task.

Expert systems aim at exploiting the specialized skills or information on specific areas. They are used for diagnostic problems from experience [START_REF] Buchanan | Rulebased Expert Systems: The MYCIN Experiments of the Stanford Heuristic Programming Project[END_REF] which is the main purpose in the deliveries cohice optimizationp roblem. Expert systemps can also be used as information guidance systems for planning and scheduling [START_REF] Ajith | Rule-based Expert Systems[END_REF], the type of application that one seeks to develop. This kind of system can analyze a set of one or more potentially complex and interacting goals in order to determine a set of actions to achieve those goals and/or provide a detailed temporal ordering of those actions, taking into account personnel, material, and other constraints [START_REF] Feigenbaum | Advanced Software Applications in Japan[END_REF]. The presented tool will be able to plan the deliveries as it acquires the corresponding knowledge. Hence, knowledge acquisition is the most important element in the development of an expert system [START_REF] Niwa | An Experimental Comparison of Knowledge Representation Schemes[END_REF].

The application's main code invokes a function which recovers the matrix containing the set of manufacturing batches with their criticality values, as well as a matrix containing the set of delivery orders (and their implicit information, delivery date, client, carrier…). After the evaluation of the dispatch rules and priorities, the assignation choice is made.

The expert system is composed of a set of rules that analyze information (usually supplied by the user of the system) about a specific class of problems, as well as providing a certain analysis of the problem and recommending a set of actions or decisions (Mariot et al., 1989). In the case of deliveries optimization, the expert system must receive the set of delivery orders and outgoing batches, then, according to the priority criteria/constraints and the criticity values, assign in the best possible way to the outgoing allocations as shown in Figure 12.

Rules database

The criticity values are contained between 1 and 10. We started to write the assignation rules considering the variation of these criticity entries starting with the destination choice for the most critical batches and finishing by the batches which represent less risk. An example of implemented rules database is presented in Table 4.

System's inference engine

The decision execution starts by counting the quantity of batches presenting the same criticity value. Then, for each rule, the engine seeks the delivery order to be affected (regarding the characteristics mentioned in Table 3), and starts to assign the batches there, taking into consideration the orders already satisfied and the priority parameters. In the case of an homogeneus production and a short set of DO's, the process can be simply algorithmic, but whenever the criticality values start to variate, as well as the clients, the assignment choice depends on several parameters wich may not be related at all. As an example, the DO's shown in Table 5 are assigned in Figure 13.

The assignment choice given by the expert system is a matrix, which contains for each batch the number of the delivery order that will be associated to it. Moreover, the system sends the most critical batches towards additional sanitary tests. Therefore, the "blocked batches" will be missing in one of the orders (assuming that we have the same number of batches to manufacture as batches ordered to dispatch) until obtaining the test results.

Evaluation of the expert system vs. FIFO allocation

In order to evaluate the performance of the obtained results, it is important to compare them with a typical FIFO delivery assignment (the most used method in the food industry). In order to do this, a quantity of manufacturing batches was considered as well as a set of delivery orders. Then, the dispatch choice was made twice: first with the expert system (considering the value of criticity given by the artificial neural network) and second using the FIFO criterion (without considering criticity). As a result, two different lists of assignment were sorted in order to be evaluated. Subsequently, several crisis cases were simulated. Thereafter, the quantity of recalled batches was counted for each method and then these values were compared (FIFO recalls vs. Expert System recalls). With the purpose of considering a wide range of cases, this procedure was done for different batch quantities of 1 000, 2 000 and 3 000 that were distributed between 8, 12, or 20 delivery orders with randomly determined requested quantities and with crisis probabilities of 0.05%, 0.10% and 0.15% proportional to the production's criticity values.

Table 6 shows the results of this evaluation, which was carried out with a Monte Carlo simulation. For each different configuration of # of batches, # of DO's and crisis probability, the number of recalled batches is presented for the expeditions choices by FIFO and ES, in each case the pourcentage of benefit obtained by the ES is shown. The obtained results are very satisfactory indeed. It is evident, there is a significant improvement in the distribution is made by the expert system in terms of recalled batches.

Figure 14 illustrates the difference between the recalls in case of crisis according to the two used Fill the orders with these products (as they come from a low risk batch, there is no harm in "spreading" them)

criteria. The surface formed by the recalls of the expert system is considerably less important than that of the FIFO. Particularly where the recall is really dramatic, the considerable impact of implementing this decision-making aid tool is clearly identifiable.

In the case illustrated in Figure 14, in 50 iterations for a crisis probability of 0.15%, the average quantity of recalls with the FIFO method was 404.7 batches, while with the optimized method it was 286.04. Then, if each iteration is actually considered to be a delivery (towards the customers), it is possible to get a global picture of the effect of an intelligent dispatching.

TECHNICAL ASSESSMENT

A technical description of the developed application is presented in in which execution times and memory sizes for each module are detailed. Measurements for calculations were made with 2 000 batches of finished products, in a three-stage production, for the dispersion analysis, and 10 delivery orders. The Pocessing time corresponds to a dual core processor running at 3.01Ghz, and with 2Go of RAM capacity.

CONCLUSIONS AND PROSPECTS

The analysis module of raw material dispersion and delivery optimization, which we just introduced, was evaluated within each stage of its development; and a complete evaluation also took place at the end of the design. The results obtained illustrate an enormous potential for this application.

The field of dispersion optimization is only in its early stage, even if the genetic algorithm proposed is able to find adequate solutions in reasonable execution times, an algorithm of this type can be refined in several manners. Moreover, the application presented considers the optimization of a simple dispersion function. For its evaluation, we do consider the participation of the raw materials in the finished products but without bearing in mind the quantity rates. In practice, the production planners consider multiple objectives, and thus multi-objective optimizations with evolutionary algorithms will take place in future developments.

Regarding the initial population dispersion, there are difficulties defining a metric to calculate the difference between a set of individuals and the gap separating them in the space of solutions.

Regarding the criticity determination after considering certain parameters, the artificial neural networks appear as a concrete application to achieve the interaction between the data-processing systems and production environments. The results obtained with our network, particularly with the standard "linear filter", are accurate. So, they led us to continue our work in order to improve the application's performance by applying modifications to it, which increases its training and speed.

Lastly, the developed expert system uses the information produced by the genetic algorithm and the artificial neural network to optimize product dispatches. We proved that the structuring of knowledge in hierarchical levels constitutes an excellent beginning for decision-making. The acknowledged information, thanks to traceability systems, enables us to build a more populated rules database. The system produces very satisfactory results, but we are aware that it is far from its optimal performance. Nevertheless, it clearly shows its significant impact on the industrial field.

# of Batches

Table 6. Mean quantity of recalled batches by the assignment criteria (FIFO vs. Expert system) for 50 iterations.

Figure

  Figure 2. Example of total ascending and descending dispersion

Figure 3 .

 3 Figure 3. Participation and quantites assignment matrices

Figure 10 .

 10 Figure 10. Criticality determination statement.

Figure 9 .

 9 Figure 8. Solution to the evaluation example dispersion = 12, time = 1.35.6 sec

Figure 11 .

 11 Figure 11. Artificial neural network's Inputs and Outputs example.

Figure 12 .

 12 Figure 12. Inputs and outputs for the expert system

Table 3 .

 3 Assignment choice criteria for the production batches deliveries.

Table 7 .

 7 Technical parameters of the developed applications.

ACKNOWLEDGEMENTS

The authors wish to thank engineers Devins Christophe and Carpentier David, from ADENTS HTI (Industrial traceability software solutions), for their contribution in fruitful discussions and critical assistances.