Metal enriched quasi-ultrafine particles from stainless steel gas metal arc welding induced genetic and epigenetic alterations in BEAS-2B cells.

Recent evidence has supported welding fume (WF)-derived ultrafine particles (UFP) could be the driving force of their adverse health effects. However, UFP have not yet been extensively studied and are currently not included in present air quality standards/guidelines. Here, attention was focused on the underlying genetic and epigenetic mechanisms by which the quasi-UFP (Q-UFP, i.e., ≤ 0.25 µm) of the WF emitted by gas metal arc welding-stainless steel (GMAW-SS) exert their toxicity in human bronchial epithelial BEAS-2B cells. The Q-UFP under study showed a monomodal size distribution in number centered on 104.4 ± 52.3 nm and a zeta potential of -13.8 ± 0.3 mV. They were enriched in Fe > Cr > Mn > Si, and displayed a relatively high intrinsic oxidative potential. Dose-dependent activation of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B signaling pathway, glutathione alteration, and DNA, protein and lipid oxidative damage were reported in BEAS-2B cells acutely (1.5 and 9 µg/cm2, 24 h) or repeatedly (0.25 and 1.5 µg/cm2, 3 × 24 h) exposed to Q-UFP (p < 0.05). Alterations of the Histone H3 acetylation were reported for any exposure (p < 0.05). Differentially regulated miRNA and mRNA indicated the activation of some critical cell signaling pathways related to oxidative stress, inflammation, and cell cycle deregulation towards apoptosis. Taken together, these results highlighted the urgent need to better evaluate the respective toxicity of the different metals and to include the Q-UFP fraction of WF in current air quality standards/guidelines relevant to the occupational settings.

[Factors related to the one-month retention of 8507 employees declared medically unfit in Hauts-de-France companies between 2014 and 2018]. / Facteurs liés au maintien dans l'entreprise à un mois chez 8507 salariés déclarés médicalement inaptes en Hauts-de-France entre 2014 et 2018.

BACKGROUND: Given the low rate of retention in a company after an employee has been found unfit for the job, our aim was to determine the factors related to employees being kept by their company one month after being declared unfit for the job due to either a musculoskeletal disease (MSD) or a mental health disorder (MHD). METHODS: This study was based on all employees declared unfit for the job by the occupational physicians in the "Unfitness" survey in the French "Hauts-de-France" region between 2014 and 2018. For each of the two groups of workers, factors related to the employees being kept by their company one month after being declared unfit for the job were studied by logistic regression. RESULTS: Only 6.9% of the 5352 workers declared unfit for the job due to MSD were kept in their company whereas 3.6% of the 3155 workers declared unfit for the job due to MHD were kept in theirs. For the two groups of workers, the proportion of employees kept by their company decreased with female gender (OR=0.63 95%CI [0.47-0.84] for MSD and OR=0.50 [0.32-0.78] for MHD for female vs. male), long sick-leave (OR=0.26 [0.18-0.40] for MSD and OR=0.22 [0.11-0.45] for MHD for sick-leave>6 months vs. no sick leave), small size of the company (<50 employees) and working in the construction field or services sector (vs. industry or administration). Concerning the employees declared unfit due to MSD alone, the proportion of employees kept by their company decreased for seniors (>50 years old) and for those with low seniority (<5 years). CONCLUSION: "Retention in a company" as a tool for "maintenance of employment" is a little-discussed subject, lending further credence to the current recommendations for reduction of inequalities in working conditions and vocational training of employees according to age and socio-occupational category, and also for reduction of inequalities in occupational pathways according to gender.

Management of work-related common mental disorders in general practice: a cross-sectional study.

BACKGROUND: General practitioners (GPs) often manage individuals with work-related common mental disorders (CMD: depressive disorders, anxiety and alcohol abuse). However, little is known about the ways in which they proceed. The aim of this study is to analyze GPs' management and patterns of referral to other health professionals of patients with work-related CMD and associated factors. METHOD: We used data from a cross-sectional study of 2027 working patients of 121 GPs in the Nord - Pas-de-Calais region in France (April - August 2014). Statistical analyses focused on patients with work-related CMD detected by the GP and examined the ways in which GPs managed these patients' symptoms. Associations between patient, work, GP and contextual characteristics and GPs' management were explored using modified Poisson regression models with robust variance. RESULTS: Among the 533 patients with work-related CMD in the study, GPs provided psychosocial support to 88.0%, prescribed psychotropic treatment to 82.4% and put 50.7% on sick leave. Referral rates to mental health specialists and occupational physicians were respectively 39.8 and 26.1%. Several factors including patients' characteristics (occupational and sociodemographic), GPs' characteristics and environmental data were associated with the type of management used by the GP. CONCLUSION: Our study emphasizes the major and often lonesome role of the GP in the management of patients with work-related CMDs. Better knowledge of the way GPs manage those patients could help GPs in their practice, improve patients care and be a starting point to implement a more collaborative care approach.

Population-based incidence of lymphomas in the French Nord-Pas-de-Calais region between 2001 and 2005: Annual estimations and spatial analysis.

BACKGROUND: Non-Hodgkin's lymphomas (NHL) are the seventh most commonly diagnosed cancer in France. Nord-Pas-de-Calais is ranked as the region with the highest incidence of cancers and deaths by cancer in France. With its rich industrial past and its contrasted population densities between urban and rural territories, Nord-Pas-de-Calais represents a geographic area of interest to study the overall incidence of NHL and examine spatial variation of NHL incidence between the 170 cantons of the region. METHODS: LYMPHONOR was a population-based multicentre retrospective study of patients residing in the Nord-Pas-de-Calais region and diagnosed with NHL between January 2001 and December 2005. Spatial distribution of NHL incidence in Nord-Pas-de-Calais was explored using two complementary approaches: adjusted smoothed standardised incidence ratio (SIR) and spatial scan statistics (detection of atypical clusters). RESULTS: Between 2001 and 2005, 2132 new cases of NHL were diagnosed in the Nord-Pas-de-Calais region. In 2005, age-standardised NHL incidence rates were 10.2 and 7.0 cases per 100,000 person-years in male and female residents, respectively. No significant spatial disparities in NHL incidence were found within the Nord-Pas-de-Calais region. The age-adjusted smoothed SIR varied from 0.82 to 1.25 between cantons. Consistently, spatial scan statistics did not detect any significant atypical cluster of high NHL incidence. CONCLUSION: Comparison with national data collected during the same period does not show an overincidence of NHL in the Nord-Pas-de-Calais region. In addition, no evidence for spatial heterogeneity and clustering of NHL incidence was found within this region. Future epidemiological research using large-scale registries is needed to better appraise spatial variation of NHL incidence in France and to investigate possible reasons for significant clusters.

mTOR pathway activation in large vessel vasculitis.

BACKGROUND: Mammalian target of rapamycin complex 1 (mTORC 1) drives the proinflammatory expansion of T helper (TH) type 1, TH17 cells and controls fibroblast proliferation, typical features of large vessel vasculitis (LVV) pathogenesis. Molecular pathways involved in arterial lesions of LVV are unknown. METHODS: We evaluate mTORC pathway activation in vascular aorta lesions and in T cell homeostasis of patients with LVV. RESULTS: Proliferation of both endothelial cells and vascular smooth-muscle cells was shown in vascular lesions in LVV. The vascular endothelium of proliferating aorta vessels from patients with LVV showed indications of activation of the mTORC1 pathway (S6RP phosphorylation). In cultured vascular endothelial cells, sera from patients with LVV stimulated mTORC1 through the phosphorylation of S6RP. mTORC1 activation was found also in Th1 and Th17 cells both systemically and in inflamed vessels. Patients with LVV exhibited a diminished S6RP phosphorylation in Tregs. Inhibition of mTORC1 pathway with rapamycin, increase Tregs and decrease effector CD4+IFNγ+, CD4+IL17+ and CD4+IL21+ T cells in patients with LVV. CONCLUSIONS: We provided evidence that mTORC1 pathway has a central role in driving T cell inflammation and vascular lesions in LVV. Targeting mTORC pathway may represent a new therapeutic option in patients with LVV.

Work intensity in men and work-related emotional demands in women are associated with increased suicidality among persons attending primary care.

BACKGROUND: A large proportion of persons died by suicide are employed at the time of death and work-related factors partly contribute to suicide risk. Our aim was to examine the association between multiple aspects of work organization and suicidal ideation in a study conducted in primary care. METHODS: Data came from a study of 2027 working patients attending a GP representative of patients in the Nord Pas-de-Calais region in France (April-August 2014). Suicidality was assessed using the MINI (Mini International Neuropsychiatric Interview). Six emergent worked-related factors were explored (work intensity, emotional demands, autonomy, social relationships at work, conflict of values, insecurity of work). Several covariates were considered: patient's and GP's characteristics, and area-level data (material and social deprivation, psychiatrist and GPs' density, suicide attempts and suicide rates). RESULTS: 8.0% of participants reported suicidal ideation in the preceding month (7.5% of men and 8.6% of women, p = .03). In multivariate analyses adjusted for covariates, suicidality was significantly associated with work intensity (OR = 1.65; 95%CI [1.18-2.31]) in men and with work-related emotional demands (OR = 1.35; 95%CI [1.01-1.80]) in women. Area-level data were not associated. LIMITATIONS: Our cross-sectional study cannot assess the direction of the relationships under study. CONCLUSION: Our results emphasise a central role for GPs in suicide prevention among workers and highlight the importance of work-related factors with regard to suicidality in primary care.

Prevalence of work-related common psychiatric disorders in primary care: The French Héraclès study.

General practitioners (GP), on the frontline for individuals with mental health problems, often deal with work-related common psychiatric disorders. We aimed to determine the prevalence of work-related common psychiatric disorders in general practice and associated patients' and GPs' characteristics. HERACLES, a cross-sectional study among 2019 working patients of 121 GPs in the Nord - Pas-de-Calais region in France. Common psychiatric disorders were assessed using the MINI International Neuropsychiatric Interview, patient-perceived psychological distress and GP-diagnosed psychiatric disorders. The work-relatedness of common psychiatric disorders was ascertained by the GP and/or the patient. Prevalence rates adjusted on age were calculated by sex and associated characteristics were ascertained using multilevel Poisson regression models. The prevalence of work-related common psychiatric disorders ascertained using the MINI was estimated at 25.6% [23.7-27.5], 24.5% [22.6-26.4] for self-reported psychological distress and 25.8% [23.9-27.7] for GP-diagnosed psychiatric disorders. Age, history of psychiatric disorders, consultation for psychological purpose and GP's characteristics were associated with MINI-identified psychiatric disorders. The prevalence of work-related common psychiatric disorders among working adults seen in general practice is high but further studies are needed to support this results.

Targeting soluble CD146 with a neutralizing antibody inhibits vascularization, growth and survival of CD146-positive tumors.

CD146 (MUC-18, MCAM) expression on cancer cells correlates with cancer progression and a bad prognosis in several tumors, including melanoma and pancreatic tumors. Deciphering the mechanism mediating the CD146 role in cancer is essential for generating new therapeutic strategies. We found that CD146 expression in cancer cells is associated with a secretion of soluble CD146 (sCD146) that constitutes an active player in tumor development. Indeed, sCD146 induces the overexpression of its binding protein, angiomotin, on both endothelial and cancer cells and promotes both paracrine effects on angiogenesis and autocrine effects on cancer cells proliferation and survival. These last effects are mediated in part through the induction and phosphorylation of c-myc in cancer cells. In mice models xenografted with human CD146-positive melanoma or pancreatic cancer cells, administration of a novel monoclonal antibody specifically targeting sCD146, but not its membrane form, successfully suppresses tumor vascularization and growth. Our findings demonstrate that sCD146 secreted by CD146-positive tumors mediates important pro-angiogenic and pro-tumoral effects. Targeting sCD146 with a novel neutralizing antibody could thus constitute an innovative therapeutic strategy for the treatment of CD146-positive tumors.

Revisited role of microparticles in arterial and venous thrombosis.

Microparticles (MPs) represent a heterogeneous population of submicronic vesicles that are released in response to cell activation or apoptosis. MPs harbor a large repertoire of cell surface receptors and mRNA and biological activities representative of their parent cells and related to their involvement in many biological functions. Although MP generation is a physiological response, a dramatic increase in circulating MPs is detectable in a variety of thrombosis-associated disorders compared with healthy individuals. In this review, we will discuss a new vision of MPs as complex and ambivalent structures that express both activators and inhibitors of coagulation but also convey fibrinolytic properties. After summarizing our current knowledge about the role of MPs in venous and arterial thrombosis, this review will explore how this new vision of MPs influences their definition as emergent biomarkers in thrombotic diseases. Among the studies that have aimed to establish a link between thrombosis and MPs, a few studies have demonstrated a predictive value of MPs. So far, it is unclear whether this limited causative association is the result of current technical concerns and limited standardization or has to be integrated into a more complex vision of the role of MPs as key systems for regulating the balance between coagulation and fibrinolysis.

[Cell-derived microparticules: key players at the crossroad between inflammation and thrombosis]. / Rôle des microparticules cellulaires à l'interface des réponses prothrombotiques et inflammatoires.

Cell-derived microparticles are complex vesicular structures that can be shedded by activated or apoptotic endothelial cells. Cell-derived microparticles are composed of a phospholipid bilayer that exposes transmembrane proteins and receptors and encloses cytosolic components such as enzymes, transcription factors and mRNA derived from their parent cells. Thus, they behave as biological conveyors playing a key role in the tuning of vascular homeostasis. This review will address the potential of microparticles as efficient vectors of biological activities in pathologies. Based on the model of endothelial vesiculation, the first part of this review will develop the contribution of endothelial microparticles to coagulation inflammation and angiogenesis and their role in vascular disorders. The second part will be focused on the multifaceted impact of cell-derived microparticles present in blood products and its relevance to transfusion medicine.

Cytomegalovirus seroprevalence in exposed and unexposed populations of hospital employees.

The objective of this work was to compare the seroprevalence of cytomegalovirus in an unexposed and exposed population, both working in a hospital, and to study the occupational risk factors related to seropositivity, while taking personal risk factors into account. We conducted a cross-sectional study in a French hospital over a period of 12 months. The overall seroprevalence among the 550 subjects was 49.5%. The multivariate analysis showed that seropositivity was significantly associated with age (36-43 years: odds ratio [OR] = 1.7; 95% confidence interval [CI]: [1.1-2.8]) and working as a pediatric nurse's aide (OR = 1.8; 95% CI: [1.1-2.8]). This study confirms the need to improve prevention procedures in the workplace, including screening, information, and hygiene rules.

[Circulating endothelial microparticles: a new marker of vascular injury]. / Microparticules endothéliales circulantes: un nouveau marqueur du dysfonctionnement vasculaire.

Cell activation or apoptosis leads to plasma membrane blebbing and microparticles (MPs) release. MPs are submicron membrane vesicles expressing a panel of oxidized phospholipids and proteins specific of the cells they originate from. Exposure of negatively charged phospholipids and tissue factor confers a procoagulant potential to MPs. Increases in plasma MPs levels, particularly those of endothelial origin, reflects cellular injury and appears now as a surrogate marker of vascular dysfunction. MPs are also biologically active and stimulate pro-inflammatory responses in target cells. Thus, MPs can promote a prothrombogenic and pro-inflammatory vicious circle leading to vascular dysfunction. A better understanding of MPs composition, as well as their effects and the mechanisms leading to their clearance will likely open new therapeutic approaches in the treatment and the prognosis of cardiovascular diseases.

Microparticles and type 2 diabetes.

Cell activation or apoptosis leads to plasma membrane blebbing and microparticles (MPs) release in the extracellular space. MPs are submicron membrane vesicles, which harbour a panel of oxidized phospholipids and proteins specific to the cells they derived from. MPs are found in the circulating blood of healthy volunteers. MPs levels are increased in many diseases, including cardiovascular diseases with high thrombotic risk. Exposure of negatively charged phospholipids and tissue factor confers a procoagulant potential to MPs. Elevation of plasma MPs levels, particularly those of endothelial origin, reflects cellular injury and appears now as a surrogate marker of vascular dysfunction. Recent studies demonstrate an elevation of circulating levels of MPs in diabetes. MPs could also be involved in the development of vascular complications in diabetes for they stimulate pro-inflammatory responses in target cells and promote thrombosis, endothelial dysfunction and angiogenesis. Thus, these studies provide new insight in the pathogenesis and treatment of vascular complications of diabetes.

Role of microparticles in atherothrombosis.

Cell activation or apoptosis leads to plasma membrane blebbing and microparticle (MP) release in the extracellular space. MPs are submicron membrane vesicles which express a panel of phospholipids and proteins specific of the cells they are derived from. Exposure of negatively charged phospholipids and tissue factor confers a procoagulant potential to MPs. MPs accumulate in the lipid core of the atherosclertotic plaque and is a major determinant of its thrombogenecity. Elevation of plasma MPs levels, particularly those of endothelial origin, reflects cellular injury and is considered now as a surrogate marker of vascular dysfunction. Thus, MPs can be seen as triggers of a vicious circle for they promote prothrombogenic and pro-inflammatory responses as well as cellular dysfunction within the vascular compartment. A better knowledge of MP composition and biological effects as well as the mechanisms leading to their clearance will probably open new therapeutic approaches in the treatment of atherothrombosis.

Prospective evaluation of the impact of organizational change on perceived stress and health in assembly-line workers in an automobile plant.

BACKGROUND: Although the competitive climate of the automobile industry is modifying the organization of work in French plants, the health consequences of these changes have not been investigated. The objective of this study was to determine the health impact on employees of an automobile manufacturing plant in northern France of a change to a "Total Quality Management" type of organization. METHODS: This before-and-after study concerned 80 factory employees. The health impact of their work was measured before the change and then 4 and 12 months after the reorganization began, with a French version of the Job Content Questionnaire, which assesses stress at work, a self-rated health scale, and the rate of infirmary visits. Paired comparisons were used to assess before-and-after changes. RESULTS: Scores for psychological and physical demands increased significantly at 4 and 12 months after the organizational changes began, while the self-rated health score diminished significantly during both follow-ups. Decision latitude and social support scores remained unchanged during follow-up, and the number of subjects under stress in the study group (high psychological demands and low decision latitude) did not increase significantly. Finally, the rate of infirmary visits increased significantly during the study period. CONCLUSION: These results show that employees'reaction to these organizational modifications differed according to the scale studied and that their overall perceptions were more complex than expected in view of the changes that occurred.

Urinary homovanillic acid and serum prolactin levels in children with low environmental exposure to lead.

Current evidence suggests that the neurotoxic effects of lead may partially be mediated through interference with the dopaminergic system. The aim of this study was to assess the levels of two peripheral dopaminergic markers--serum prolactin (Pro-S) and urinary homovanillic acid (HVA-U)--in children living around two lead smelters, who are presumed to be exposed to high environmental lead pollution (n = 200), and compare their results with 200 age- and sex-matched controls living in an area unpolluted by heavy metals, giving a total of 400 children (200 boys and 200 girls). The influence of lead exposure on HVA-U and Pro-S was assessed by stepwise multiple regression, testing lead concentrations in blood (Pb-B), age, sex and area of residence as predictors. Though lead levels were significantly higher in boys and in the lead-polluted environment, mean Pb-B values were relatively low, indicating a low uptake of lead in the contaminated environment (39.5 micrograms l-1, range 4.6-165 micrograms l-1, n = 200), and no significant correlation could be found with either Pro-S or HVA-U. However, when the subgroup of 121 children with Pb-B levels above 50 micrograms l-1 were considered, a weak positive correlation was found between Pb-B and HVA-U (r2 = 0.04, p = 0.03), whilst in the even smaller subgroup of 15 children with Pb-B levels above 100 micrograms l-1, Pro-S appeared to be positively correlated with Pb-B, though the numbers of children were too small for the correlation to reach statistical significance (p = 0.095). These weak associations, probably not important in biological terms, indicate that Pro-S and HVA-U are not useful biomarkers at present exposure levels to lead in the environment. Nevertheless, the finding of subtle biochemical alterations in the dopaminergic system at Pb-B levels of around 100 micrograms l-1 supports the recommended setting of the action level at this value.

Environmental exposure to lead in a population of adults living in northern France: lead burden levels and their determinants.

As part of the assessment of a site in northern France polluted by metals from two smelters (in particular, lead, cadmium and mercury), a cross-sectional study was carried out which intended to estimate the levels of the lead burden of the adult population living on the site and the factors associated with these levels. The exposed zone included 10 municipalities in the Nord-Pas de Calais region, located in the vicinity of two non-ferrous metal smelters. The soils in these municipalities contained between 100 and 1700 ppm of lead. The non-polluted zone contained 20 municipalities from the same region, drawn randomly from those in the region of comparable size but free from any industrial lead exposure. The adult study population (301 men and 300 women) was stratified according to age, sex, employment status and exposure level. The inclusion criteria required subjects who were aged between 20 and 50 years and had been living in the exposed zone for at least 8 years; the exclusion criteria were pregnancy, cancer, kidney disease and diabetes. No more than 10% of the subjects participating could work at one of the two smelters. Data collection took place at home; visiting nurses interviewed subjects to complete a questionnaire and also took blood samples. The lead assay was performed by atomic absorption spectrometry. The geometric mean of the blood-lead levels was 74 microg/l, 95% CI = 69-80 among men and 49 microg/l, 95% CI = 46-53 among women. Blood-lead levels exceeding 100 microg/l were found among 30% of men and 12% of women. Several factors were associated with variation of the mean blood-lead level: the blood-lead level was significantly higher among the men for subjects living less than 1 km from the smelters (geometric mean x 1.3, 95% CI = 1.1-1.6), for those who drink alcoholic beverages (x 1.1, 95% CI = 1.0-1.2 for consumption of 30 g/day), those who smoke (x 1.2, 95% CI = 1.0-1.3 for 20 cigarettes/day), and for subjects with occupational exposure; among the women, for subjects living less than 1 km from the smelters (geometric mean x 1.5, 95% CI = 1.2-1.7), for those who drink alcohol (x 1.1, 95% CI = 1.1-1.2 for a daily consumption of 10 g), and for women living in a building constructed before 1948 (x 1.2, 95% CI = 1.0-1.4).

Determinants of cadmium burden levels in a population of children living in the vicinity of nonferrous smelters.

This report covers part of the assessment of a site in northern France polluted by industrial metal emissions. Our objectives were to assess the cadmium burden in children aged 8 to 11 years and look for factors that affected it. A cross-sectional population-based study took place in 1996-1997 and included 400 children (200 in the metal-polluted area). The geometric mean of the blood cadmium (CdB) levels of children living on the polluted site was 0.51 microg/L (95% CI=[0.49-0.53]); that of the nonexposed children was 0.47 microg/L (95% CI=[0.45-0.49]) (P<0.01). The geometric mean of the urinary cadmium (CdU) levels of children living on the polluted site was 1.16 microg/g creatinine (95% CI=[1.01-1.34]); that of the nonexposed children was 0.99 microg/g creatinine (95% CI=[0.86-1.14]) (P=0.10). Mean CdB was higher among children within 4 km of a zinc smelter and consuming > or =500 ml of tap water daily (x1.34; 95% CI=[1.14-1.51]) compared with children living more than 4 km away and consuming <500 ml of tap water daily. Independently of this association, consumption of fish and shellfish (> or =once a week vs. or =once daily vs.

Prevalence of cytomegalovirus infection among health care workers in pediatric and immunosuppressed adult units.

The prevalence of cytomegalovirus (CMV) infection varies not only from one country to another, but also with social, economic, and environmental conditions and with professional activity. Health care workers in contact with the main vectors of the CMV (i.e., children and immunosuppressed patients) are particularly exposed to the infection. We assessed the prevalence of the virus among health care personnel in light of CMV epidemiology and the recent shift in living conditions and family size. Our study was included in a broader program evaluating the risk of infection among female hospital workers of childbearing age. The goal of the program was to implement appropriate preventive measures for personnel who were not immune to the infection. Consequently, we included only female caregivers who worked with children or immunosuppressed patients. The study was based on a clinical examination, a medical and occupational questionnaire, the assessment of tasks performed; and CMV serologic testing. The overall seroprevalence was 44.25% in our population (n = 400) and was comparable regardless of the place of work. Prevalence differed significantly with age and parity, and we also found that it was higher among personnel who worked in closer contact with the patients (nurse's aides, pediatric nurse's aides) than among those whose tasks required more technical skills (nurses, pediatric nurses) (57.3% vs 34.5%, P < 0.01). The logistic regression analysis between prevalence of CMV antibodies, age, parity, and type of job showed that "contact job" was as significant a factor as parity to explain immunization in our population (odds ratio, 2.2). We also determined a correlation between the prevalence of CMV antibodies and tasks performed. In addition, we found a non-negligible group of non-immune personnel (55.75%) and young workers (mean age: 33.4) who were potentially exposed to infection. This points to the need to establish a prevention program.