Novel pharmacological targets for calcific aortic valve disease: Prevention and treatments.

Calcific aortic valve disease (CAVD) is the most common valvular disorder in the elderly, with the incidence of 3% in general population of Western countries. The initial phase of CAVD is characterized by leaflet thickening and possible spotty calcification (i.e. aortic valve sclerosis (AVSc)), while advanced stages have leaflets structure degeneration (i.e. aortic valve stenosis (AS)). The pathological cellular and molecular mechanisms, involved in CAVD, are extracellular matrix degradation, aberrant matrix deposition, fibrosis, mineralization, inflammation, lipid accumulation, and neo-angiogenesis. CAVD clinical risk shares considerable overlap with those of atherosclerosis and they include hypertension, smoking habits, and hyperlipidemia. Unfortunately, surgical aortic valve replacement and transcatheter aortic valve implantation are the only available treatments when the disease become severe and symptoms occur. Indeed, no approved pharmacological approach is available for CAVD patients. In this review, we describe the current literature evidence on possible future therapeutic targets for this debilitating and fatal disease such as PCSK9, P2Y2 receptor, cadherin 11, and DDP-4.

Medical Treatment for Acromegaly does not Increase the Risk of Central Adrenal Insufficiency: A Long-Term Follow-Up Study.

Central adrenal insufficiency (CAI) in acromegaly may be related to pituitary adenoma or induced by various medical treatments, transsphenoidal neurosurgery (TNS) or radiotherapy (RT), alone or combined. We assessed the role of all available treatments for acromegaly in inducing CAI. We retrospectively studied 97 patients. CAI was diagnosed if morning serum cortisol was <138 nmol/l, or if its response was inadequate in the low-dose short synacthen test. Seventy-four subjects underwent TNS (and 17 of whom also underwent RT), and 23 were on primary medical therapy: overall we diagnosed 21 cases of CAI. Duration of acromegaly, invasion of cavernous sinus, disease control, and type of medical treatment were much the same for patients with and without CAI, which was identified in 18% of patients (10/57) after one TNS, and in 53% (9/17) after RT (p=0.01); repeat surgery increased the risk of CAI (p=0.02). The risk of CAI onset during the follow-up was lower among patients treated with TNS or medical therapy than after RT (p=0.035). Medical treatment did not raise the risk of CAI, whereas a 5- and 4-fold higher risk of CAI was associated with repeat TNS and RT, respectively. Basal or stimulated cortisol levels were similar among acromegalic patients without CAI and matched controls with nonsecreting pituitary lesions. A significant proportion of patients with acromegaly developed CAI over time. While primary or secondary medical treatment did not contribute to the risk of CAI, repeat TNS and RT correlated with pituitary-adrenal axis impairment.

Assessment of Hippocampal-Related Behavioral Changes in Adolescent Rats of both Sexes Following Voluntary Intermittent Ethanol Intake and Noise Exposure: A Putative Underlying Mechanism and Implementation of a Non-pharmacological Preventive Strategy.

Ethanol (EtOH) intake and noise exposure are particularly concerning among human adolescents because the potential to harm brain. Unfortunately, putative underlying mechanisms remain to be elucidated. Moreover, implementing non-pharmacological strategies, such as enriched environments (EE), would be pertinent in the field of neuroprotection. This study aims to explore possible underlying triggering mechanism of hippocampus-dependent behaviors in adolescent animals of both sexes following ethanol intake, noise exposure, or a combination of both, as well as the impact of EE. Adolescent Wistar rats of both sexes were subjected to an intermittent voluntary EtOH intake paradigm for one week. A subgroup of animals was exposed to white noise for two hours after the last session of EtOH intake. Some animals of both groups were housed in EE cages. Hippocampal-dependent behavioral assessment and hippocampal oxidative state evaluation were performed. Results show that different hippocampal-dependent behavioral alterations might be induced in animals of both sexes after EtOH intake and sequential noise exposure, that in some cases are sex-specific. Moreover, hippocampal oxidative imbalance seems to be one of the potential underlying mechanisms. Additionally, most behavioral and oxidative alterations were prevented by EE. These findings suggest that two frequently found environmental agents may impact behavior and oxidative pathways in both sexes in an animal model. In addition, EE resulted a partially effective neuroprotective strategy. Therefore, it could be suggested that the implementation of a non-pharmacological approach might also potentially provide neuroprotective advantages against other challenges. Finally, considering its potential for translational human benefit might be worth.

Fitness for work in health care workers from the prospective of ethics, science and good practices.

Fitness for work (FFW) is the final task of both risk assessment and health surveillance, aimed at protecting workers' health and working capacity. There are numerous specific concerns regarding health care workers. In particular: i) the frequent difficulty in determining at pre-employment/pre-placement examinations the specific task that the individual worker will perform; ii) the prevalence of female workers and the contemporary presence of numerous occupational risk factors that are a potential cause of harmful effects on women's reproductive health; iii) the progressive aging of the staff especially nurses; iv) the risk to third parties, with particular reference to the issues of biological risk and substance abuse, also in relation to shift work, fatigue and occupational stress; v) the increasing number of immigrant workers among support staff In such cases the occupational physician, respecting both ethical principles and regulations and with an appropriate balance between scientific evidence and the precautionary principle, should express a FFW judgment that allows both the adaptation of work to the worker and vice versa, as recommended by the World Health Organization (WHO) and the International Commission on Occupational Health (ICOH). Proper FFW judgment also permits the expected benefits to be achieved, not only for the workers but also for employers, companies and society.

[Management of occupational dermatitis. Nine years' experience]. / Dermatiti occupazionali: problematiche gestionali. Nove anni di esperienza.

OBJECTIVES: To evaluate management problems concerning 301 workers with occupational dermatitis (OD) referred to the Occupational Health Institute of Brescia in the period 2000-2008. METHODS: We considered gender, age, job, referring physicians, diagnosis, latency between the onset of symptoms and the etiological diagnosis, examinations and tests performed before referral to our Institute. RESULTS: We diagnosed 168 cases of allergic contact dermatitis, 101 cases of irritant contact dermatitis and 32 other forms of dermatitis. 51.8% of the workers had been referred by general practitioners and 45.9% by occupational physicians. The mean latency between onset of symptoms and etiological diagnosis was 36 months and was significantly longer for construction workers (60 months). General practitioners referred workers to dermatologists or allergists and prescribed appropriate treatment more frequently than occupational physicians. We performed specific allergological tests in 292 workers (97%): in 48 subjects the correlation between symptoms and occupational exposure was unclear and was verified more than once, in 29 workers we requested a dermatological consultation due to severe skin lesions. Frequently it was necessary to collect further detailed information on occupational exposure, thereby postponing the diagnosis by about 3-10 weeks. CONCLUSIONS: Management of OD is still not satisfactory due to inadequate information to workers on occupational risks, limited presence of occupational physicians in the workplaces, low quality health surveillance, underestimation of occupational risks by general practitioners who are frequently the main referents for workers, poor collaboration between all physicians involved in OD management.

Assessment of New Coronary Features on Quantitative Coronary Angiographic Images With Innovative Unsupervised Artificial Adaptive Systems: A Proof-of-Concept Study.

Background and Purpose: The Active Connection Matrixes (ACMs) are unsupervised artificial adaptive systems able to extract from digital images features of interest (edges, tissue differentiation, etc.) unnoticeable with conventional systems. In this proof-of-concept study, we assessed the potentiality of ACMs to increase measurement precision of morphological structures (e.g., stenosis and lumen diameter) and to grasp morphological features (arterial walls) from quantitative coronary angiography (QCA), unnoticeable on the original images. Methods: Archive images of QCA and intravascular ultrasound (IVUS) of 10 patients (8 men, age 69.1 ± 9.7 years) who underwent both procedures for clinical reasons were retrospectively analyzed. Arterial features derived from "IVUS images," "conventional QCA images," and "ACM-reprocessed QCA images" were measured in 21 coronary segments. Portions of 1-mm length (263 for lumen and 526 for arterial walls) were head-to-head compared to assess quali-quantitative between-methods agreement. Results: When stenosis was calculated on "ACM-reprocessed QCA images," the bias vs. IVUS (gold standard) did not improve, but the correlation coefficient of the QCA-IVUS relationship increased from 0.47 to 0.83. When IVUS-derived lumen diameters were compared with diameters obtained on ACM-reprocessed QCA images, the bias (-0.25 mm) was significantly smaller (p < 0.01) than that observed with original QCA images (0.58 mm). ACMs were also able to extract arterial wall features from QCA. The bias between the measures of arterial walls obtained with IVUS and ACMs, although significant (p < 0.01), was small [0.09 mm, 95% CI (0.03, 0.14)] and the correlation was fairly good (r = 0.63; p < 0.0001). Conclusions: This study provides proof of concept that ACMs increase the measurement precision of coronary lumen diameter and allow extracting from QCA images hidden features that mirror well the arterial walls derived by IVUS.

[Role of the occupational physician in occupational injuries prevention: across ethics, science and good practices]. / Ruolo del medico competente nella prevenzione degli infortuni sul lavoro: tra etica, scienza e buone prassi.

Occupational injuries (OI) are a relevant issue in workplaces, being responsible for a range of individual and socio-economic consequences, with an enormous toll paid by workers, enterprises and society. Despite all these issues, OI prevention has not received significant field research attention, with studies mainly addressed to reporting data a posteriori instead of evaluating the effectiveness of prevention programs. In addition, the role of occupational physician (OP) seems to be largely underplayed. OP may and should be involved in OI prevention and control, in respect of codes of ethics, current legislation and scientific evidence. A multifaceted intervention in foundries, which showed effectiveness in reducing OI rates and improving quantitative and qualitative outcomes, gave us the opportunity to highlight OP's key role in implementing good occupational health and safety practices in workplaces.

[Work: disease and health. The role of occupational medicine]. / Lavoro: malattia e salute. Il ruolo della Medicina del Lavoro.

To assess the role of Occupational Medicine in the promotion of workers'health over the last forty years, the author studied the evolution of this discipline from a clinical-diagnostic approach to the current emphasis on prevention. However, it is stressed that in Occupational Medicine even preventive measures are based on clinical methodology, as for example in health surveillance, where the main tasks are the identification of individual hyper-susceptibility and the assessment of early and reversible health effects due to occupational risks. Moreover, the traditional clinical-diagnostic approach is still of utmost importance. In fact, the classical occupational diseases do not present with the specific clinical features of the recent past. Instead, today it is necessary to evaluate whether occupational risk factors play a concomitant role in the origin of diseases that affect the general population. Moreover, new occupational diseases are emerging, due to the continuous changes in manufacturing processes and work organization. To assess the role that Occupational Medicine has played in the binomial expression "disease-health", topics which particularly suit the Author's cultural background are considered and are used as "indicators" of the various scientific, cultural, social, economic, and legislative aspects that contribute to the professional development of Occupational Physicians. Important results have been achieved over the last 40 years, however Occupational Physicians face new problems that impose a continuous updating process, not only on medical topics but also on the development of technological processes. The laws and the recommendations of the most prestigious national and international organizations and the principles of the ICOH Code of Ethics should guide Occupational Physicians in their profession and their actions must imply full professional independence. They must acquire and maintain the necessary competence for their duties and adequate conditions to carry out their tasks according to good practice and professional ethics.

Carotid Atherosclerosis Progression in Postmenopausal Women Receiving a Mixed Phytoestrogen Regimen: Plausible Parallels with Kronos Early Estrogen Replacement Study.

This randomized double-blinded, placebo-controlled clinical trial evaluated the progression of intima-media thickness of common carotid artery (cIMT) and the effect of phytoestrogen therapy on atherosclerosis development in early and late postmenopausal women. The 2-year cIMT progression was evaluated in 315 early postmenopausal women aged 40-55 years and in 231 late postmenopausal women aged 60-69 years free of cardiovascular disease. B-mode ultrasound was done at baseline and after 12 and 24 months of follow-up. The study revealed no significant changes in the rate of cIMT progression in 315 early postmenopausal women. By contrast, a statistically significant difference in the rate of atherosclerosis development was observed in late postmenopausal women treated with phytoestrogens compared to placebo (p = 0.008). The rate of cIMT progression in the placebo group was 0.019 mm/year led to a significant increase of cIMT during the observation period (p = 0.012), while the rate of cIMT progression in phytoestrogen late postmenopausal recipients was 0.011 mm/year, and total change did not reach statistical significance during the follow-up period (p = 0.101). These results suggest that late postmenopausal women can be a suitable cohort for trials assessing the anti-atherosclerosis effects of phytoestrogen preparations. In particular, the beneficial effect of phytoestrogens on cIMT progression was demonstrated in late postmenopausal women.

Effects of timing and extent of smoking, type of cigarettes, and concomitant risk factors on the association between smoking and subclinical atherosclerosis.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the effects of timing and extent of smoking, type of cigarettes, and concomitant vascular risk factors (VRFs) on the association between smoking and carotid intima-media thickness (C-IMT) in a lipid clinic population. METHODS: 1804 patients (869 men, age 21 to 85 year) participated in the study. Smoking habits were recorded and C-IMTs were measured by B-mode ultrasound. The associations of C-IMT with smoking status (never, former, and current) and with the cigarettes' content of tar, nicotine, and carbon monoxide (alone or combined to define "light" or "regular" cigarettes) as well as the interactions between smoking status, gender, and VRFs were evaluated before and after adjustment for confounders. RESULTS: C-IMT was highest in current smokers, lower in former, and lowest in never smokers. C-IMT of former and current smokers differed only after data adjustment for variables describing the extent and timing of smoking exposure. C-IMT was positively related to the number of pack-years (number of cigarettes smoked per day [cigarettes/d] multiplied by number of years smoked/20) in both former and current smokers. There were no differences in C-IMT between smokers of cigarettes with high or low nicotine, tar, or carbon monoxide content. Both diabetes and hypertension interacted positively with smoking in determining C-IMTs. CONCLUSIONS: In the present cross-sectional observational investigation, carried out in a cohort of patients attending a lipid clinic, consumption of light cigarettes does not reduce the atherogenic effect of smoking on C-IMT. The number of pack-years, cigarettes/d, and years of smoking are relevant covariates in evaluating the effects of smoking on vascular health. The presence of diabetes or hypertension strengthens the association between smoking and cardiovascular risk.

Implications of metal exposure and liver function in Parkinsonian patients resident in the vicinities of ferroalloy plants.

Valcamonica is an Italian valley where ferro-manganese industries have been active for a century and where an increased prevalence of parkinsonism was observed. A group of 93 patients (65 from Valcamonica, 28 from the reference area of Brescia city) and 76 controls (52 from Valcamonica, 24 from Brescia) were screened for serum Cu, Zn, Fe, Mn in blood (MnB) and urine (MnU), transferrin, peroxides, alanine (ALT) and aspartate (AST) transaminases and direct bilirubin. Test results were compared among groups according to the residential area and related to the disease severity. Valcamonica patients had a serum-increase of Cu, as well as of AST/ALT ratio, and a serum-decrease of Zn and Fe compared with other subgroups of cases and controls. Cases and controls from Valcamonica had higher MnB and MnU levels compared to cases and controls from Brescia. After controlling for the duration of illness, the Unified Parkinson's Disease Rating Scale III domain correlated with serum Cu and AST/ALT ratio. Our results suggest the possibility that, in this area, a lifetime exposure to neurotoxicants and to Mn in particular, when accompanied to a subclinical liver dysfunction, may pose an increased risk for neurodegenerative disorders via metal metabolism (Cu, Zn, Fe) abnormalities.

[A multidisciplinary preventive intervention in a large Italian hospital]. / Prevenzione dei disturbi del rachide nei lavoratori di un ospedale: intervento multidisciplinare e valutazione di efficacia.

BACKGROUND: A multidisciplinary intervention is necessary to tackle the occupational risk of low back disorders in manual handling ofpatients and to evaluate the effectiveness. METHODS: An intervention was carried out which included risk assessment, testing and purchasing of patient handling devices, training programmes, health surveillance and collection of quantitative and qualitative outcomes to evaluate effectiveness, in a before-after design. RESULTS: The intervention was effective in reducing exposures, increasing knowledge and skills in patient-handling techniques, decreasing low back pain prevalence and injuries related to patient handling; absenteeism seemed to show a decreasing trend. CONCLUSIONS: The multidisciplinary approach was useful in the overall management of low back pain in health care workers performing patient handling.

[Updating in occupational health for health care workers]. / Aggiornamenti in tema di tutela della salute occupazionale dei lavoratori della sanità.

The board of the Thematic Section on Preventive Medicine for Health Care Workers of the Italian Society of Occupational Medicine and Industrial Hygiene (SIMLII) programmed a national conference on occupational risks of health care workers to be held in late 2009. Main topics will be: a) biohazards; b) biomechanical risk; c) psychosocial factors. Three different working groups were established to tackle critical aspects and suggest practical recommendations to occupational health professionals. Preliminary issues are presented while final results will be presented at the conference on September 2009.

[Tuberculin skin test (TST) survey among healthcare workers (HCWs) in hospital: a systematic review of the literature]. / Sorveglianza sanitaria dell'esposizione a Mycobacterium tuberculosis in ospedale mediante intradermoreazione secondo Mantoux: revisione sistematica della letteratura.

OBJECTIVES: To summarize the evidence on the Tuberculin Skin Test (TST) survey among healthcare workers (HCWs) in hospital, in the last decade. METHODS: A systematic search was conducted in PubMed and in the Proceedings of the congresses of the Italian Society of Occupational Health and Industrial Hygiene (SIMLII); researches conducted in areas with medium-high incidence of Tuberculosis were excluded. FINDINGS: 25 publications were identified. The compliance of HCWs to TST surveys ranged from 80 to 100%, the incidence of TST-conversion from 0.07 to 3.7% and the prevalence of positive TST from 5,7 to 57%. TST-conversion and positive TST were significantly associated to BCG vaccination and foreign-born. Most studies found an association between TST-conversion and occupational exposure in certain location (emergency facilities, internal medicine, infectious diseases, intensive care units, pathology, microbiology) and occupational categories (nurses, laboratory technicians). In some studies, period of hospital employment do not increased TST conversion rate. DISCUSSION: Positive TST and TST conversion rate seem to be associated with occupational exposure to Mycobacterium Tuberculosis in hospital, considering non-occupational factors. Evidence from literature seemed to support the use of TST in the tuberculosis screening programme of HCWs in hospital.

[Susceptibility to varicella-zoster, measles, rosacea and mumps among health care workers in a Northern Italy hospital]. / Suscettibilità per varicella, morbillo, rosolia e parotite negli operatori sanitari di un ospedale del Nord Italia.

BACKGROUND: Nosocomial transmission of varicella (V), rubella (R), mumps (Mu) and measles (Me) may be a significant cause of morbidity in health care workers (HCW). Susceptible HCW might be a relevant part of the workforce. METHODS: A seroprevalence study was performed in a public hospital. Antibodies (Ab) against V, R, Mu and Me were determined by ELISA. Sociodemographic, clinical, occupational data and sera were obtained during health surveillance. RESULTS: 2934 tests on 1106 HCW were performed. Seropositivity was 91% for V, 89% for R, 80% for Mu, 92% for Me. No significant differencies were found for the variables tested, except for age (< 36 years) and certain job tasks (e.g. residents). 22% of HCW tested were seronegative for at least 1 virus. More seronegatives were detected as compared with the majority of literature data. DISCUSSION: This study showed a relevant number of susceptible to V, R, Mu and Me. Seroprevalence data are useful for risk assessment, HCW health surveillance, to evaluate fitness for work and to promote vaccination programmes, according to scientific guidelines. OP should include serological screening for Me, Mu, V and R to protect HCW and third parties.

Neurological and neuropsychological features in Parkinsonian patients exposed to neurotoxic metals.

BACKGROUND: Environmental exposure to heavy metals and especially manganese (Mn) took place in Valcamonica, Italy, where a high prevalence of Parkinsonism was observed (age and sex standardized 407/100,000; 95% CI: 393.87-420.12), and the Standardized Morbidity Ratios was associated with environmental Mn levels. METHODS: A cross sectional study compared Parkinsonian patients residents in Valcamonica with patients from Brescia, Italy. Age- and sex-matched healthy individuals were recruited as controls. The protocol included information on clinical, occupational, residential history and life habits, neuro-psychological testing, and assessment of genetic polymorphism. RESULTS: The target group included 65 patients and 52 controls from Valcamonica, 28 patients and 14 controls from Brescia. Age at onset of the disease was lower in women from both areas. After adjusting for age and age at onset, patients from Valcamonica showed more severe motor impairment at the UPDRS scale, higher damage of cognitive and motor functions at MMSE, Token and Trial Making tests. Genetic variables showed a different allelic distribution of DRD4 gene between cases and controls, outside Valcamonica, where a less frequent familiarity for parkinsonism was reported. CONCLUSIONS: Parkinsonian patients with previous exposure to metals showed a more severe neuropsychological phenotype, without detectable contribution from genetic factors.

[Implementation of a health education programme in a sample of hairdressing trainees]. / Applicazione di un programma di educazione sanitaria in un campione di apprendisti acconciatori.

BACKGROUND: Skin and respiratory diseases and upper limb cumulative trauma disorders are common in practising hairdressers but unfortunately also in hairdressing trainees. Recent data showed that prevention by education in this working area is of fundamental importance. OBJECTIVES: The purpose of this study was to assess the knowledge that hairdressing trainees have of the risks present in their workplaces and to apply and verify, the efficacy of a specific educational programm METHODS: The programme was aimed at hairdressing trainees, aged from 15 to 21 years, attending 3 technical schools. The school training was part-time (1 day per week) and was completed in 3 years. Educational meetings were organized during the first year (154 students participated) and two years later at the end of the school training (only 83 students completed the training). The programme included a booklet and 3 self-administered questionnaires: one for the assessment of risks knowledge, work-related symptoms and preventive measures adopted, one for the assessment of long-term learning and one, after two years,for the assessment of changes in daily hairdressing practice, symptoms and preventive measures. RESULTS: At the beginning of the school training all the trainees were working as apprentices, only 76% reported using gloves (powdered latex gloves in 90% of cases) none used respiratory protective devices, 22.7% were atopic. 39% reported work-related skin lesions, 19.5% work-related rhinitis, 5.8% work-related conjunctivitis, 0.6% asthma, 9.1% work-related low back pain and 2.6% shoulder and/or elbow pain. At the end of school training most of the trainees were performing advanced procedures such as hair-drying and cutting instead of shampooing, dyeing and perming; almost all reported using gloves during technical activities and the use of non-latex gloves and skin care products increased; the percentage of work-related skin symptoms was significantly lower but the percentage of work-related musculoskeletal disorders was significantly higher. CONCLUSIONS: At the end of school training hairdressing trainees have a better knowledge of work-related risks and the importance of their prevention. Some changes in hairdressing practice (e.g use of gloves, barrier creams, skin care products) and procedures were evident and were associated with a decrease in work-related dermatitis; in this field the efficacy of specific educational programmes is significant. Nevertheless the increase in musculoskeletal disorders, probably related to the increase in performing advanced procedures (e.g. hair drying or cutting) often characterized by unsafe postures and few rest breaks, could be reduced only if employers too are involved and informed on practical aspects of prevention since, for these risk factors, changes in workplace and work organization are required.

Evaluation of fitness for work: the most challenging situations.

Evaluation of fitness for work (FW) is the final task of both health surveillance and risk evaluation. It's aim is to protect the physical and psychological health of workers and respect their professional skills. The Occupational Physician faces several difficulties in the evaluation of FW. Moreover, Italian legislation on this topic can be variously interpreted and this can cause conflicting evaluations. In this session, the most challenging situations in FW evaluation will be taken into consideration.

Fitness for work in difficult cases: an occupational medicine experience in a University Hospital.

BACKGROUND: Fitness for work (FW) in certain clinical cases poses significant professional challenges for Occupational Physicians (OPs). OBJECTIVES: to discuss the role of a public Institute of Occupational Medicine (IOM) in FW, thorough description of clinical cases. METHODS: the IOM at the University of Brescia is a public clinic available to general practitioners, OPs, other specialists, insurance companies, health authorities, employers, trade unions. IOM expert opinion on FW may be requested by OPs, employers or workers. In each case, occupational and clinical histories are taken, physical examinations, laboratory and instrumental tests might be performed, and technical and clinical documentation is acquired; expert opinions from other specialists might also be sought. Risk assessment (RA) stems from worksite inspections and information from company health and safety representatives, or health authorities. RESULTS: a few peculiar clinical cases are reported: tremors in a dental hygienist trainee, chorioretinitis in a welder, spasmofilia in a nursing aide, obstructive sleep apnoea in a steel worker, epilepsy in a metal engineering worker, as well as a number of cases fom the same workplace. CONCLUSIONS: FW judgement made by a IOM had several advantages from clinical and RA aspects. Work restrictions may not always be evidence based and it might be difficult to balance rights and duties of patients, employers and OPs; the IOM's wider experience, case discussion with the relevant parties, scientific and technical documentation of diagnostic and FW processes, strengthen the role of the IOM in dealing with difficult cases and as a guarantee from technical and ethical viewpoints.