A formal verification framework and associated tools for enterprise modeling : application to UEML

The aim of this paper is to propose and apply a verification and validation approach to Enterprise Modeling that enables the user to improve the relevance and correctness, the suitability and coherence of a model by using properties specification and formal proof of properties

Requirements modelling and formal analysis using graph operations

The increasing complexity of enterprise systems requires a more advanced analysis of the representation of services expected than is currently possible. Consequently, the specification stage, which could be facilitated by formal verification, becomes very important to the system life-cycle. This paper presents a formal modelling approach, which may be used in order to better represent the reality of the system and to verify the awaited or existing system’s properties, taking into account the environmental characteristics. For that, we firstly propose a formalization process based upon properties specification, and secondly we use Conceptual Graphs operations to develop reasoning mechanisms of verifying requirements statements. The graphic visualization of these reasoning enables us to correctly capture the system specifications by making it easier to determine if desired properties hold. It is applied to the field of Enterprise modelling

2012 update of French guidelines for the pharmacological treatment of postmenopausal osteoporosis

OBJECTIVES: To update the evidence-based position statement published by the French National Authority for Health (HAS) in 2006 regarding the pharmacological treatment of postmenopausal osteoporosis, under the auspices of the French Society for Rheumatology and Groupe de Recherche et d\u27Information sur les Ostéoporoses (GRIO), and with the participation of several learned societies (Collège National des Gynécologues et Obstétriciens Français, Groupe d\u27Étude de la Ménopause et du Vieillissement hormonal, Société Française de Chirurgie Orthopédique, Société Française d\u27Endocrinologie, and Société Française de Gériatrie et de Gérontologie). METHODS: A multidisciplinary panel representing the spectrum of clinical specialties involved in managing patients with postmenopausal osteoporosis developed updated recommendations based on a systematic literature review conducted according to the method advocated by the HAS. RESULTS: The updated recommendations underline the need for osteoporosis pharmacotherapy in women with a history of severe osteoporotic fracture. In these patients, any osteoporosis medication can be used; however, zoledronic acid is the preferred first-line medication after a hip fracture. In patients with non-severe fractures or no fractures, the appropriateness of osteoporosis pharmacotherapy depends on the bone mineral density and FRAX(®) values; any osteoporosis medication can be used, but raloxifene and ibandronate should be reserved for patients at low risk for peripheral fractures. Initially, osteoporosis pharmacotherapy should be prescribed for 5 years. The results of the evaluation done at the end of the 5-year period determine whether further treatment is in order. CONCLUSIONS: These updated recommendations are intended to provide clinicians with clarifications about the pharmacological treatment of osteoporosis

Pamidronic acid and cabergoline as effective long-term therapy in a 12-year-old girl with extended facial polyostotic fibrous dysplasia, prolactinoma and acromegaly in McCune-Albright syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>McCune-Albright syndrome is a complex inborn disorder due to early embryonal postzygotic somatic activating mutations in the <it>GNAS</it>1 gene. The phenotype is very heterogeneous and includes polyostotic fibrous dysplasia, typically involving the facial skull, numerous café-au-lait spots and autonomous hyperfunctions of several endocrine systems, leading to hyperthyroidism, hypercortisolism, precocious puberty and acromegaly.</p> <p>Case presentation</p> <p>Here, we describe a 12-year-old Caucasian girl with severe facial involvement of fibrous dysplasia, along with massive acromegaly due to growth hormone excess and precocious puberty, with a prolactinoma. Our patient was treated with a bisphosphonate and the prolactin antagonist, cabergoline, resulting in the inhibition of fibrous dysplasia and involution of both the prolactinoma and growth hormone excess. During a follow-up of more than two years, no severe side effects were noted.</p> <p>Conclusion</p> <p>Treatment with bisphosphonates in combination with cabergoline is a suitable option in patients with McCune-Albright syndrome, especially in order to circumvent surgical interventions in patients suffering from polyostotic fibrous dysplasia involving the skull base.</p

Value of biomarkers in osteoarthritis: Current status and perspectives

Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the ‘omics’ (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial

Genetic Effects on Bone Loss in Peri- and Postmenopausal Women: A Longitudinal Twin Study

This longitudinal twin study was designed to assess the heritability of bone loss in peri- and postmenopausal women. A sample of 724 female twins was studied. Baseline and repeat BMD measurements were performed. Results of genetic model-fitting analysis indicated genetic effects on bone loss account for similar to 40% of the between-individual variation in bone loss at the lumbar spine, forearm, and whole body. Introduction: BMD and bone loss are important predictors of fracture risk. Although the heritability of peak BMD is well documented, it is not clear whether bone loss is also under genetic regulation. This study was designed to assess the heritability of bone loss in peri- and postmenopausal women. Materials and Methods: A sample of 724 female twins (177 monozygotic [MZ] and 185 dizygotic [DZ] pairs), 45-82 yr of age, was studied. Each individual had baseline BMD measurements at the lumbar spine, hip, forearm, and total body by DXA and at least one repeat measure, on average 4.9 yr later. Change in BMD (Delta BMD) was expressed as percent of gain or loss per year. Intraclass correlation coefficients for ABMD were calculated for MZ and DZ pairs. Genetic model-fitting analysis was conducted to partition the total variance of ABMD into three components: genetic (G), common environment (C), and specific environment, including measurement error (E). The index of heritability was estimated as the ratio of genetic variance over total variance. Results: The mean annual Delta BMD was -0.37 +/- 1.43% (SD) per year at the lumbar spine, -0.27 +/- 1.32% at the total hip, -0.77 +/- 1.66% at the total forearm, -0.36 +/- 56% at the femoral neck, and -0.16 +/- 0.81% at the whole body. Intraclass correlation coefficients were significantly higher in MZ than in DZ twins for all studied parameters, except at the hip sites. Results of genetic model-fitting analysis indicated that the indices of heritability for ABMD were 0.38, 0.49, and 0.44 for the lumbar spine, total forearm, and whole body, respectively. However, the genetic effect on ABMD at all hip sites was not significant. Conclusions: These data suggest that, although genetic effects on bone loss with aging are less pronounced than on peak bone mass, they still account for similar to 40% of the between-individual variation in bone loss for the lumbar spine, total forearm, and whole body in peri- and postmenopausal women. These findings are relevant for studies aimed at identification of genes that are involved in the regulation of bone loss

Cost of non-persistence with oral bisphosphonates in post-menopausal osteoporosis treatment in France

<p>Abstract</p> <p>Background</p> <p>During the last decade, oral bisphosphonates (BP) became the most widely prescribed pharmacologic class for post-menopausal osteoporosis. However, many surveys revealed the important issue of poor persistence with those drugs resulting in a failure of treatment to reduce fracture risk sufficiently. Using a published Markov model, this study analyses the economic impact of non-persistence with bisphosphonates in the context of the introduction of generics in France.</p> <p>Methods</p> <p>Direct costs of vertebral, hip and wrist fracture were assessed and included in an existing 10-year Markov model developed to analyse consequences of non-persistence. Three alternatives of comparison were set: no treatment, real-world persistence, and ideal persistence. Simulated patients' characteristics matched those from a French observational study and the real-world adherence alternative employed persistence data from published database analysis. The risk of fracture of menopausal women and the risk reduction associated with the drugs were based on results reported in clinical trials. Incremental cost-effectiveness ratios (ICERs) were calculated first between real-world adherence and no treatment alternatives, and second between ideal and real-world persistence alternatives. The cost of non-persistence was defined as the difference between total cost of ideal and real-world persistence alternatives.</p> <p>Results</p> <p>Within fractured women population, mean costs of 10-year management of fracture were significantly different between the three alternatives with €7,239 (± €4,783), €6,711 (± €4,410) and €6,134 (± €3,945) in the no-treatment, the real-world and ideal persistence alternatives, respectively (p < 0.0001). Cost-effectiveness ratio for real-world treatment persistence compared with no-treatment alternative was found dominant and as well, alternative of ideal persistence dominated the former. Each ten percentage point of persistence gain amounted to €58 per patient, and extrapolation resulted in a global annual cost of non-persistence of over €30 million to the French health care system, with a substantial transfer from hospital to pharmacy budgets.</p> <p>Conclusion</p> <p>Within term, improving persistence with oral bisphosphonates should be economically dominant on levels currently known in real-world. Given this potential savings, ambitious adherence-enhancing interventions should be considered in osteoporotic patients.</p

Changes in total body bone mineral density following a common bone health plan with two versions of a unique bone health supplement: a comparative effectiveness research study

<p>Abstract</p> <p>Background</p> <p>The US Surgeon General's Report on Bone Health suggests America's bone-health is in jeopardy and issued a "call to action" to develop bone-health plans that: (1) improve nutrition, (2) increase health literacy and, (3) increase physical activity. This study is a response to this call to action.</p> <p>Methods</p> <p>After signing an informed consent, 158 adults agreed to follow an open-label bone-health plan for six months after taking a DXA test of bone density, a 43-chemistry blood test panel and a quality of life inventory (AlgaeCal 1). Two weeks after the last subject completed, a second group of 58 was enrolled and followed the identical plan, but with a different bone-health supplement (AlgaeCal 2).</p> <p>Results</p> <p>There were no significant differences between the two groups in baseline bone mineral density (BMD) or in variables related to BMD (age, sex, weight, percent body fat, fat mass, or fat-free mass). In both groups, no significant differences in BMD or related variables were found between volunteers and non-volunteers or between those who completed per protocol and those who were lost to attrition.</p> <p>Both groups experienced a significant positive mean annualized percent change (MAPC) in BMD compared to expectation [AlgaeCal 1: 1.15%, <it>p </it>= 0.001; AlgaeCal 2: 2.79%, <it>p </it>= 0.001]. Both groups experienced a positive MAPC compared to baseline, but only AlgaeCal 2 experienced a significant change [AlgaeCal 1: 0.48%, <it>p </it>= 0.14; AlgaeCal 2: 2.18%, <it>p </it>< 0.001]. The MAPC in AlgaeCal 2 was significantly greater than that in AlgaeCal 1 (<it>p </it>= 0.005). The MAPC contrast between compliant and partially compliant subjects was significant for both plans (<it>p </it>= 0.001 and <it>p </it>= 0.003 respectively). No clinically significant changes in a 43-panel blood chemistry test were found nor were there any changes in self-reported quality of life in either group.</p> <p>Conclusions</p> <p>Following The Plan for six months with either version of the bone health supplement was associated with significant increases in BMD as compared to expected and, in AlgaeCal 2, the increase from baseline was significantly greater than the increase from baseline in AlgaeCal 1. Increased compliance was associated with greater increases in BMD in both groups. No adverse effects were reported in either group.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01114685">NCT01114685</a></p

McCune-Albright syndrome

McCune-Albright syndrome (MAS) is classically defined by the clinical triad of fibrous dysplasia of bone (FD), café-au-lait skin spots, and precocious puberty (PP). It is a rare disease with estimated prevalence between 1/100,000 and 1/1,000,000. FD can involve a single or multiple skeletal sites and presents with a limp and/or pain, and, occasionally, a pathologic fracture. Scoliosis is common and may be progressive. In addition to PP (vaginal bleeding or spotting and development of breast tissue in girls, testicular and penile enlargement and precocious sexual behavior in boys), other hyperfunctioning endocrinopathies may be involved including hyperthyroidism, growth hormone excess, Cushing syndrome, and renal phosphate wasting. Café-au-lait spots usually appear in the neonatal period, but it is most often PP or FD that brings the child to medical attention. Renal involvement is seen in approximately 50% of the patients with MAS. The disease results from somatic mutations of the GNAS gene, specifically mutations in the cAMP regulating protein, Gs alpha. The extent of the disease is determined by the proliferation, migration and survival of the cell in which the mutation spontaneously occurs during embryonic development. Diagnosis of MAS is usually established on clinical grounds. Plain radiographs are often sufficient to make the diagnosis of FD and biopsy of FD lesions can confirm the diagnosis. The evaluation of patients with MAS should be guided by knowledge of the spectrum of tissues that may be involved, with specific testing for each. Genetic testing is possible, but is not routinely available. Genetic counseling, however, should be offered. Differential diagnoses include neurofibromatosis, osteofibrous dysplasia, non-ossifying fibromas, idiopathic central precocious puberty, and ovarian neoplasm. Treatment is dictated by the tissues affected, and the extent to which they are affected. Generally, some form of surgical intervention is recommended. Bisphosphonates are frequently used in the treatment of FD. Strengthening exercises are recommended to help maintaining the musculature around the FD bone and minimize the risk for fracture. Treatment of all endocrinopathies is required. Malignancies associated with MAS are distinctly rare occurrences. Malignant transformation of FD lesions occurs in probably less than 1% of the cases of MAS