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Aim of the report This report provides a final assessment by DG JRC of the 'EU MIR form pilot' project, concerning the use of nomenclature for manufacturer incident reporting. The purpose of this analysis is to exploit the submitted data in view of addressing the following key questions: 1. Is reporting of adverse events using nomenclature feasible and helpful? 2. Are existing nomenclatures relating to device problems and evaluations of causes adequate? 3. Is there a need for introducing new terms, e.g. to cover novel technologies? 4. What are the lessons learned from the pilot study in terms of international harmonisation of nomenclatures (IMDRF) and development of future reporting tools (e.g. EUDAMED)? Key findings This report focuses on the use of adverse 'event-type' and 'evaluation' terms which relate to problems with the medical device. The device-related terms were used in a 'Manufacturer Incident Report' form, which was designed for the pilot study, and was called the MIR pilot form. 786 forms, which were submitted by 13 manufacturers reporting from 15 European countries, were analysed. Concerning nomenclature usage, the report analyses whether incidents were reported adequately using (1) existing nomenclature (ISO/TS 19218), (2) newly introduced nomenclature (EDMA's IVD-related terms), and (3) newly proposed terms (by the participating manufacturers of the pilot study). The analysis has shown a number of important issues which concern five main topics: 1. Pilot data relate to approx. 50% of device categories on the market Due to voluntary participation, the submitted MIR pilot forms reflect only a certain proportion of medical devices on the market. This needs to be considered when interpreting and using the pilot data. 2. No participation of SMEs in the pilot project Additional bias may be due to (1) the absence of SME participation; and (2) a single manufacturer submitting >60% of the total number of forms (bias towards a particular device category). 3. Adequacy of term selection by manufacturers We assessed the adequacy of term use by comparing textual incident descriptions with the categorised terms chosen by reporters. It was based on a set of 100 randomly selected pilot forms representative of the pilot's overall device portfolio. Both, the event-type and evaluation terms chosen by manufacturers for reporting incidents were largely adequate. Moreover, the analysis shows that three choices per level to describe the incident (event-type terms) or final investigation (evaluation terms) appear sufficient. 4. Available terminology (ISO/TS 19218) is not fully adequate On the basis of the frequency of some proposed terms it appears that the existing ISO/TS 19218 terms are overall not sufficient. This is not surprising given the fact that the terms were derived from FDA's terminology in 2005 and have, since then, not been updated. To resolve the most frequently encountered issues in the analysis, the JRC has proposed several changes to terms used (cf. Fig. 18-24). 5. Proposals for new terms by manufacturers ISO/TS 19218 uses a 2-level hierarchical coding structure for reporting adverse events. Though the pilot study allowed for new proposals at these levels (level 1, 2), it was particularly designed for new proposals at an additional more granular third level. In line with this is the observation that the majority of new terms proposed concern level three terms. The analysis also showed that, although selection of existing terms was overall adequate, many of the new terms proposed by manufacturers are either redundant or do not reflect device problems but are, in fact, patient outcome terms. This clearly shows a need for reporters to have a better understanding of the terms and the reporting form used. Some of the confusion may stem from the simple fact that ISO's medical device problem terminology is called "Adverse Event Terms", i.e. seemingly suggesting that this nomenclature should be used to report adversity, i.e. clinical phenomena at patient / user level. In cases where level one event-type terms have been proposed, these related mainly (>80%) to the orthopaedic device category (cf. Fig. 13). It therefore appears that there is a need for a more elaborate nomenclature in this device category. Proposed terms that were deemed valid when compared with ISO/TS 19218 were subsequently compared with FDA's terms for device problems. This led to the identification of a number of proposed terms that could be proposed for incorporation into ongoing efforts in the development of a globally used nomenclature in the context of the work of the Adverse Event Terminology Working Group of IMDRF. EDMA has proposed new terms to cover specific needs of reporting incidents with in vitro diagnostic medical devices (IVDs). These were meant to complement the ISO/TS 19218 terms, and several of them have been used in the submissions. A closer look at the definitions of some of EDMA's terms does, however, show that they would need to be revised, for example four terms (corresponding to level 2) have identical definitions adding unnecessary ambiguity to their use. The report also provides in Annex I a summary of agreements reached during the workshop and topics that remain to be addressed when developing future tools for incident reporting including concerns voiced by stakeholders. Annex I also considers additional reflections made after the workshop and provides, as a synthesis, key recommendations for a way forward. In summary, this report shows that the outcome of the 'EU MIR form pilot' project has proven to be extremely useful for three reasons. 1. It confirmed the general feasibility of categorised reporting of incidents by manufacturers. 2. It identified inadequacies of the existing ISO/TS 19218 nomenclature suggesting the need for increased efforts into the development of freely available, scientifically and technically satisfying and, from a regulatory and end-user point of view, adequate nomenclature for adverse event reporting of incidents and events also in the pre-market space. 3. It led to the proposal of several potentially useful terms in view of future developments of nomenclature for incident / adverse event reporting., JRC.F.2-Consumer Products Safety

Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.

Glucocorticoid receptor (GR) transduces the glucocorticoid (GC) signal that could lead to metabolic derangements depending on the tissue responsiveness to GC. We aimed to investigate possible causative relation of the GR functional properties in peripheral blood mononuclear cells of women with polycystic ovary syndrome (PCOS), with their clinical and biochemical characteristics. Thirty women with PCOS [mean age: 26.5 +/- A 5.1 years, mean body mass index (BMI) 24.5 +/- A 5 kg/m(2)], and thirty respective controls were analyzed for the number of GR sites per cell (B (max)), apparent equilibrium dissociation constant (K (d)), and binding potency (GR potency). A strong association between B (max) and K (d) (r = 0.70, P < 0.0001), and GR potency with age (r = 0.49, P = 0.009) was observed in PCOS women. The multiple regression analyses within the PCOS group revealed that independent predictors for K (d) were BMI, total cholesterol, and dehydroepiandrosterone-sulfate (DHEA-S) (r = 0.58, P = 0.038), while for GR potency (r = 0.687, P = 0.013) were age, BMI, DHEA-S, and basal cortisol concentration. The results suggest that PCOS pathophysiology may be related to alterations of a cross stalk between glucocorticoid signaling, age, and metabolic parameters. These findings should be further explored in studies on the role of GR in PCOS-related metabolic derangements. Ministry of Science of Serbia [143003]

Objective: To assess total, active and active to total serum ghrelin ratio in normal weight women with polycystic ovary syndrome (PCOS) and in healthy ovulatory control women.Study design: The study included 50 normal weight women with PCOS with a mean age of 23.70 +/- 4.99 years and 10 control women with a mean age of 30 +/- 5.80 years. The diagnosis of PCOS was based on the presence of biochemical hyperandrogenemia, chronic anovulation and polycystic ovarian morphology according to the Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group. Serum total and active ghrelin were measured by RIA, using commercially available kits. Results: A significantly lower serum active/total ghrelin ratio was noted in the more severe form of PCOS with hyperandrogenemia, chronic anovulation and polycystic ovarian morphology. Both total and active serum ghrelin levels were negatively correlated to hirsutism score, to plasma glucose levels and to QUICKI and HOMA-IR indices of Insulin Resistance. A statistically significant difference was detected between the more severe and the milder forms of PCOS, concerning serum levels of total ghrelin (p = 0.017), active ghrelin (p = 0.007) and the active/total ghrelin ratio (p = 0.026). Conclusions: The results of the present study demonstrate an altered active to total ghrelin ratio, as well as a tendency towards lower both total and active fasting serum ghrelin levels in normal weight PCOS, more pronounced in the more severe forms of the syndrome. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Background: The present study was designed to measure plasma visfatin levels in normal weight with polycystic ovary syndrome (PCOS) and to assess possible correlations between visfatin and the hormonal or metabolic parameters of the syndrome. Methods: Twenty-five normal weight [body mass index (BMI) < 25 kg/m(2)] women with PCOS, 24 obese and overweight (BMI > 25 kg/m(2)) controls (ovulating women without clinical or biochemical hyeperandrogenism), and 24 normal weight controls were studied. Blood samples were collected between the 3rd and the 7th days of menstrual cycle in the control groups and during a spontaneous bleeding episode in the PCOS groups at 9:00 A.M., after an overnight fast. Circulating levels of LH, FSH, prolactin (PRL), testosterone (T), Delta 4-androstenedione (Delta 4-A), dehydroepiandrosterone sulfate (DHEA-S), 17 alpha-OH-progestrone (17OH), sex hormone-binding globulin (SHBG), insulin, glucose, and visfatin were measured. Results: Plasma visfatin levels and the visfatin-to-insulin ratio were significantly lower in normal weight controls than in both normal weight women with PCOS and overweight or obese controls. Plasma visfatin levels were found to be positively correlated with LH and Delta(4)A levels, as well as with free androgen index (FAI) values, and negatively correlated with SHBG, LH and SHBG levels were found to be the only independent significant determinants of circulating visfatin. In the control groups, plasma visfatin levels were significantly correlated with BMI, waist (W) measurement, and waist-to-hip ratio (WHR). Conclusions: Visfatin levels are positively associated with obesity in healthy women of reproductive age. Moreover, the present study indicates, for the first time, a possible involvement of increased visfatin levels in PCOS-associated metabolic and hormonal disturbances. (c) 2007 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

The aim of the present study was to investigate the localization/immunohistochemical distribution of AGEs and RAGE, as well as their putative signalling mediator NF-kappa B in ovaries of women with polycystic ovary syndrome (PCOS) compared to normal. Archival ovarian-tissue samples from biopsies of six women with PCOS and from six healthy of similar age women, were examined immunohistochemically with monoclonal anti-AGEs, anti-RAGE and anti-NF-kappa B(p50/p65) specific antibodies. In healthy women, AGE immunoreactivity was observed in follicular cell layers (granulosa and theca) and luteinized cells, but not in endothelial cells. PCOS specimens displayed AGE immunoexpression in theca interna and granulosa cells as well as in endothelial cells, but staining of granulosa cells was stronger than in that of normal ovaries. RAGE was highly expressed in normal and PCOS tissues. Normal tissue exhibited no staining differences between granulosa cell layer and theca interna. However, in PCOS ovaries, granulosa cells displayed stronger RAGE expression compared to theca interna cells in comparison to controls. NF-kappa B(p50/p65) was expressed in the cytoplasm of theca interna and granulosa cells of both normal and PCOS ovaries; whereas the NF-kappa B p65 subunit was only observed in granulosa cells nuclei in PCOS tissue. In conclusion, these findings demonstrate for the first time that RAGE and AGE-modified proteins with activated NF-kappa B are expressed in human ovarian tissue. Furthermore, a differential qualitative distribution of AGE, RAGE and NF-kappa B p65 subunit was observed in women with PCOS compared to healthy controls, where a stronger localization of both AGE and RAGE was observed in the granulosa cell layer of PCOS ovaries.

Metformin therapy in polycystic ovary syndrome (PCOS) improves metabolic and hormonal profiles. Its therapeutic effect on cardiovascular risk factors is under investigation. Advanced glycation end products (AGEs), well-known atherogenic molecules, were recently found to be elevated in plasma of women with PCOS. The purpose of the study was to investigate the effect of metformin treatment in plasma AGE levels of women with PCOS. This was a descriptive clinical trial. The study involved 22 patients with PCOS (age, 25.09 +/- 1.05 years; body mass index [BMI], 28.44 +/- 1.51 kg/m(2)) and 22 healthy women (age, 26.50 +/- 0.85 years; BMI, 25.62 +/- 1.30 kg/m(2)). Measurements of plasma AGE levels (U/mL) were performed, and the metabolic and hormonal profiles were determined in all subjects. All women with PCOS received a dose of 1700 mg metformin daily for 6 months. AGEs levels were reduced after metformin administration in 22 women with PCOS (9.98 +/- 0.13 [before metformin] vs 9.86 +/- 0.11 [after metformin], P =.05). In a subgroup analysis, of 16 women with PCOS and normal glucose tolerance, the drop of AGE levels was potentiated (9.98 +/- 0.19 [before] vs 9.81 +/- 0.15 [after], P =.02). Body mass index as well as the other parameters studied remained unchanged after metformin therapy apart from a drop of testosterone levels (P =.01) and free androgen index (P =.009). In conclusion, after metformin therapy, the atherogenic AGE molecules were reduced in the serum of women with PCOS. The clinical relevance of this finding in PCOS, a high-risk group for type 2 diabetes mellitus and cardiovascular disease, remains to be seen. Future studies are required to confirm the need of therapeutic intervention for short-term abnormalities and for prevention of long-term sequelae characterizing this syndrome. (c) 2007 Elsevier Inc. All rights reserved.

Objective: This study was designed to: [1] measure, for the first time, metastin (kisspeptin) levels in women with polycystic ovary syndrome (PCOS), a condition associated with hypersecretion of LH and hyperandrogenemia; and [2] investigate the possible correlations between metastin and PCOS-related reproductive and metabolic disturbances. Design: Clinical study. Setting: University hospital. Patient(s): Twenty-eight obese and overweight (body mass index [BMI] > 25 kg/m(2)) women with the syndrome, and 13 obese and overnight controls (ovulatory women without clinical or biochemical hyperandrogenemia) were selected. Intervention(s): Blood samples were collected between day 3 and day 6 of a sponataneous bleeding episode in the PCOS groups and a menstrual cycle of the controls, at 9:00 AM, after an overnight fast. Main Outcome Measure(s): Circulating levels of LH, FSH, PRL, T, Delta(4)-androstenedione (A), DHEAS, 17 alpha OH-P, sex hormone-binding globulin (SHBG), insulin, glucose, and metastin were measured. Result(s): Both normal weight women with PCOS and obese controls were less insulin resistant and had significantly higher metastin levels, compared to obese and overweight women with the syndrome. Plasma kisspeptin levels were negatively correlated with BMI, free androgen index, and indices of insulin resistance. Conclusion(s): These results indicate that metastin is negatively associated with free androgen levels. The PCOS-associated insulin resistance and consequent hyperinsulinemia probably contribute to this effect by [1] stimulating androgen synthesis by the polycystic ovary (PCO) and [2] suppressing SHBG production in the liver.