Panagiotis ; Anagnostis

Dr Zoe A Efstathiadou

Stergios A Polyzos

Fotini Adamidou

Aristidis Slavakis

Michalis Sapranidis

Ioannis D Litsas

Simoni Katergari

Despina Selalmatzidou

Marina Kita

Dr Graham Jackson

Aristides Slavakis

Acromegaly: presentation, morbidity and treatment outcomes at a single centre

Keywords: Acromegaly, Growth hormone, Insulin-like growth factor-1, Transsphenoidal surgery, Somatostatin analogues

come

Reviewer: 2 General and specific comments to the authors In this retrospective study are reported the clinical characteristics, the efficacy of treatment, and the morbidity in a cohort of 115 acromegalic patients with mean follow-up 8.8 years from a single center in Greece. These data are valuable though the number of patients is relatively small. However there are some points that should be stressed. 1. The assessment of good disease control is based on targets, which have been set by consensus. However, since epidemiological studies have shown that active acromegaly is associated with increased mortality the targets that establish the remission of the disease have recently changed, as you also have mentioned in the text. For the sake of clarity for the reader I consider that the recent guidelines should follow the previous ones.

We acknowledge that comment and we make a comment about the previous guidelines before the most recent ones in page 5, 1 st paragraph, lines 2-4: "Till recently, the consensus guidelines for acromegaly cure recommended normal age-and sex-adjusted IGF-I levels, along with a nadir GH<1 µg/L during an OGTT, irrespective of concurrent treatment [START_REF] Melmed | Guidelines for acromegaly management: an update[END_REF]. The latest....." 2. It is known that the lack of reliable assays for serum GH and IGF-1 measurements is a major issue in the interpretation of the results. Therefore it is important to be presented the characteristics of the assays used regarding at least the used standard and their sensitivity.

We acknowledge the reviewer's comment and we have inserted a paragraph in the methods section, page 6, 2 nd paragraph, lines 6-8:

"The detection limits and assay analytical sensitivity for ICMA method are 0.05-40 ng/ml and 0.01 ng/ml respectively for GH and 0.00-1600 ng/ml and 20 ng/ml for IGF-I."

3. Authors comment on the importance of an experienced surgeon and speculate that the results of their series could be better if they had an experienced pituitary neurosurgeon. This raises a question about the neurosurgeon's experience and skillful. This lack of clearness should be resolved.

We have added a new reference on the subject and two sentences clarifying the matter in page 14, 2 nd paragraph, lines 2-6: "A recent review has shown that focused clinical practice and large transsphenoidal surgical volume appear to be important outcome determinants for patients with pituitary tumors [START_REF] Shahlaie | The role of outcomes data for assessing the expertise of a pituitary surgeon[END_REF]. The fact that in our country there is no regionalization of care to higher volume pituitary tumor centers of excellence is a major drawback to better surgical outcomes. Consequently….." 4. The role of SSA therapy in achieving tumor shrinkage is not well defined. Some data in the literature indicate that the presurgical use of SSA may improve surgical outcome. Is there any evidence in your data regarding this issue? Since there were only 7 patients who received pharmacotherapy prior to surgery, no safe conclusions can be drawn for that matter. adenomas secreting GH. However, its beneficial effect appears progressively over years. It would be interesting to comment on this in your cohort.

We comment that in the discussion session: page16, last paragraph, lines 1-2. To further clarify that we have added the sentence: "Conventional radiotherapy is usually used as an adjuvant therapy in pituitary adenomas secreting GH. However, its beneficial effect appears progressively over years", at the beginning of the same paragraph.

Furthermore, the time of remission is described in the sentence (lines 7-9): "It must be noted that radiotherapy outcomes were manifest at 12-34 years of follow-up, except for 1 patient, who had already achieved remission at 7 years." 6. Two inconsistencies are noticed in Table 1; In the second row "surgery alone" it appears that from the 22 patients, remission was achieved in 9 patients but this number is not equal to the sum of micro-and macroadenomas in remission (last two columns). The same inconsistency is also observed in the fourth row "Surgery/Radiotherapy" This inconsistency is due to the fact that the initial size was not available in 2 patients, 1 treated with surgery alone and 1 with surgery/radiotherapy. Both achieved remission, as it is stated in the comments at the bottom of the table 1. (We have corrected surgery/pharmacotherapy to surgery/radiotherapy (comments in table 1).

We thank you again for the constructive comments, which were contributed to our manuscript. Having addressed all these comments we hope that the revised manuscript would be acceptable for publication at the International Journal of Clinical Practice. What's known:

Sincerely,

• Acromegaly is a rare chronic disease characterized by hypersecretion of GH, which leads to an increased production of IGF-I.

• Acromegaly is associated with significant morbidity and an increased mortality rate.

• Transsphenoidal surgery is the first line treatment for acromegaly. In case of persisting disease treatment with somatostatin analogues and/or radiotherapy (conventional or γ-knife) are applied.

What's new:

• Neurosurgery alone is not effective for disease control in the majority of cases.

• Medical therapy with SSA, either as adjuvant to surgery, or as monotherapy is effective, but might have unfavourable side-effects, such as impaired glusose homeostasis and cholelithiasis.

• Remission of the disease is usually achieved by combination of multiple treatment modalities.

Introduction

Acromegaly is a rare chronic disease characterized by hypersecretion of GH which leads to an increased production of IGF-I (1-2). In the majority of cases (>95%) it results from a GH-secreting pituitary adenoma (1-2).

The incidence of acromegaly is about 3 cases per million persons with an estimated prevalence of 60 per million [START_REF] Holdaway | Epidemiology of acromegaly[END_REF]. The disease onset takes place during the 4 th decade of life with an equal distribution between genders (1-2).

Acromegaly affects almost every organ and is associated with increased morbidity and mortality mainly due to the aggregate of cardiovascular risk factors such as hypertension, diabetes mellitus (DM) and lipid disorders and to the appearance of cardiomyopathy associated with the disease [START_REF] Colao | Systemic complications of acromegaly: epidemiology, pathogenesis, and management[END_REF]. In a recent meta-analysis of 16 series, the mortality ratio of patients with acromegaly was 1.72 compared with the general population, and remained high (1.32) even after surgical management of the disease [START_REF] Dekkers | Mortality in acromegaly: a metaanalysis[END_REF].

Despite the progress that has been made over the years in terms of therapeutic modalities, acromegaly still remains under-diagnosed, with a mean delay of 7-10 years after the estimated onset of symptoms (1-2). The introduction of highly sensitive and specific GH assays has recently led to a re-evaluation of the biochemical criteria needed for the diagnosis of acromegaly. This is based on nadir GH levels >1 µg/L during an oral glucose tolerance test (OGTT) in combination with IGF-I above the upper level of normal for age and sex (1-2).

Although remarkable advances in terms of the medical management of the disease have been made, transsphenoidal surgery (TSS) remains the treatment of choice resulting in disease control in 75-95% of patients harbouring microadenomas and in 40-68% of those with macroadenomas [START_REF] Melmed | Acromegaly[END_REF][START_REF] Giustina | Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults[END_REF][START_REF] Melmed | Guidelines for acromegaly management: an update[END_REF]. In case of persisting disease after surgical and medical approach, radiotherapy (conventional or γ-knife) is a reasonable approach (1-2, 6). Till recently, the consensus guidelines for acromegaly cure recommended normal age-and sex-adjusted IGF-I levels, along with a nadir GH<1 µg/L during an OGTT, irrespective of concurrent treatment [START_REF] Melmed | Guidelines for acromegaly management: an update[END_REF]. The latest guidelines for acromegaly cure recommend random GH <1 µg/L or nadir GH <0.4 µg/L during an OGTT combined with age-and sex-adjusted normal IGF-I levels [START_REF] Giustina | A consensus on criteria for cure of acromegaly[END_REF]. If IGF-I and GH are elevated, additional therapy should be considered [START_REF] Melmed | Guidelines for acromegaly management: an update[END_REF][START_REF] Giustina | A consensus on criteria for cure of acromegaly[END_REF]. In case of discordant IGF-I and GH measurements -in most cases normal GH and elevated IGF-I ( 7), the decision for acromegaly management should be based on clinical judgement [START_REF] Melmed | Guidelines for acromegaly management: an update[END_REF]. In these cases, multiple GH sampling is also recommended [START_REF] Giustina | A consensus on criteria for cure of acromegaly[END_REF].

The aim of the present study was to describe the clinical characteristics, the morbidity and the efficacy of treatment in a cohort of patients with acromegaly, who were followed-up at a single centre.

Patients and methods

This was a retrospective study conducted in the department of Endocrinology in "Hippokration" General Hospital of Thessaloniki, Greece, a tertiary referral centre for endocrinology and diabetes. Data from all patients who were diagnosed with acromegaly or referred to the centre with the diagnosis of acromegaly between 1987 and 2009 were extracted from the department's electronic database and thoroughly reviewed. Inclusion criteria were: 1) abnormal nadir GH levels (>1 µg/L) during a 75g OGTT along and/or abnormal IGF-I levels for age and gender 2) imaging characteristics suggestive of a pituitary adenoma 3) at least 1 complete clinical and biochemical assessment. Disease remission was defined by normal IGF-I for sex and age along with nadir GH <1 µg/L, for GH measurements after the year of 2000, when The assays used for GH measurement changed over the years. For the period 1987-1999, radioimmunoassay (RIA) was used, while from 2000 and thereafter GH was measured by an immunochemiluminencent assay (ICMA) (Immulite 2500, DPC, Los Angeles, USA). ICMA was also used for IGF-I assessment from 2000 to 2009, while before 2000, it was measured using enzyme-linked immunosorbent assay (ELISA). The detection limits and assay analytical sensitivity for ICMA method are 0.05-40 ng/ml and 0.01 ng/ml respectively for GH and 0.00-1600 ng/ml and 20 ng/ml for IGF-I.

All patients underwent physical examination, visual field perimetry and basal biochemical assessment. In addition, laboratory evaluation of the other pituitary hormones was performed in order to unmask potential pituitary deficiencies: LH/FSH, ACTH, TSH, both before and after surgical intervention. In case of signs and symptoms of hypopituitarism, stimulation tests were performed. Gonadotrophin Macroadenomas were defined as those with maximum diameter >1cm, and microadenomas when maximum diameter was ≤1cm. The duration of follow-up was estimated as the time between the first and last GH secretion assessment.

Statistical analysis

Data for continuous variables are presented as mean ± standard error of the mean (SE). Data for categorical variables are presented as numbers and/or percentages. Kolmogorov-Smirnov test was used to check the normality of distribution of continuous variables. Chi-square test or Fischer's exact test were used to identify differences between categorical variables. Independent-sample T-test or Mann-Whitney test was used to identify differences between two independent groups of continuous variables. The analysis of variance (ANOVA) or Kruskal-Wallis test were used to identify differences among three or more groups of continuous variables. The General Linear Model (GLM) (repeated measures ANOVA) was used to identify differences within continuous variables in cases of serial measurements. Adjustment for violations of the sphericity assumption was performed with the Greenhouse-Geisser correction. Bivariate correlations were tested by Pearson's (r) or Spearman's (r s ) coefficients of correlation. A p value less than 0.05 was considered statistically significant in all the above tests. Statistical analysis was performed with SPSS 13.0 for Windows (SPSS Inc., Chicago, Illinois, USA). The mean age at diagnosis was 47±1 years (range 14-84). The mean size of adenomas was 1.7±0.1 cm (range 0.4-4.0); 26% were microadenomas and 74% macroadenomas with extrasellar extension in 44%. In 2 cases acromegaly was detected on radiological examination performed for signs/symptoms unrelated to pituitary disease, that is, head trauma in one case and stroke in the other. There was a strong correlation between GH and nadir GH (r=0.961, p<0.001) at baseline.

Results

Patient characteristics

Both GH and nadir GH were also correlated with adenoma size (r=0.293, p=0.030 and r=0.324, p=0.020, respectively). The mean duration of follow-up was 8.8±0.8 years (range 0-22). Follow-up data for ≥12 months were available for 93 patients.

Morbidity associated with acromegaly

At baseline

At presentation, visual field defects were detected in 36 of the 84 cases (43%) whose perimetry tests were available. Five patients (14%) with visual disorders were harbouring microadenomas with diameter 0.9-1 cm.

In terms of acromegaly-related morbidity, 46% of the patients presented with arterial hypertension (data available for 84). Data on glucose homeostasis were available for 87 patients at presentation and were diagnostic for DM in 25%, for impaired glucose tolerance (IGT) in another 25%. Dyslipidemia was present in 35% (data available in 60 subjects).

At follow-up

Of the 93 acromegalic patients with available follow-up data, 10 (11%) were diagnosed with coronary artery disease and 46 (50%) had cardiac hypertrophy on

Treatment Surgical treatment

Pituitary surgery was performed in 73 patients with follow-up data (79%). Of these, 6 (8%) were operated twice, due to uncontrolled or recurrent disease. The majority of the surgical procedures (n=64, 88%) were performed by the transsphenoidal route. In 10 cases with invasive tumours, transcranial surgery was selected-in 2 of them secondary to transsphenoidal approach. In 1 case the surgical approach was not known. Except for the tumour's size and the invasion into neighbouring structures, the choice of surgical approach was also based on neurosurgeon's experience. Twenty-two patients were exclusively managed with neurosurgery and remission was reported in 9 (41%). Three had microadenomas and 5 macroadenomas, while initial size was not available in 1. Interestingly, only 1 in 6 macroadenomas with extrasellar extension achieved remission after surgery alone. In 1 patient managed successfully with surgery alone initial size was unknown (table 1).

Radiotherapy

Conventional radiotherapy -at a standard dose of 45 Gy in 25 fractions-was selected for 27 patients (29%) either as monotherapy or adjuvant to either surgery or SSA. It involved macroadenomas in 24 cases. In general, remission was observed in 14 irradiated patients (52%). Twenty patients (27% of the surgically treated) received conventional radiotherapy post-surgically, either alone or in combination with pharmacotherapy [mainly SSA and/or dopamine agonists (DA)], while 1 patient was managed with γ-knife plus SSA postoperatively.

Remission was reported in 5 of the 8 patients (63%) who received radiotherapy as adjuvant to neurosurgery. On the other hand, in a total of 12 patients with refractory disease, where SSA treatment was necessary after surgery and radiotherapy, only 4 finally responded. (table1).

Pharmacotherapy

Pharmacotherapy was the exclusive treatment in 13 patients (9 micro-and 4 macroadenomas). SSA were the agents of choice with the exception of 2 patients who received DA. Lack of compliance and/or patient's refusal was the reason for not selecting SSA in these patients. DA treatment was not successful. On the contrary, SSA treatment led to remission in 8 patients (73% of those exclusively on SSA). It is noteworthy that all the responders had microadenomas, whereas no macroadenoma achieved remission with SSA alone. Treatment with pegvisomant either alone or in combination with SSA was preserved for 4 patients (2 males and 2 females) with refractory disease, after having undergone surgical therapy, radiotherapy and SSA administration. Two patients achieved remission at 6-8 months of follow-up, at a daily dose of 10mg as monotherapy, whereas the other 2, despite being on a combination regimen with SSA, have persistently active acromegaly.

Combination of neurosurgery and pharmacotherapy was reported in 30 patients: in 7 prior to surgery, in 13 post-surgery and in 10 both pre-and postsurgery. Two patients received DA treatment, whereas the rest were treated with SSA.

Remission was achieved in 16 (53%). In particular, 100% of microadenomas (n=8) and 43% (n=6) of macroadenomas managed with this approach showed no evidence of active disease during follow-up (table 1).

Effect of different treatment modalities on adenoma size, visual fields and pituitary function

Adenoma size and GH/IGF-1 levels

With respect to adenoma size, 11 of 17 microadenomas (65%) and 21 of 53 macroadenomas (40%) achieved tumour shrinkage after surgery (alone or with concomitant radiotherapy or pharmacotherapy) (p= 0.081). Baseline adenoma size was not available in 2 cases.

Disease remission was independent of the tumour invasiveness: remission was achieved in 8 cases (38%) with extrasellar extension, compared with 6 cases (38%) in which adenoma growth was limited in the sellar space (p=0.97). During the first 5 years, GH, IGF-1 and tumor size decreased significantly. The changes in GH, GH nadir , IGF-I and adenoma size during a 5 year follow-up are presented in table 2. However, no significant association was observed between baseline GH (p= 0.28), nadir GH (p=0.227) or IGF-I (p=0.512) and treatment outcomes.

Visual field defects

Twenty-five patients with visual field defects were operated and 14 showed improvement postoperatively. Another 5 patients received only pharmacotherapy, which resulted in better perimetry tests in 2. Among the three patients who were managed exclusively with pituitary irradiation only 1 had a positive response in vision. Follow-up data regarding changes in visual disorders were absent in 6 patients.

Pituitary reserve

Post-treatment, partial or total hypopituitarism was detected in 33 cases, in contrast with the finding of only 8 cases of hypopituitarism at baseline (p=0.001).

Post-surgery, after the exclusion of patients submitted to complementary conventional radiotherapy or radiosurgery, 16 patients developed hypopituitarism. Interestingly, none of 7 patients treated with radiotherapy alone or plus SSA presented hypopituitarism during follow-up.

Discussion

This retrospective study outlines the actual presentation and management of acromegalic patients at a single endocrine centre in Greece. The acromegalics in the present cohort had increased morbidity in keeping with previous series. However, more patients were reported to have arterial hypertension than in other European registries: 46% vs. 39% in both the Belgian [START_REF] Bex | AcroBel--the Belgian registry on acromegaly: a survey of the 'real-life' outcome in 418 acromegalic subjects[END_REF] and the Spanish (10) studies. In addition, higher rates of cholelithiasis were reported after SSA treatment: 53% vs. 31% in Acrobel [START_REF] Bex | AcroBel--the Belgian registry on acromegaly: a survey of the 'real-life' outcome in 418 acromegalic subjects[END_REF] and 15% in REA [START_REF] Mestron | Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA)[END_REF]. This observation might reflect the very strict selection of patients for ultrasound testing.

Furthermore, diabetes onset after SSA was reported in 45%, a little bit higher than in the REA registry.

The aims of therapy in acromegaly are suppression of GH hypersecretion, normalization of IGF-I levels and control of tumor size, as well as preservation of normal pituitary function. Using the aforementioned criteria, the overall success rate in our series was 52% -65% for microadenomas and 41% for macroadenomas. These percentages are in close proximity with the rates presented in Acrobel (49%) [START_REF] Bex | AcroBel--the Belgian registry on acromegaly: a survey of the 'real-life' outcome in 418 acromegalic subjects[END_REF] and in West Midlands studies (46%) [START_REF] Ayuk | Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly[END_REF].

Although the number of patients was small for drawing safe conclusions for the effectiveness of surgery, this approach was not proven successful as exclusive therapeutic means for most patients. Remission was achieved in 34 (48%) patients who underwent surgery. Only 50% of microadenomas and 33% of macroadenomas (none of those with extrasellar extension) were in remission after surgery. This is in accordance with other "real life" observational series [START_REF] Bex | AcroBel--the Belgian registry on acromegaly: a survey of the 'real-life' outcome in 418 acromegalic subjects[END_REF]. Surgical series that adopted the current remission criteria -nadir GH<1 µg/L and/or postoperative random GH levels ≤2.5 µg/L and normal sex-and age-adjusted IGF-I level-have reported remission rates of 52-70% [START_REF] Kreutzer | Surgical management of GHsecreting pituitary adenomas: an outcome study using modern remission criteria[END_REF][START_REF] Beauregard | Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly[END_REF][START_REF] Nomikos | The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical 'cure[END_REF]. The timing of post-surgical GH status evaluation seems to play a capital role on the outcome, since higher cure rates are reported short term after pituitary surgery and tend to dramatically weaken with time [START_REF] Biermasz | Ten-year follow-up results of transsphenoidal microsurgery in acromegaly[END_REF]. In our The outcomes of surgical intervention are mainly dependent on initial adenoma size and preoperative basal GH levels. In particular, an inverse relationship between surgical outcomes and adenoma size as well as basal GH levels has been described [START_REF] Nomikos | The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical 'cure[END_REF][START_REF] Abosch | Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results[END_REF].

Remission rates have been reported in 75-95% of microadenomas and in 40-71% of macroadenomas [START_REF] Nomikos | The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical 'cure[END_REF][START_REF] Abosch | Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results[END_REF]. Extrasellar tumour growth and dural invasion by the adenoma are associated with poor outcomes (about 30%) [START_REF] Nomikos | The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical 'cure[END_REF][START_REF] Abosch | Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results[END_REF]. Regarding the impact of basal GH levels on surgical outcomes, different thresholds have been used and, in general, remission rates are about 86-90% in patients with basal GH <10 µg/L, which may drop to 50% and 25% for GH levels >25 µg/L and >50 µg/L respectively [START_REF] Nomikos | The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical 'cure[END_REF][START_REF] De | Transsphenoidal surgery for acromegaly in wales: results based on stringent criteria of remission[END_REF][START_REF] Fahlbusch | Surgical management of acromegaly[END_REF]. In our series, there was a significant association between surgical outcomes and initial adenoma size, since we found that patients who achieved remission had significantly smaller adenomas at baseline in comparison with those with uncontrolled disease. However, no significant association was observed between baseline GH nadir GH or IGF-I and treatment outcomes.

The importance of an experienced surgeon, exclusively for the pituitary, cannot be adequately stressed. A recent review has shown that focused clinical practice and large transsphenoidal surgical volume appear to be important outcome determinants for patients with pituitary tumors [START_REF] Shahlaie | The role of outcomes data for assessing the expertise of a pituitary surgeon[END_REF]. The fact that in our country there is no regionalization of care to higher volume pituitary tumor centers of excellence is a major drawback to better surgical outcomes. Consequently, the lack of better surgical outcomes in our study could partly be attributed to the lack of a single efficiently trained and experienced pituitary surgeon at our region.

Medical therapy as adjuvant to surgery resulted in remission in about half of the patients. Interestingly, all microadenomas and less than half of macroadenomas responded to SSA. Improved outcomes with combination therapy have also been reported by others [START_REF] Beauregard | Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly[END_REF]. It seems that surgical tumor debulking enhances the response to SSA [START_REF] Colao | Partial surgical removal of growth hormone-secreting pituitary tumors enhances the response to somatostatin analogs in acromegaly[END_REF]. Moreover, a high proportion of microadenomas (89%) achieved remission with SSA monotherapy, in contrast to none of macroadenomas. Although the number of these patients was small, the success rates were higher than usually demonstrated [START_REF] Melmed | Guidelines for acromegaly management: an update[END_REF]. More specifically, remission has been reported in up to 80% of the microadenomas (and intrasellar macroadenomas), but in less than 50% for larger macroadenomas [START_REF] Giustina | Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults[END_REF][START_REF] Melmed | Guidelines for acromegaly management: an update[END_REF][START_REF] Sheppard | Primary medical therapy for acromegaly[END_REF][START_REF] Colao | Octreotide LAR vs. surgery in newly diagnosed patients with acromegaly: a randomized, open-label, multicentre study[END_REF].

Although, there is a wide consensus that TSS is the first treatment choice for patients with acromegaly, SSA are increasingly being used as first-line therapy. Of note, a recent study comparing TSS with octreotide-LAR as first-line therapy in acromegalics (harbouring mainly macroadenomas) reported similar results in terms of optimal disease control at 48-week interval [START_REF] Colao | Octreotide LAR vs. surgery in newly diagnosed patients with acromegaly: a randomized, open-label, multicentre study[END_REF]. Additional data indicate that SSA monotherapy may offer equivalent biochemical control to secondary treatment after unsuccessful surgery or radiotherapy [START_REF] Newman | Octreotide as primary therapy for acromegaly[END_REF]. Furthermore, in terms of adenoma size, shrinkage >20% occurs in about 50-75% of acromegalics receiving SSA [START_REF] Giustina | Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults[END_REF][START_REF] Melmed | Guidelines for acromegaly management: an update[END_REF], although this percentage was lower in the present series.

Interestingly, about half of the patients having received SSA in our study developed cholelithiasis, as well as IGT or DM. Gallstones are a frequent entity in acromegalics treated with SSA, may occur at any time, but rarely are symptomatic or require acute surgery [START_REF] Attanasio | Somatostatin analogs and gallstones: a retrospective survey on a large series of acromegalic patients[END_REF]. In addition, SSAs exert an unfavourable effect on glucose metabolism, due to their inhibitory effect on pancreatic insulin secretion [START_REF] Ronchi | Effects of two different somatostatin analogs on glucose tolerance in acromegaly[END_REF], which must be taken into account during therapy.

Conventional radiotherapy is usually used as an adjuvant therapy in pituitary adenomas secreting GH. However, its beneficial effect appears progressively over It is reported to lead to biochemical control in about 50-60% of the cases of acromegaly [START_REF] Giustina | Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults[END_REF][START_REF] Melmed | Guidelines for acromegaly management: an update[END_REF], which is in line with results of our series. Postoperative radiotherapy was more effective than surgery alone, as also shown in other reports [START_REF] Beauregard | Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly[END_REF][START_REF] Trepp | Treatment outcomes and mortality of 94 patients with acromegaly[END_REF]. Radiotherapy as monotherapy or with adjuvant treatment with SSA was equally successful; however the number of patients was small for safe conclusions. It must be noted that radiotherapy outcomes were manifest at 12-34 years of follow-up, except for 1 patient, who had already achieved remission at 7 years. Consequently, data on radiotherapy can lead to safe conclusions on disease activity (>10 years of follow-up).

Nevertheless, radiotherapy carries some risks that cannot be overlooked such as hypopituitarism, and higher incidence of a second intracranial tumour or cerebrovascular events [START_REF] Giustina | Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults[END_REF][START_REF] Melmed | Guidelines for acromegaly management: an update[END_REF]. Interestingly, with a longer than 10-year follow-up interval, none of our patients undergoing radiotherapy alone or with SSA experienced hypopituitarism in contrast to 2/3 of those treated with combination of surgery plus radiotherapy and to 1/3 of those with surgery alone. Successful treatment usually controls the commorbidities associated with acromegaly to variable degrees, but some may persist despite biochemical control [START_REF] Melmed | Acromegaly[END_REF][START_REF] Giustina | Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults[END_REF]. However, even partial control of the disease may result in significant improvement of these commorbidities, as we have previously reported [START_REF] Delaroudis | Amelioration of cardiovascular risk factors with partial biochemical control of acromegaly[END_REF]. Both GH and IGF-I (mainly GH) correlate with mortality and, when they are controlled, mortality is close to the levels expected in the general population [START_REF] Giustina | Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults[END_REF].

Despite the meticulous data recorded from our department's database throughout the years, we acknowledge the following limitations to our study: 1) it constitutes a retrospective study, but it reflects the "real life" approach and problems of patients with acromegaly in Greece; 2) the number of patients might look small in an era of national acromegaly databases, but it derives from the larger endocrine centre of northern Greece and, to our knowledge, this is the first report on Greek population; 3) data on commorbidities were sometimes missing; 4) mortality assessement was not possible.

In conclusion, in this series, acromegaly was characterized by a wide range of systematic complications. Neurosurgery remains the cornerstone of treatment. An increase in remission rates was achieved with complementary conventional radiotherapy. However, the longitudinal risk of postoperative hypopituitarism was higher with this combination. Medical treatment was effective as adjuvant to surgery for macroadenomas and even as monotherapy for microadenomas. Yet, the appearance of cholelithiasis and abnormal glucose homeostasis are important unfavourable events with these agents.

F

  with increased rates of cholelithiasis and impaired glucose homeostasis.

  cure of acromegaly changed[START_REF] Giustina | Criteria for cure of acromegaly: a consensus statement[END_REF]. For the years 1987-1999, a cut-off value for nadir GH of 2 µg/L was used. In case of discordant IGF-I and GH results, the decision for further therapeutic interventions was based on clinical judgment.

  deficiency was defined as low or 'inappropriately normal' LH and FSH levels combined with serum testosterone and serum oestradiol below the reference range or inadequate response to (LH-Releasing Hormone) LHRH test. ACTH deficiency was detected in case of an insufficient increase (<18 µg/dl) in cortisol levels during a cosyntropin-stimulation test or a glucagon-stimulation test. TSH-deficiency was determined by low or 'inappropriately normal' TSH with thyroid hormone levels (free T4 and/or free T3) below the normal range.The patients were revaluated at 6-to 12-month intervals by clinical, routine biochemical laboratory and hormonal (IGF-I and GH levels during an OGTT) by MRI. CT was the only means available for pituitary imaging before 1993. Shorter intervals between follow-up visits were applied in cases of significant alterations in clinical status or changes in therapeutic regimen.

  ninety-three patients were retrieved from our electronic database with a pituitary adenoma. One hundred and fifteen patients (45 males and 70 females) met the study's criteria.

  -five percent of those undergoing colonoscopy had polypodiasis, 74% mono-or multinodular thyroid disease assessed by ultrasonography and 18% of those submitted to abdominal CT or MRI were harbouring an adrenal mass.Cholelithiasis was detected in 20 of 44 patients examined by ultrasound of the upper abdomen. Notably, the majority (90%) of patients with gallstones had received SSA treatment. The frequency of cholelithiasis in patients on SSA treatment was 53% (18 of 34 patients who underwent ultra-sound).Glucose homeostasis was assessed in 45 patients who were given SSA pharmacotherapy. Twenty four patients with abnormal glucose homeostasis (IGT or DM) at baseline received SSA and glucose control deteriorated in 8, improved in another 8 and remained stable in the rest. On the other hand, 11 out of 21 euglycaemic patients at baseline developed IGT or DM after SSA administration. These data for glucose metabolism were independent of disease remission.

  alone resulted in a decrease in size in 3 of 13 adenomas, (2 with SSA and 1 with DA).

  Patients who achieved remission had significantly smaller adenomas at baseline compared with those who did not (1.3±0.2 vs. 1.7±0.1, respectively, p=0.014).

  surgery was followed by medical treatment or radiotherapy the remission rate increased to 53% and 63% respectively.

Table 1 .

 1 Outcomes of different therapeutic strategies in acromegalyComments: initial size was not available in 2 patients, 1 of which after surgery alone and 1 after surgery/radiotherapy achieved remission

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Table 2 .

 2 Changes in baseline and nadir GH levels, IGF-I levels and adenoma size

	during follow-up
		Baseline	1 st year	3 rd year	5 th year
	GH (μ μ μ μg/L)	24.4±24.3	12.4±22.1	6.4±17.2	5.1±7.9
	GH nadir (μ μ μ μg/L)	22.0±22.1	9.7±17.7	7.2±18.9	4.6±7.1
	IGF-I (μ μ μ μg/L)	945±843	609±719	372±278	278±154
	Adenoma size (cm)	1.66±0.90	1.2±0.7	1.1±0.6	1.0±0.6

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Conflict of interest: The authors have no conflict of interest to disclose

Conflict of interest

This paper was written independently. The authors did not receive financial or professional help with the preparation of the manuscript.


Mike Geoffrey Kirby
email: kirbym@globalnet.co.uk

Gabriel Schnetzler

Kelly Zou

Tara Symonds

Kirby Mg

Zou Kh

Michael G Kirby

in men with erectile dysfunction receiving phosphodiesterase type 5 inhibitors in the United Kingdom: A retrospective database study

Keywords: Erectile dysfunction, phosphodiesterase type 5 inhibitors, underlying disease, prevalence, cumulative incidence, clinical assessment, THIN database, disease detection

What is already known about this topic?

ED can be caused by a variety of potentially underlying and reversible factors. Recently, ED has been identified as an independent risk factor for CVD, including angina, myocardial infarction, stroke and transient ischaemic attack. Management recommendations for ED suggest a clinical assessment to detect underlying conditions when prescribing a PDE5i.

What does this article add?

These findings suggest that most men with ED have known comorbidities, identified during routine healthcare assessments and not in the context of a PDE5i prescription. However it may be beneficial that men are regularly asked about erection problems in clinical practice, as the opportunistic identification of ED can be a trigger to address CVD risk factors more effectively, enabling the targets of the UK Quality and Outcomes Framework to be achieved.

INTRODUCTION

Erectile dysfunction (ED), defined as the inability to attain and/or maintain an erection sufficient for satisfactory sexual intercourse, is a prevalent medical condition affecting approximately 10-50% of the male population aged over 40 years [START_REF] Feldman | Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study[END_REF][START_REF] Green | An investigation of erectile dysfunction in Gwent, Wales[END_REF][START_REF] Nicolosi | Sexual behavior and sexual dysfunctions after age 40: the global study of sexual attitudes and behaviors[END_REF][START_REF]on Impotence. Impotence -NIH Consensus Conference[END_REF]. The origin of ED can be physical (organic ED), psychological or a combination of the two, and the condition is influenced by vasculogenic (including cardiovascular disease [CVD]), neurogenic, anatomical/structural, hormonal (e.g. hypogonadism), drug-induced, and psychogenic factors [START_REF] Gratzke | Anatomy, physiology, and pathophysiology of erectile dysfunction[END_REF][START_REF] Mcvary | Clinical practice. Erectile dysfunction[END_REF].

Since the launch of the first oral phosphodiesterase type 5 inhibitor (PDE5i) sildenafil more than a decade ago [START_REF] Goldstein | Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group[END_REF], PDE5is have become the first-line therapeutic option for the treatment of ED due to their established efficacy and favourable safety profile [START_REF] Hackett | British Society for Sexual Medicine guidelines on the management of erectile dysfunction[END_REF][START_REF] Hatzimouratidis | Guidelines on male sexual dysfunction: Erectile dysfunction and premature ejaculation[END_REF][START_REF] Montorsi | Summary of the recommendations on sexual dysfunctions in men[END_REF]. ED has recently been identified as an independent risk factor for CVD, including angina, myocardial infarction, stroke and transient ischaemic attack. In an analysis of data from more than 9,000 men aged 55 years or older enrolled in the Prostate Cancer Prevention Trial, men with ED were reported to have an approximate twofold increased risk of CVD compared with men without ED [START_REF] Thompson | Erectile dysfunction and subsequent cardiovascular disease[END_REF]. Furthermore, ED has been reported to precede a major cardiovascular event by an average of about five years [START_REF] Hodges | The temporal relationship between erectile dysfunction and cardiovascular disease[END_REF]. These findings may be explained by the artery size hypothesis. Penile arteries are smaller than coronary arteries (1-2 mm vs 3-4 mm), potentially explaining why ED presents in advance of coronary artery disease (CAD) symptoms; as a similar degree of endothelial dysfunction may be subclinical in the larger vessels. This could further explain the high frequency of ED symptoms observed in patients with CAD, and the lack of concomitant symptoms of CAD observed in most patients with ED [START_REF] Montorsi | The artery size hypothesis: A macrovascular link between erectile dysfunction and coronary artery disease[END_REF]. Additionally, current evidence suggests that organic ED and CAD share a common aetiology in endothelial dysfunction [START_REF] Costa | The endothelial-erectile dysfunction connection: An essential update[END_REF](15)[START_REF] Tikkanen | Erectile dysfunction as a risk factor for coronary heart disease: implications for prevention[END_REF].

Based on the variety of potentially underlying and reversible factors leading to ED, and the strong association between ED and the subsequent development of clinical cardiovascular events, both international [START_REF] Hatzimouratidis | Guidelines on male sexual dysfunction: Erectile dysfunction and premature ejaculation[END_REF][START_REF] Montorsi | Summary of the recommendations on sexual dysfunctions in men[END_REF][START_REF] Kostis | Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference)[END_REF] and UK-based (8) treatment guidelines recommend a targeted medical and psychosexual assessment of ED (including cardiovascular risk factors) prior to treatment with a PDE5i. However, despite the known burden and extent of comorbid conditions in patients with ED [START_REF] Hackett | The burden and extent of comorbid conditions in patients with erectile dysfunction[END_REF], data on the detection rate of underlying medical conditions in men assessed for the treatment of ED are limited to specialist single-centre studies [START_REF] Hatzichristou | Diagnostic steps in the evaluation of patients with erectile dysfunction[END_REF][START_REF] Solomon | Erectile dysfunction: cardiovascular risk and the role of the cardiologist[END_REF]. So far, no study has assessed the detection rate for previously unknown The aim of this study was to determine the outcome of diagnostic activities performed in the temporal context of a PDE5i prescription by assessing the detection rate of newly diagnosed medical conditions following the initial prescription. Several analyses were conducted to account for potential influencing factors including the known difference in prevalence rates for cardiovascular risk factors in the ED population compared with a male population who had not previously received a PDE5i prescription, and the diagnostic assessments prior to and post prescription. Differences in diagnostic activities performed at the time when PDE5is were introduced (in the late nineties) and in more recent years (when ED became recognised as a potential harbinger for CVD) were also investigated.

METHODS

This was a non-interventional, retrospective database study of medical records registered in

The Health Improvement Network (THIN) database in the UK (www.thin-uk.com), a primarycare administrative database containing the electronic medical records of 5% of the UK population from the clinical systems of over 385 GP practices. As a managed database, records undergo systematic quality assessments. This database has previously been validated for epidemiological research [START_REF] Lewis | Validation studies of the health improvement network (THIN) database for pharmacoepidemiology research[END_REF] and has recently been used for epidemiological research in the field of urology [START_REF] Kell | Factors that predict changing the type of phosphodiesterase type 5 inhibitor medication among men in the UK[END_REF][START_REF] Morant | Diagnosis and treatment of lower urinary tract symptoms suggestive of overactive bladder and bladder outlet obstruction among men in general practice in the UK[END_REF][START_REF] Morant | Increased sexual dysfunction in men with storage and voiding lower urinary tract symptoms[END_REF]. The THIN Data Collection Scheme was approved by the South-East Multicentre Research Ethics Committee (SE-MREC) in the UK. This study protocol was approved by the independent scientific review committee of THIN.

The primary objectives of the study were to determine the prevalence of underlying disease in male patients prior to receiving a first (index) PDE5i prescription, to establish the detection rate of new diagnoses (defined as the cumulative incidence of such a diagnosis in the 3 months [day 0 to day 91] following the index prescription), and to determine the role of ED assessment in the identification of underlying disease in men receiving their first PDE5i prescription. The diagnoses of interest investigated in this study were adapted from the diagnostic evaluations recommended in the European Urology Association Guidelines on Male Sexual Dysfunction [START_REF] Hatzimouratidis | Guidelines on male sexual dysfunction: Erectile dysfunction and premature ejaculation[END_REF][START_REF] Wespes | European Association of Urology Guidelines on Male Sexual Dysfunction: Erectile dysfunction and premature ejaculation[END_REF] and were divided into a vasculogenic, neurogenic, anatomic/structural, hormonal, pharmacologic (drug prescribed <1 year before index prescription) and psychogenic category (Table 1). In addition, diagnoses of hypertension, hypercholesterolaemia, diabetes and hypogonadism were specifically assessed. The PDE5i prescription index date was used as a surrogate parameter for the time when a complete medical check would have been indicated. The 3-month time period following the index Secondary study objectives included comparison of the prevalence and detection rate of underlying disease identified in the study subjects at index prescription with an age-matched control population not receiving a PDE5i. In addition, the detection rate of new diagnoses at index prescription was compared with that in a 3-month period immediately before the index PDE5i prescription (day -92 to day -1) and a 3-month period one year after the index prescription (day 366 to day 457) in patients with a continuous medical history of ≥457 days following their index prescription (target sub-group population) to assess the detection of underlying conditions pre-and post PDE5i prescription. Finally, temporal trends were analysed among the target population by comparing the prevalence and 3-month post index detection rate of underlying medical conditions in subjects with an index prescription between January 1 st , 1999 and December 31 st , 2001 with that in subjects with a more recent index prescription (between July 1 st , 2006 and June 30 th , 2008). This was done to see if the increased awareness of ED as a marker of underlying disease had made any impact on the detection rate.

Patient population

Study participants were identified from anonymised THIN patient records. Records of acceptable quality (THIN patflag "A" and "C") of men aged ≥18 years who received an index PDE5i prescription (sildenafil, tadalafil or vardenafil) between January 1 st , 1999 and June 30 th , 2008 were identified from the database (target population). Men not meeting these criteria and females were excluded.

A reference population of age-matched controls was identified from the database (control population). The same inclusion criteria applied with the exception of a PDE5i prescription during the study period. For each subject of the target population, three control subjects were randomly selected based on the age at the first data entry date in any given year, and strata were filled starting at the end of the study period and working backwards (towards 1999). only one code per diagnosis was captured, and the presence of at least one diagnosis defined whether a disease of a given category was present. All ever-coded diagnoses during the 60 months prior to the first PDE5i prescription (or date used for matching of control patients) were used to define the prevalence of underlying medical conditions at the time of index prescription. The cumulative incidence, i.e. the proportion of new diagnoses of interest within the 3-month period (0-91 days) following the index PDE5i prescription (or date used for matching controls) in each population was used to define the detection rate.

Statistical analysis

Categorical data were reported as counts and proportions, whereas continuous data were reported using descriptive statistics (mean, standard deviation). For the three age-matched controls per study participant, an average of the proportion or value was computed.

Comparisons of the detection rates between groups were made using the difference in proportions for categorical data and the difference in the means for continuous data, along with 95% confidence intervals (CI). For inferential analysis based on large samples, the Chisquare test was used to compare categorical data for the groups of interest. The analysis of proportions and the two-sample t-test were performed to compare the overall mean prevalence, detection rates and the mean age at which men received a new diagnosis for the study participants and the control population. A two-sided p-value of <0.05 was considered statistically significant.

For study subjects who died after their index prescription date or reference index date (day 0), the last observation carried forward imputation method was used i.e. all observations (diagnostic codes) between day 0 and the date of death were carried forward and defined as a new diagnosis during the time period from day 0 until day 91.

To adjust for potential confounding effects on the difference in incidence of new diagnoses between the target and control populations, a multivariate regression analysis was performed using cardiovascular risk factors (hypertension, diabetes, hypercholesterolaemia, smoking and obesity [body mass index >30]) and year of inclusion in the study cohort as covariates.

All statistical analyses were conducted using SAS 9.1 and 9.2 of the SAS Institute Inc., Cary, NC (www.sas.com).

RESULTS

A total of 89,781 men who received an index PDE5i prescription between January 1 st , 1999 and June 30 th , 2008 were identified from the THIN database. Among these patients, 24,708 met the inclusion criteria and were included in the target population. A total of 24,479 men in the target population had a continuous medical history of ≥457 days and were included in the subgroup target population. The control group comprised 74,124 male patients. The baseline characteristics of the target population and control group are summarised in Table 2.

Prevalence of existing diagnoses

The prevalence of any coded diagnosis before the index PDE5i prescription was 70.23% (95% CI: 69.66-70.80). When each specific diagnosis was considered, vasculogenic diagnoses and co-medication (pharmacologic category) were found to have the highest prevalence rates of 48.20% (95% CI: 47.58-48.83) and 42.97% (95% CI: 42.36-43.59), respectively. The prevalence of all other categories was low (<10%). The most prevalent vasculogenic diagnoses were hypertension 19.93% (95% CI: 19.43-20.43), diabetes 9.69% (95% CI: 9.32-10.06) and hypercholesterolaemia 8.26% (95% CI: 7.92-8.61).

Hypogonadism was present in 0.19% (95% CI: 0.17-0.25) of the men prior to receiving a PDE5i. [Figure 1]

Incidence of new diagnoses

The detection rate of any previously unknown underlying condition in the 3 months following the index PDE5i prescription was 11.53% (95% CI: 11.13-11.93). The detection rate of a vasculogenic diagnosis was 4.07% (95% CI: 3.82-4.32), including new detection of hypertension, hypercholesterolemia or diabetes in 1.21% (95% CI: 1.07-1.34), 1.04% (95% CI: 0.92-1.17) and 0.69% (95% CI: 0.59-0.80) of men, respectively [Table 3].

Comparison versus an age-matched control population

Compared with the control population, the target population had a significantly higher prevalence of existing diagnoses overall (70.23% vs 55.73%; p<0.001) and in each category [Figure 1]. The detection rate of new diagnoses overall was also significantly higher in the target population compared with the control population (11.53% vs 7.49%; p<0.001), and similar findings were seen when each specific category or diagnosis was considered. The absolute difference between the detection rates was calculated and shown in Table 3. The mean age of men who received a new diagnosis of diabetes or urologic, neurogenic, hormonal, or psychogenic ED in the three months post-prescription was significantly lower in the target population compared with the age-matched controls (Table 4). No significant difference was found for vasculogenic diagnoses or hypogonadism. Adjustment for potential confounders Table 3 summarises the odds ratio based on multivariate logistic regression analysis for the detection of a new diagnosis after adjustment for pre-existing cardiovascular risk factors (hypertension, hypercholesterolaemia, diabetes, smoking and obesity) and the year of inclusion in the study cohort. Odds ratios remained statistically significant for all diagnostic categories, except for vasculogenic disease.

Comparison of detection rate to a 3-month period prior to the index date and a

3-month period one year after the index date

The detection rates in the 3 month period prior to index prescription (day -92 to -1), and the 3 month period 1 year after prescription (day 366 to 457), were both lower than that in the 3 months post-index prescription for all diagnoses except for the urologic diagnoses and diabetes (which were diagnosed with a significantly higher frequency in the 3 months prior to index prescription) [Figure 2]. While the detection rate for any new diagnosis immediately prior to the prescription was not statistically different to that in the 3 months post-index prescription (11.08% vs 11.49%; p=0.153), it was significantly lower one year later when compared to the time of prescription (5.65% vs 11.49%; p<0.001).

Change of prevalence and detection rate of underlying conditions over time

Prevalence of any underlying condition was significantly lower in the population receiving a PDE5i in the early study period included in 1999 and 2001 (n=892) compared with the population included between mid 2006 and mid 2008 (n=9,862), the end of the study period (67.49% vs 72.14%; p=0.004). The proportion of men with vasculogenic disease (44.39% vs 54.66%; p<0.001) or co-medication (43.50% vs 48.74%; p=0.003) at index prescription was significantly lower in the early study population, whereas the prevalence of psychogenic conditions (12.33% vs 8.27%; p<0.001) was significantly higher, compared with the later period. However, detection rates overall (11.32% vs 11.06%; p=0.813), and for each category, were not statistically different over time [Figure 3].

DISCUSSION

This retrospective database study using records from THIN found that seven out of ten men have an established diagnosis of underlying disease before they receive their first PDE5i prescription. The most common underlying medical conditions were vasculogenic diagnoses and co-medication, with prevalence rates of 48% and 43%, respectively. As expected, the prevalence of underlying disease (all medical conditions combined and considered separately) which could potentially lead to ED was significantly higher among patients receiving a PDE5i prescription compared with the reference population of age-matched controls with no PDE5i prescription. Similarly, the detection rate of conditions potentially underlying ED was statistically significantly higher compared with the detection rate of a control population (11.5% vs 7.5% for any diagnosis).

The outcome of diagnostic activities recommended for the assessment of ED at a PDE5i prescription was further assessed using the absolute differences in detection rates between the target and the control population. The study results suggest that following clinical assessment for ED, the absolute number of newly detected underlying diagnoses (per 10,000 men) above the normal detection rate is 45 for hypertension, 61 for hypercholesterolemia, and 38 for diabetes. Furthermore, previously undiagnosed hypogonadism was detected in an additional 5 out of 10,000 men assessed for an initial PDE5i prescription. The odds ratios remained statistically significant for subjects in the target group versus the control group, even when adjusted for potential confounding factors in the ED population (resulting from a higher prevalence of pre-existing CV risk factors) and the skewed inclusion date of the control population (towards the end of the study period), with the exception of new vasculogenic diagnosis where the odds ratio suggested no difference when adjusted for pre-existing CV risk factors. These findings imply that only a relatively small number of men with ED will have a previously undiagnosed, important underlying disease uncovered at the time of an initial PDE5i prescription. However, it may remain beneficial that men are regularly asked about erection problems in clinical practice, given that a substantial proportion of men with ED do not seek medical advice or treatment [START_REF] Fisher | The multinational Men's Attitudes to Life Events and Sexuality (MALES) Study Phase II: Understanding PDE5 inhibitor treatment seeking patterns, among men with erectile dysfunction[END_REF][START_REF] Kubin | Epidemiology of erectile dysfunction[END_REF] or access treatment from sources outside of the healthcare system [START_REF] Schnetzler | Characteristics, behaviors, and attitudes of men bypassing the healthcare system when obtaining phosphodiesterase type 5 inhibitors[END_REF].The opportunistic identification can be a trigger to assess and manage ED according to accepted treatment recommendations [START_REF] Hackett | British Society for Sexual Medicine guidelines on the management of erectile dysfunction[END_REF][START_REF] Hatzimouratidis | Guidelines on male sexual dysfunction: Erectile dysfunction and premature ejaculation[END_REF][START_REF] Montorsi | Summary of the recommendations on sexual dysfunctions in men[END_REF], and to address CVD risk factors more effectively, enabling the targets of the UK Quality and Outcomes Framework (QOF) to be achieved.

The detection rates reported in this study are similar or somewhat lower than those described in two single-centre studies. Hatzichristou et al. reported that blood tests identified a previously undiagnosed medical condition in 6.2% of 1,276 evaluable patients with ED (mean duration 4.9 years) [START_REF] Hatzichristou | Diagnostic steps in the evaluation of patients with erectile dysfunction[END_REF]. Diabetes mellitus and abnormal lipid profiles were newly detected in 11 (0.9%) and 37 (2.9%) patients, respectively, and hypogonadism and hyperprolactinaemia were uncovered in 22 (1.7%) and 8 (0.6%) patients, respectively. In 28 patients (2.2%), a previously unknown urinary tract disease was diagnosed, and in 8 patients (0.6%) tests revealed a previously unknown neurologic disorder. Solomon et al. described even higher rates following an assessment of 174 subjects in a joint urologic and cardiologic referral practice using the Princeton Consensus Guideline. The detection rate of vasculogenic conditions was high, with a new diagnosis of hyperlipidaemia, hypertension or diabetes, and suspected significant angina reported in 26%, 10% and 6% of men, respectively [START_REF] Solomon | Erectile dysfunction: cardiovascular risk and the role of the cardiologist[END_REF]. Additionally, a potential urologic disorder was identified in five men and hyperprolactinaemia was reported in one man.

The overall mean age of the target population of men at the time of their first index prescription for PDE5i in this analysis of general population data was 59 years. For some diagnoses, the mean age of men in the target group in the period three months postprescription was significantly lower than that in the control population. As this study was not specifically intended to investigate the age at which these diagnoses were made, it remains questionable whether ED assessment in the context of a PDE5i prescription currently would lead to an earlier detection of some potentially underlying conditions.

Two factors may have contributed to the lower diagnosis rates reported in this retrospective database study compared with the two specialist single-centre studies. First, patients who complained about ED might have received a PDE5i prescription only after all the results of the clinical assessments were available, although guidelines do not explicitly recommend a deferred treatment. Interestingly, a considerable number of new diagnoses were made in the 3 months prior to the PDE5i prescription, and were substantially lower in the period one year after the index prescription. The detection rate seen in this later period is within a similar range to the rate seen in an age-matched control population without a PDE5i prescription.

A second factor which may account for the lower detection rates reported in this observational study, compared with previous studies from specialist centres which specifically investigated the presence of underlying conditions, is the extent to which these investigations are actually performed by physicians in general practice. Although no information on this is available from general practitioners, a survey among urologists suggests these investigations are often abbreviated or deferred: Of 1,590 participating delegates of the annual congress of the European Association of Urologists 2008, 33% reported that they would perform further interviews, with 19%, 15% and 7%, respectively, reporting that they would assess cardiovascular risk factors, order laboratory tests and perform blood pressure measurements in a man presenting with ED [START_REF] Schnetzler | Current erectile dysfunction management: a survey among delegates of the 2008 annual EAU congress in Milan[END_REF]. It is difficult to assess the level of clinical investigation performed during routine GP practice; however, the comparable detection rates of underlying conditions during the early phase and the later phase of the study suggest that there was no change over time, despite the statistically higher prevalence of known vasculogenic diagnoses and co-medication in the cohort receiving a PDE5i between July 2006 and June 2008. The 2004 UK QOF targets would likely have contributed to this finding [START_REF] Carey | SD, standard deviation. Smoking was excluded as data on this was not routinely recorded until QOF commenced in 2005. If weight and BMI values were outside of pre-defined ranges (<40 to >200 kg and <14 to >48 kg/m 2 , respectively) they were[END_REF].

This study has limitations inherent to any retrospective database study (31), including the potential effect that under-and misreporting would have on prevalence and detection rates. Further limitations of this study include the fact that the data represent a temporal rather than a causal relationship between the detection rate of new diagnoses and the PDE5i prescription. Furthermore, it can not be ruled out that some men in the control population may have had ED (diagnosed or undiagnosed) but did not receive treatment. Current knowledge of the pharmacologic effect and the safety of PDE5i does not support an inversion of the interpretation, i.e. that hypertension or diabetes is induced by a PDE5i prescription [START_REF] Kostis | Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference)[END_REF]32,33). More importantly, it is impossible to determine in this study, whether the symptoms of ED were the cause of the GP visit, or whether ED was identified as part of other health-related assessments. This could lead to an overestimation of the detection rates for underlying conditions. Alternatively, and as discussed above, the presented detection rates could be lower than in reality, since the PDE5i prescription index date was used as a surrogate parameter for the time when a complete medical check would be performed. This excludes the detection of underlying conditions diagnosed before the PDE5i was actually prescribed. Finally, patients with private PDE5i prescriptions were not included in the analysis and the impact of this on the study outcome remains unknown.

CONCLUSION

The high prevalence and low detection rates observed in this study suggest that in current clinical practice many of the diagnoses associated with ED, including vasculogenic conditions are identified during routine healthcare assessments and not as a result of a diagnostic work-up for ED. As a consequence, the vast majority of men with ED have a previously known medical condition when asking for a PDE5i treatment. Routine clinical assessments in the context of a PDE5i prescription appear to uncover an additional case of

  in men with ED undergoing medical evaluation for a PDE5i prescription in general practice in the UK.

  sufficient to include any new diagnosis identified based on additional tests requested at the time of PDE5i prescription. In order to fully capture the prevalence of underlying diseases, only patients with a continuous medical history of ≥60 months prior to the index prescription were included in the study.

Figure 1 .Figure 2 .Figure 3 .

 123 Figure 1. Prevalence (% and 95% CI) of underlying disease in men receiving a PDE5i (target population) and in age-matched controls without a PDE5i prescription (control population). All differences between target and control populations were significant (p<0.001). 156x85mm (600 x 600 DPI)

Table 1 :

 1 hypertension, hypercholesterolaemia or diabetes in approximately one out of 200 men and a hypogonadism in one out of 2000 men compared with the normal detection rate in an agematched control population. No change was seen in the detection rate over the past 10 years. Brooks J, Clark MA, et al. A checklist for retrospective database studies-Report of the ISPOR Task Force on Retrospective Databases. Value Health 2003; 6: 90-7. 32 Giuliano F, Jackson G, Montorsi F, Martin-Morales A, Raillard P. Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database. Int J Clin Pract 2010; 64: 240-55. Categories of conditions potentially leading to ED (adapted from the European Urology Association Guidelines)(9,25) Drug must have been given in the year prior to initial PDE5i prescription/reference index date

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Table 2 .

 2 Baseline characteristics of the study and control populations

	Target population
	(n=24,708)

International Journal of Clinical PracticeInternational Journal of Clinical Practice

Jackson G, Montorsi P, Adams MA, et al. Cardiovascular aspects of sexual medicine. J Sex Med 2010; 7:

1608-26.

Vlachopoulos C, Ioakeimidis N, Rokkas K, Stefanadis C. Cardiovascular effects of phosphodiesterase type 5 inhibitors. J Sex Med 2009; 6: 658-74.

ACKNOWLEDGEMENTS

The authors would like to thank John McPeek and William Moritz of Eliassen, Katie Elsworth and Cornea Venter of Quanticate, and Alexa Parliyan of Pfizer Inc for programming support for database analysis, and Dr Jamie Ashman of Prism Ideas for providing editorial support during the preparation of this article. Funding for editorial support and for programming support by Quanticate was provided by Pfizer.

This study was funded by Pfizer

FUNDING

This study was funded by Pfizer Page 13 of 23 International Journal of Clinical Practice International Journal of Clinical Practice

Data collection and study endpoints

The relevant READ codes for all diagnoses and Multilex drug codes for the pharmacological compounds were used to search the records of study participants and age-matched controls for instances of diagnoses of the medical conditions detailed in Table 1. To avoid multiplicity,

AUTHOR CONTRIBUTIONS

Design of the study: MK, GS, KHZ, TS Analysis of the data: GS, KHZ Interpretation of the data: MK, GS, KHZ, TS Drafting of the manuscript and review for content: MK, GS, KHZ, TS

CONFLICTS OF INTEREST


S Rudz

K Chetehouna
email: khaled.chetehouna@ensi-bourges.fr

O Séro-Guillaume

Metrological tool for the characterization of flame fronts based on the coupling of heat flux approach with image processing data

Keywords: Simplified flame model, radiative thermal methodology, multiple thermal sensors, inverse method, image processing

The aim of this paper is to present some improvements in the metrology of forest fire flames by coupling image processing and radiative heat flux measurement. A new metrological tool using a visual video camera and a specific multiple thermal sensor is proposed. By means of an appropriate segmentation algorithm and the Direct Linear Transformation, the image processing methodology gives the forward or the backward fire front positions as input data to a radiative heat flux approach. Using a simplified flame model, this technique provides fire front positions versus time, and average values for the flame length, flame depth, flame tilt angle, apparent flame temperature and flame emissivity. The rates of spread, obtained by a linear regression of the determined fire front positions, as well as the thermal and radiative properties of the flame, are compared favorably to those given in the literature.

Nomenclature

Introduction

In wildland fires the most advanced line of the fire, orthogonal to the propagation direction, defines the so-called fire front position. From this position the rate of spread, which is an important parameter in fire risk management, can be easily deduced. In several laboratory experiments and controlled fires [START_REF] Viegas | Analysis of fire behaviour in Mediterranean shrubs: The Gestosa fire experiments (Portugal)[END_REF][START_REF] Santoni | Instrumentation of wildland fire: Characterisation of a fire spreading through a Mediterranean shrub[END_REF][START_REF] Sullivan | Convective Froude number and Byram's energy criterion of Australian experimental grassland fires[END_REF][START_REF] Chetehouna | On the experimental determination of flame front positions and of propagation parameters for a fire[END_REF] various devices and protocols have been used to detect the fire front position. The following tools are widely used in fire metrology: threads positioned perpendicular to the propagation direction, thermocouples aligned on the fire spreading axis and deployment of wireless sensor networks on the observed field [START_REF] Lloret | A Wireless Sensor Network Deployment for Rural and Forest Fire Detection and Verification[END_REF]. The drawback with these devices, however, is that they give a discontinuous signal and a limited amount of data. More recently, image processing methods have been used, enabling the front position to be extracted from video (or infrared) recordings by different types of image processing algorithms [START_REF] Pastor | Computing the rate of spread of linear flame fronts by thermal image processing[END_REF][START_REF] Martinez-De Dios | Computer vision techniques for forest fire perception[END_REF][START_REF] Chetehouna | On the two ways for the computing of the fire front positions and the rate of spread. Modelling, Monitoring and Management of Forest Fires[END_REF].

These methods are simple, cheap, easy to use and give positions all along the fire front contour, unlike threads or thermocouples which only give mean positions.

Concurrently, a physical measurement tool has been designed [START_REF] Chetehouna | Detection of the Positions and Computing the Rate of Spread of Fire Fronts Using a Radiative Flame Model and Inverse Method[END_REF] to access both average geometrical (length, tilt angle, depth) and physical (temperature, radiative coefficients) flame characteristics by means of the inverse method and a simplified flame model. This model has been derived using the hypothesis of a thin flame [START_REF] Chetehouna | On the experimental determination of flame front positions and of propagation parameters for a fire[END_REF][START_REF] Séro-Guillaume | On large Scale Forest Fires Propagation Models[END_REF] in order to avoid integration of the Radiative Transfer Equation.

In the expression of heat fluxes, the above-mentioned parameters are involved and it is relevant to determine these parameters by minimizing the differences (in the Euclidean norm) between calculated and computed heat fluxes during propagation. Unfortunately, the fire front positions are parameters of the radiative heat flux method. This is a weakness of the method because if too many positions are to be identified, the number of variables in the optimisation process increases the difficulty of finding a minimum. Therefore, the key point to improve the radiation heat transfer approach is to reduce the number of parameters. Recently [START_REF] Rudz | Comparison of two methods for estimating fire positions and the rate of spread of linear flame fronts[END_REF], image processing and radiation heat transfer measurement methods have been favourably compared and both give the same positions for the fire front.

The aim of this paper is to combine these two approaches in order to reduce the number of parameters by inputting the fire front positions given by image processing into the radiation heat transfer measurement method. The second section summarizes the formulae required for the optimisation protocol and describes the wireless multiple thermal sensor used. The image processing approach is detailed in section three. In the fourth section, we present the objective function and the optimisation algorithm. The fifth section describes the experimental set-up. The paper concludes with the presentation of some results and discussions.

Radiative heat fluxes 2.1 Theoretical modelling

In this section we derive the equations necessary to calculate the theoretical radiative heat flux emitted by the flame and received by a wireless thermal sensor [START_REF] Chetehouna | Detection of the Positions and Computing the Rate of Spread of Fire Fronts Using a Radiative Flame Model and Inverse Method[END_REF]. The sensor is centred at the end of the combustion table at a point 0 0 ( , )

x y M on top of the vegetation bed. The inclination angle of the combustion table from the horizontal plane is s α . The flame model proposed in this paper is derived from the radiative transfer equation [START_REF] Siegel | Thermal radiation heat transfer[END_REF] as explained below. In the model, the thermal effects of the surrounding walls are considered negligible as the walls are covered by a thermal insulator, and the flame is considered as a parallelepiped with variable backward and forward positions respectively B f y and F f y (see Figure 1), characterized by the following average parameters: length f l , tilt angle f α , temperature and an extinction coefficient . The theoretical radiative heat flux coming from the fire front and received by a target with a unit vector can be written [START_REF] Chetehouna | On the experimental determination of flame front positions and of propagation parameters for a fire[END_REF][START_REF] Séro-Guillaume | On large Scale Forest Fires Propagation Models[END_REF]:

th i Φ i n [ ] ( ) 4 2 cos cos cos( ) 1 cos ( ) cos sin f f th i ff f f s B K T dx dy r α β θ β θ π α β Σ - + ⋅ -- ⋅ Φ = ∫ i i w n f n M (1)
The convective heat flux is the same on each face given the small size of the gauges. In this study the rear gauge never sees the fire front; it only measures the convective heat flux contribution. The rear gauge measurements are therefore subtracted from the others in order to obtain only the radiative contribution. In this case, the unit vector has two directions for the wireless thermal sensor: Gauge facing the fire ( j n i = ).

In this case we must calculate:

[ ] ( ) 4 2 cos cos cos( ) 1 cos ( ) cos sin f f th a ff f f s B K T dx dy r α β θ β θ π α β Σ - + ⋅ -- Φ = ∫ w ⋅ j f j M (2)
Note that sinφ ⋅ = w j and sin sin

w f α φ ⋅ = f j
, so the theoretical heat flux received by the front face of the wireless thermal sensor can be written as:

( ) ( ) 4 2 cos ( )
sin cos sin cos sin sin 1 cos sin sin sin

f f th a ff f f s w f B K T dx dy r α π β α φ β α φ θ φ β Σ Φ = × θ ⎡ ⎤ - - + ⎣ ⎦ ∫ M (3)
where ( , ) w α = k f is the flame inclination angle due to the competition between buoyancy and wind.

Gauges oriented obliquely to the flames (gauge 4) (

i n i = ).
We must calculate:

[ ] ( ) ( 4) 4 4 2 cos cos cos( ) 1 cos ( ) cos sin f f th f f f f s B K T dx dy r α β θ β θ π α β Σ - + ⋅ -- Φ = ∫ w i f i M ⋅ (4)
Inserting cosφ ⋅ = w i and sin cos

w f α φ ⋅ = f i
in this equation, we obtain:

( ) ( ) ( 4)
f f th f f f f s w f B K T dx dy r α π β α φ β α φ θ φ β θ Σ Φ = × ⎡ ⎤ - - + ⎣ ⎦ ∫ M (5)
where (4) f Σ is the part of f Σ viewed by gauge 4 of the wireless thermal sensor.

Gauges oriented obliquely to the flames (gauge 2) ( = -

i n i).
We must calculate:

( ) [ ] ( 2) 4 2 2 cos 1 cos cos cos( ) ( ) cos sin f f th f f f f s B K T dx dy r α θ β θ β π α β Σ - ⋅ - - + ⋅ Φ = ∫ f i w i M (6)
Inserting cosφ ⋅ = w i and sin cos

w f α φ ⋅ = f i
in this equation, we obtain:

( ) ( ) ( 2)
f f th f f f f s w f B K T dx dy r α π β α φ β α φ θ φ β θ Σ Φ =- × ⎡ ⎤ - - + ⎣ ⎦ ∫ M (7)
where (2) f Σ is the part of f Σ viewed by gauge 2 of the wireless thermal sensor, cos sin cos( )

w f β α φ φ = - , 2 2 2 sin 1 sin cos ( ) w f β α φ φ = - - and cot cot sin f r l θ β β = - .
In this study, the flame propagates in the direction of the target, meaning that the projection u of the unit flame vector f on the plane f Σ is collinear to the unit vector w. Consequently, the angle

F f B f y y x W f th w s a f f s x W y y f w f Yl B dX K T dY r r l r l α α π α α - - + - + Φ = - + ∫ ∫ M (8) 0 0 0 0 4 4 2 2 2 cos( ) ( ) cos 2 sin F f B f y y x f th w s f f s x W y y f w f Xl B dY K T dX r r l r l α α π α α - + - + Φ = - + ∫ ∫ M (9) 0 0 0 0 4 2 2 2 2 cos( ) ( ) cos 2 sin F f B f y y x W f th w s f f s x y y f w f Xl B dY K T dX r r l r l α α π α α - - - + Φ =- - + ∫ ∫ M (10)
where

2 2 r X Y = + , 0 f X x x = -, 0 f Y y y = - and 0 0 ( , )
x y is the location on the plane f Σ of a target measuring the radiative heat flux coming from the flame. W is the half-width of the flame and f x , f y are the fire coordinates on the x-axis and y-axis respectively.

By integrating equation ( 8) over the y-axis and equations ( 9) and ( 10) over the xaxis, the theoretical radiative heat fluxes received by the multiple thermal gauges become:

( ) ( ) 0 0 4 2 2 2 2 2 2 cos( ) ( ) cos ( )sin ( ) sin cos ( ) ln ( ) ( )sin ( ) sin cos x W th w s a f f s x W f B w B f w f w F B f F w F f w f w B K T l R X R X l l R X dX R X l R X R X l l α α π α α α α α - + + Φ = × ⎛ ⎞ - + - + ⎜ ⎟ ⎜ ⎟ ⎜ ⎟ - + - + ⎝ ⎠ ∫ M α α (11) ( ) (
)

0 0 4 4 2 2 2 1 1 2 2 2 2 1 2 2 cos( ) ( ) cos ( )sin ( ) sin cos ( ) ln ( ) ( )sin ( ) sin cos F f B f y y th w s f f s y y f w f w f w f w f w f B K T l R Y R Y l l R Y dY R Y l R Y R Y l l α α π α α α α α - - + Φ = × ⎛ ⎞ - + - + ⎜ ⎟ ⎜ ⎟ ⎜ ⎟ - + - + ⎝ ⎠ ∫ M w α α (12) ( ) (
)

0 0 4 2 2 2 2 1 1 2 2 2 2 1 2 2 cos( ) ( ) cos ( )sin ( ) sin cos ( ) ln ( ) ( )sin ( ) sin cos F f B f y y th w s f f s y y f w f w f w f w f w f B K T l R Y R Y l l R Y dY R Y l R Y R Y l l α α π α α α α α - - + Φ =- × ⎛ ⎞ - + - + ⎜ ⎟ ⎜ ⎟ ⎜ ⎟ - + - + ⎝ ⎠ ∫ M w α α (13)
where ( )

2 2 0 ( ) B B f R X y y X = - + , ( )
2 2 0 ( ) F F f R X y y X = - + , ( )
2 2 1 0 ( ) R Y Y x W = + + , 2 2 2 0 ( ) R Y Y x = + , 2 1 ( ) 2 0 R Y Y x = + and
( )

2 2 2 0 ( ) R Y Y x W = + - .
In this work the fire propagated through a fuel bed under slope and no-wind conditions, and the heat flux sensor was centred on the x-axis on 0 0 x = .

According to this experimental configuration, and equations ( 11) to ( 13) can be expressed as:

2 4 ( ) ( ) ( ) th th th l Φ =Φ =Φ M M M ( ) ( ) ( ) ( ) 2 2 2 2 0 0 4 2 2 2 2 0 0 ( ) ln F B W f f f f th a ff B F W f f f f y y X l y y X l B K T dX y y X l y y X l π - ⎛ ⎞ - + + - + + ⎜ ⎟ Φ = ⎜ ⎟ ⎜ ⎟ - + + - + + ⎝ ⎠ ∫ M 2 2 ( 14
) 0 0 2 2 2 4 2 2 2 2
( ) ln

F f B f y y f f th l f f y y f f l Y W l B Y K T dY Y W l Y l π - - ⎛ ⎞ + + + ⎜ ⎟ Φ = ⎜ ⎟ + + + ⎝ ⎠ ∫ M (15)

Experimental determination

The wireless heat flux sensor used in this paper consists of a steel body, 4 copper plates, a thin heat insulating layer, a glue layer and 9 type K thermocouples (see Figure 2). From a previous theoretical study conducted by Chetehouna et al. [START_REF] Chetehouna | Detection of the Positions and Computing the Rate of Spread of Fire Fronts Using a Radiative Flame Model and Inverse Method[END_REF], the total heat flux received by each gauge is calculated as follows:

st co e co co i R R R dt d C t i i θ θ θ ϕ 1 1 1 ) ( 1 exp - ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ + + = (16)
where exp R models the heat transfer between the sensor and the surroundings. These physical parameters included in ( 16) were all obtained by calibration experiments and are provided in Table 1. As mentioned above, in our experiments the rear gauge (gauge 3) never sees the fire front, so it measures only the convective heat flux contribution. Consequently the radiative heat fluxes measured by the frontal and lateral gauges can be expressed as:

⎪ ⎪ ⎩ ⎪ ⎪ ⎨ ⎧ - = - = Φ ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ + + = Φ

Image processing methodology

The first step in the image processing technique used to obtain the forward or backward fire front positions was to acquire images of the fire with a video camera (30 images per second and a resolution of 640×480 pixels). Knowing the dimension of the burning area (the size of the combustion table), a Direct Linear Transformation was then performed in order to obtain real ground coordinates from pixel coordinates. This technique is used in a wide range of applications, including studies of fire behaviour [START_REF] Pastor | Computing the rate of spread of linear flame fronts by thermal image processing[END_REF]. The Ko et al. fire segmentation algorithm [START_REF] Ko | Fire detection based on vision sensor and support vector machines[END_REF] was then applied on the images in order to eliminate non-fire pixels from the fire scene. Note that the choice of this algorithm for these experiments has been discussed in [START_REF] Rudz | On the Evaluation of Segmentation Methods for Wildland Fire[END_REF] using a supervised evaluation criterion. Lastly, the fire front lines positions can be deduced by taking the ground contour of the remaining fire pixels. This image processing technique can be summarized in the following four steps: i) Cropping images of the propagation zone from a video recording.

ii) Direct Linear Transformation (DLT) to find real fire coordinates from camera fire pixel coordinates.

iii) Segmentation of the fire front lines. iv) Computation of the fire front lines positions. This segmentation algorithm [START_REF] Ko | Fire detection based on vision sensor and support vector machines[END_REF] works in the RGB colour space with a Gaussian probability distribution model assuming the independence of the RGB channels for each pixel given by: ( )

2 2 ( , ) 1 ( , ) exp 2 2 i i i i i I x y p x y μ σ πσ ⎛ ⎞ - ⎜ ⎟ = ⎜ ⎟ ⎝ ⎠ (18)
In this expression ( , ) i I x y is the colour value for the i th colour channel in a fire image, µ i and σ i are respectively the mean value and the standard deviation of i I .

To declare a pixel as a fire candidate, a threshold τ is used and the following condition is proposed:

( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , , , if , then ( , ) is a fire-pixel else ( , ) is not a fire-pixel R R G G B B

, p I x y p I x y p I x y p I x y p I x y I x y

I x y τ ⎧ = × × ⎪ ⎪ > ⎨ ⎪ ⎪ ⎩ (19)
The final step in the image processing method was to calculate the fire front lines positions in order to produce accurate fire positions as input parameters for the thermal methodology. In the mathematical radiative flame model derived in section 2, the fire positions are determined only by their centred positions. Hence, only those positions are taken into account in the image processing approach. In order to compute the best estimation of the different fire front lines positions, a Savitzky-Golay smoothing filter [START_REF] Orfanidis | Introduction to Signal Processing[END_REF] was applied to the fire front lines positions to eliminate the noise due to flame oscillations.

Combining the two approaches

Recently Rudz et al. [START_REF] Rudz | Comparison of two methods for estimating fire positions and the rate of spread of linear flame fronts[END_REF] showed that the positions obtained after applying the image processing method are as reliable and accurate as those obtained after applying the heat flux approach. These authors highlighted the possibility of coupling the two methods to design a new metrological tool which would calculate average geometrical (fire front positions, tilt angle, flame length) and average physical (temperature, emissivity) parameters of the flame with a lower computational time than without coupling [START_REF] Chetehouna | On the experimental determination of flame front positions and of propagation parameters for a fire[END_REF][START_REF] Chetehouna | Detection of the Positions and Computing the Rate of Spread of Fire Fronts Using a Radiative Flame Model and Inverse Method[END_REF]. The main idea is to give fire front positions calculated by image processing as fixed parameters for the radiative heat flux approach in order to reduce the number of unknown parameters involved.

Over the last two decades the inverse method used in engineering has been widely discussed by several authors [START_REF] Huang | Inverse problem of determining unknown wall heat flux in laminar flow through a parallel plate duct[END_REF][START_REF] Li | Inverse convection problem for determining wall heat flux in annular duct flow[END_REF][START_REF] Lee | Inverse radiation analysis using repulsive particle swarm optimization algorithm[END_REF]. The problem presented in this paper is one of parameter estimation because the flame model is known, but not the variables involved [START_REF] Beck | Inverse Heat Conduction, Ill-Posed Problems[END_REF].

The inverse problem considered here can be stated as the following bound constrained minimization problem:

( )

exp exp exp 1 2 exp 1,2,4 minimize ( ) subject to 1 with ( ) ( ) ( ) ( ) l u th th th a l l k k J J 4 ξ ξ ξ ξ ξ ξ ξ ξ = ≤ ≤ = Φ -Φ + Φ -Φ + Φ -Φ Φ ∑ (20) where ( ) 1 2
, ,..., , ,

N k k k f f f f y y y l f ξ φ =
is the decision variables vector that will be identified, l ξ , u ξ are respectively the lower and upper bounds of these variables, the

B B F F f f f f y y t y y t = =
A Generalized Pattern Search algorithm [START_REF] Lewis | Pattern Search Algorithms for Bound Constrained Minimization[END_REF], provided by the "Genetic Algorithm and Direct Search" Toolbox of Matlab ® , is used to solve the bound constrained optimization problem of relation [START_REF] Lewis | Pattern Search Algorithms for Bound Constrained Minimization[END_REF]. The particularity of this optimization algorithm is that it does not require any information about the gradient of the objective function, whereas traditional optimization methods need gradient or higher derivatives information to search for an optimal point. In fact, this method is a global algorithm, named direct search method, which searches a set of points around the current point, looking for one where the value of the objective function is lower than the value at the current point.

Experimental conditions

The fuel bed used for the experiments was a load of 1.2 kg.m -2 of straw placed on a combustion table. The table is made of cellular concrete and has an effective burning area of 2 m 2 (2 m × 1 m) with a depth of 0.2 m. The table can be inclined in order to simulate slope conditions. The different slopes simulated were -10°, 0°, 10° and 20°. The complete experimental device also includes a wireless heat flux sensor and a video camera (see Figure 3 and Figure 4).

Results and discussion

This section presents the results obtained for laboratory experimental fires after combining the two methodologies. Fire front positions were determined by image processing (see Figure 5) and then introduced as inputs in equation ( 20), the objective function which had to be minimized.

The calculation of flame characteristics by the inverse method gave the results presented in Table 2. It should be noted that the apparent flame temperature was computed according to equation [START_REF] Monod | Infrared radiative properties of vegetation involved in forest fires[END_REF] and that flame emissivity was obtained thanks to Beer's law [START_REF] Monod | Infrared radiative properties of vegetation involved in forest fires[END_REF], given by formula [START_REF] Pérez | Experimental study of the emissivity of flames resulting from the combustion of forest fuels[END_REF], after assuming an extinction coefficient of 0.72 m -1 experimentally determined for forest fuels by Àgueda et al. [START_REF] Pérez | Experimental study of the emissivity of flames resulting from the combustion of forest fuels[END_REF].

1/ 4 f f f T K B φ π ⎛ ⎞ = ⎜ ⎟ ⎜ ⎟ ⎝ ⎠ (21)
1 exp( )

f f f K ε δ = - - (22)
with f δ the mean flame depth for each slope value. It should be pointed out that the values of f ε calculated by this relation and reported in this table are in the range of 0.11 to 0.66 for a flame depth from 0.27 to 1.88 m and 0.12 to 0.94 for a flame depth from 0.15 to 2 m given respectively by Beyreis et al. [START_REF] Beyreis | Properties of wood crib flames[END_REF] and Hägglund and Persson [START_REF] Hägglund | An Experimental Study of the Radiation from Wood Flames. Försvarets Forskningsanstalt Huvudenhet[END_REF]. The same range of emissivity values is also obtained by Dupuy et al. [START_REF] Dupuy | Thermal infrared emission-transmission measurements in flames from a cylindrical forest fuel burner[END_REF].

Conclusion

Several studies in the forest fire literature have used image processing to provide geometrical characteristics of the fire front. However, there has been little research into the determination of these characteristics with other physical parameters using the measurement of heat flux which is the only relevant physical quantity that is measurable.

In this paper, a flame model with mean thermal and radiative properties has been derived from the radiative transfer equation. The equations obtained give simple relations to minimize the differences, in terms of the usual Euclidean norm, between the theoretical and the experimentally measured radiative heat fluxes. It has been shown that coupling image processing and the wireless heat flux sensor gives results that are in good agreement with those found in the literature and can help to design a new robust metrological tool for forest fires. An important advantage is that the computational time of the new metrological tool proposed here is twice as fast as the one without implementation of the image processing method.

  flux received by the i th target of sensor f ε flame emissivity

Figure 1 .

 1 Figure 1. Schematic view of flame and heat flux sensor.

  flames and perpendicular to the gauge facing the fire). Let us now consider these two configurations:

θ

  heat flux received by the i th face of the multigauge heat flux sensor, is the i th copper plate temperature and st θ is the sensor body temperature. is the specific heat capacity of each gauge, co C R is a thermal resistance modelling the contact between the copper plate and the steel body and 1 e

Figure 2 .

 2 Figure 2. Photograph of the wireless heat flux sensor.

  heat flux of the flame per unit volume. ⋅ denotes the usual Euclidean norm, , are the theoretical radiative heat fluxes given respectively by expressions (14) and (15) and are the experimental radiative heat fluxes measured by the wireless multiple thermal gauges. Note that we should identify the two functions, but that in order to reduce the computational cost these functions have been considered at discrete time values.

Figure 3 .

 3 Figure 3. Schematic overview of the experimental device.

Figure 4 .

 4 Figure 4. Photograph of the experimental device.

Figure 5 .Table 2 .Figure 6 .

 526 Figure 5. Example of fire forward front profile at different times for a fire spreading without slope.

Figure 7 .

 7 Figure 7. Computed rate of spread for down-slope and up-slope fires spread across straw bed.

Table 1 .

 1 Values

of the sensor parameters necessary to experimentally compute the total heat flux received by each gauge.