PhD, Post-Doc Marianne Canonico
email: canonico@vjf.inserm.fr

MD Geneviève Plu-Bureau

O Lowe

Pierre-Yves Scarabin

Gordon D O Lowe

Pierre- Yves Scarabin

PhD Gynecologist Gordon

MD D Lowe

MD Pierre-Yves Scarabin

Hormone replacement therapy and risk

teaching and research institutions in France or abroad, or from public or private research centers.

Introduction

Hormone therapy can improve the quality of life of women with hypo-oestrogenic symptoms [START_REF] Rymer | Making decisions about hormone replacement therapy[END_REF] . Despite recent data showing that overall health risks may exceed benefits of long-term hormone therapy 2 , many women are still prescribed estrogen therapy to treat postmenopausal climacteric symptoms. Hormone therapy is also effective for preventing osteoporotic fractures among current users 2 3 . By contrast, harmful effects of hormone therapy include breast cancer and venous thromboembolism [START_REF] Beral | Evidence from randomised trials on the long-term effects of hormone replacement therapy[END_REF] . Furthermore, randomised controlled trials showed that hormone therapy might increase the risk of coronary heart disease and stroke 2 5 .

Despite evidence that oral oestrogen activates blood coagulation in postmenopausal women [START_REF] Caine | Coagulation activation following estrogen administration to postmenopausal women[END_REF] , hormone therapy had, until 1996, long been believed to have little effect on the risk of venous thromboembolism [START_REF] Miller | Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force[END_REF] . However, observational studies recently showed consistent associations between current use of hormone therapy and an increased risk of venous thromboembolism in postmenopausal women 5 w1-w11 . These findings have been confirmed by randomised controlled trials 5 w12-w20 .

Most previous studies of venous thromboembolism in users of hormone therapy were done among women using conjugated equine oestrogens alone or combined with medroxyprogesterone acetate 8 9 . These results cannot be generalized to other regimens of hormone therapy, especially those used in some European countries.

Recent data have suggested the importance of the route of oestrogen administration in determining risk of venous thromboembolism [START_REF] Scarabin | Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk[END_REF] .

The purpose of this review was to estimate the risk of venous thromboembolism among hormone therapy users. This quantitative assessment takes into account the study design (observational studies or randomized controlled trials) and the characteristics of both hormone therapy (route of oestrogen administration, unopposed or combined with progestogens, duration of treatment) and venous thromboembolism (idiopathic or secondary).

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Methods

Literature search

An electronic search of medical literature was carried out on the MEDLINE database from 1974 to 2007. Relevant keywords relating to hormone therapy (eg, "estrogen replacement" or "oestrogen replacement" or "estrogen" or "estrogen therapy" or "oestrogen" or "oestrogen therapy" or "estrogen replacement therapy" or "oestrogen replacement therapy" or "hormone" or "hormone replacement therapy" or "hormone therapy" or "hormonal therapy" or "hormonal replacement therapy") were used in combination with words relating to venous thromboembolism (eg, "venous thrombosis" or "venous thromboembolism" or "thrombosis" or "pulmonary embolism" or "embolism" or "emboli") We also identified original articles by back-referencing from general reviews published after 1970 7-9 11-17 .

Study selection

We screened all articles identified by key words using Medline Database (n=1890).

We first excluded publications not in English, not related to the topic, on contraception and biological studies. The selected articles (n=111) were reviewed and we excluded general reviews and articles which did not assess venous thromboembolism risk. Twenty four studies (nine randomised controlled trials w12-w20 , twelve case-control studies w1-w3 w5-w7 w9-w11 w21-23 and three prospective cohort studies w4 w24-w25 ) were eligible for inclusion in meta-analysis and were assessed for quality.

Quality assessment

We assessed the quality of randomized controlled trials and observational studies separately. Regarding randomized controlled trials, we assessed studies for quality of randomization, blinding, reporting of withdrawals, generation of random numbers and concealment of allocation. Trials scored one point for each area addressed, therefore receiving a score between 0 and 5 (highest level of quality) 18 19 . We included in the meta-analysis trials which had a score higher or equal to 4 w12-w20 (Table 1). We assessed the quality of observational studies using a specific checklist consistent with the consensus recommendations by the Meta-analysis Of Observational Studies in Epidemiology MOOSE group [START_REF] Stroup | Metaanalysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group[END_REF] . Case-control studies received a score between 0

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5/34 and 6 (highest level of quality) and we included in the meta-analysis studies which had a score higher or equal to 5 w1 w3 w5 w9-w11 w21 (Table 2). Cohort studies received a score between 0 and 7 (highest level of quality) and we included in the meta-analysis studies which had a score higher or equal to 6 w4 (Table 3) (see Quality assessment in appendix).

Data extraction

Included studies were independently reviewed by two authors (PYS and MC).

Disparities were resolved by discussion.

Study characteristics

Each study was classified according to the design (either observational study or randomised controlled trials). Relevant data on the characteristics of hormone therapy (route of oestrogen administration, type of oestrogens, unopposed or opposed hormone regimen, duration of treatment) as well as the characteristics of venous thromboembolism (idiopathic or secondary, deep vein thrombosis or pulmonary embolism, ascertainment of venous thromboembolism) were extracted and used to provide an overall estimate.

Statistical methods

For each study, the most adjusted relative risks (RR) or odds ratios (OR) and their 95% confidence interval (95% CI) were used. Homogeneity between the studies was analyzed using the ² and I² statistics 21 22 . The results of homogenous studies were pooled and an overall estimate of relative risk was obtained from a fixed-effects model [START_REF] Dersimonian | Meta-analysis in clinical trials[END_REF] . Briefly, a weighted average of relative risks was calculated, with the weights being the inverse of variance of relative risk [START_REF] Fleiss | The statistical basis of meta-analysis[END_REF] . For each study, the variance of relative risk was estimated from the 95% confidence interval. When between studies heterogeneity was detected, a random-effects model was used [START_REF] Dersimonian | Meta-analysis in clinical trials[END_REF] . Statistical analyses were performed using SAS statistical software (version 9.1, SAS Institute Inc, Cary, NC).

Results

Characteristics of the studies

General characteristics of subjects, sample size and types of treatment were studied for each observational study and randomized controlled trial.

 Observational studies

We selected seven case-control studies w1 w3 w5 w9-w11 w21 and one cohort study w4 (figure 1 and appendix). Characteristics of included studies are summarized in the table 4.

All the studies have investigated the risk of venous thromboembolism in relation to oral oestrogen use w1 w3-w5 w9-w11 w21 and four of them have evaluated the risk of venous thromboembolism in relation to transdermal route of oestrogen administration w1 w5 w10 w11 .

With regard to the characteristics of hormone therapy, women were treated by either 17-oestradiol w1 w3 w5 w11 or conjugated equine oestrogens w1 w3-w5 w9 w11 w21 or esterified oestrogen w3 w9 . Women were generally classified as current users if they had used hormone therapy at any time in the past 1 to 6 months before inclusion date.

In most of the studies, the clinical endpoint was a first-time idiopathic venous thromboembolism (i.e. without provoking risk factors [START_REF] White | Is the current classification of venous thromboembolism acceptable? No[END_REF] ), either deep venous thrombosis or pulmonary embolism. The Nurses' Health Study was restricted to first episode of either idiopathic or non idiopathic pulmonary embolism w4 and Smith included first-time idiopathic and non idiopathic venous thromboembolism w9 . The clinical events were mostly validated by ultrasound (deep vein thrombosis) or lung scanning (pulmonary embolism).

 Randomised controlled trials (Table 5) HERS was the first clinical trial designed to investigate the effect of hormone therapy on coronary heart disease recurrence. Starting in 1993, HERS was a multi-centre randomised, double-blind, placebo-controlled trial that enrolled 2763 postmenopausal women (mean age 66.7 years) with an intact uterus. Intervention was 0.625 mg conjugated equine oestrogens plus 2.5 mg medroxyprogesterone acetate or placebo.


Venous thromboembolism was used as a secondary outcome in HERS. Venous thromboembolism occurred in 34 women in the hormone therapy group and in 12 women in the placebo group.

 OEstrogen in Venous ThromboEmbolism Trial (EVTET) w14

EVTET was a randomised double-blind trial, comparing 2 mg oestradiol plus 1 mg norethisterone acetate to placebo in postmenopausal women with previously documented venous thromboembolism. The study was stopped prematurely after a mean follow-up of 1 year and 4 months. More women experienced recurrent venous thromboembolism in the hormone therapy group than in the placebo group (8 and 1, respectively).

 OEstrogen Replacement and Atherosclerosis trial (ERA) w15

The ERA trial examined the effects of hormone therapy on the progression of coronary atherosclerosis in 309 postmenopausal women who had angiographically verified coronary heart disease. Women were randomly assigned to receive conjugated equine oestrogens (0.625 mg per day) alone or conjugated equine oestrogens (0.625 mg per day) plus medroxyprogesterone acetate (2. The oestrogen plus progestin component of the WHI was a randomised controlled primary prevention trial in which 16 608 postmenopausal women with an intact uterus were randomly assigned to receive conjugated equine oestrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo w18 . A total of 218 venous thromboembolism was enumerated (151 in the hormone therapy group and 67 in the placebo group).

The oestrogen alone component of the WHI was a randomised controlled primary prevention trial in which 10 739 postmenopausal women with prior hysterectomy were randomly assigned to receive conjugated equine oestrogens (0.625 mg per day) or placebo w19 . Venous thromboembolism occurred in 167 oestrogen treated women and in 76 placebo treated ones.

 The Women's International Study of long Duration Oestrogen after Menopause (WISDOM) w20

The WISDOM trial was a randomized, double blinded, placebo controlled trial, set up in United Kingdom, Australia and New Zealand to assess the long term risk and

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9/34 benefits of hormone therapy in women aged 50 to 69 years without an arterial disease within the past 6 months before inclusion (n=5692). Women were randomly assigned to receive either conjugated equine oestrogens (0.625 mg per day) alone or conjugated equine oestrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. It was planned to compare conjugated equine oestrogens plus medroxyprogesterone acetate with placebo and conjugated equine oestrogens plus medroxyprogesterone acetate with conjugated equine oestrogens alone. Ten years of treatment were been planned but WISDOM was prematurely closed following publication of the WHI results. After a mean follow-up of 11.9 months, venous thromboembolism occurred in 22 women in the conjugated equine oestrogens plus medroxyprogesterone acetate group and in 3 women in the placebo group. Comparison of conjugated equine oestrogens plus medroxyprogesterone acetate versus conjugated equine oestrogens alone outcomes revealed no significant differences.

Results of the meta-analysis

Pooled risk of venous thromboembolism was assessed from eight observational studies and nine randomized controlled trials. From observational studies, the risk of venous thromboembolism was estimated by route of oestrogen administration. In addition, the risk of venous thromboembolism was estimated according to the characteristics of both treatment (type, duration) and venous thromboembolism (idiopathic or secondary, type of diagnostic).

 Venous thromboembolism risk by characteristics of hormone therapy

Figure 2 shows pooled OR of first-time venous thromboembolism in relation to hormone therapy use by study design and route of oestrogen administration. All but one observational studies w21 consistently reported an association between oral oestrogen use and an increased risk of venous thromboembolism w1 w3-w5 w9-w11 . Four of them investigated the impact of transdermal oestrogen use on risk of first episode of venous thromboembolism w1 w5 w10 w11 . Pooled OR (95% CI) for oral and transdermal oestrogen was 2.5 (1.9-3.4) and 1.2 (0.9-1.7), respectively. The upper 95% CI for transdermal use (1.7) was lower than the lowest 95% CI for oral use (1.9).

The association of venous thromboembolism with oral oestrogen use was confirmed by results from randomized controlled trials (pooled OR=2.1; 95%CI: 1.4-3.1). The 10/34 combined odds ratio from both trials and observational studies in oral estrogen users was 2.4 (1.9-3.0) and was higher than the summary risk among women using transdermal estrogen (p<0.001). No trials have investigated the effect of transdermal estrogen on the risk of venous thromboembolism.

One study suggested that the type of oestrogen might be an important determinant of the risk of venous thromboembolism. In this study, conjugated equine oestrogen was associated with increased risk, whereas esterified oestrogen was not w9 .

Data on the risk of venous thromboembolism in past users of hormone therapy compared with never users were available in four observational studies w1 w4 w10 w11 and showed that past use of hormone therapy was not associated with an increased risk of venous thromboembolism (pooled OR=1.2; 95%CI: 0.9-1.7) (Figure 3).

The impact of unopposed and opposed oral oestrogen therapy on the risk of venous thromboembolism has been investigated in six observational studies w1 w3 w5 w9-w11 . No significant difference in the risk of venous thromboembolism was observed between oral oestrogen alone and oral oestrogen/progestogen therapy (pooled OR=2.2; 95%CI: 1.6-3.0 and pooled OR=2.6; 95% CI: 2.0-3.2, respectively).

Finally, the risk of venous thromboembolism has been assessed according to the duration of treatment. Information on duration of oral oestrogen was available in only five case-control studies w1 w3 w5 w10 w11 . Results from these studies showed that the risk of venous thromboembolism was significantly higher within the first year of treatment (pooled OR=4.0; 95% CI: 2.9-5.7 for a duration of hormone therapy less than one year and pooled OR=2.1; 95% CI: 1.3-3.8 for a duration of hormone therapy more than one year, p<0.05) (Figure 3).

 Risk of venous thromboembolism by type of diagnosis

When analysis was restricted to the first episode of idiopathic events w1 w3-w5 w10 w11

 Women at high risk for venous thromboembolism

The impact of prothrombotic mutations 26 27 on the risk of venous thromboembolism, with or without hormone therapy, has been investigated in four case-control studies w28-w31 and in both WHI clinical trials w26 w27 . Overall the presence of the Factor V Leiden mutation or prothrombin G20210A mutation increased the risk of venous thromboembolism more than 3-fold (pooled OR=3.3; 95%CI: 2.6-4.1). The combination of thrombogenic mutations and oral oestrogen use, especially conjugated equine oestrogen, with or without progestin, further enhanced the risk of venous thromboembolism (OR=8.0; 95% CI: 5.4-11.9) compared with women without mutations who did not use any treatment. However, in one study, there was no significant difference in the risk of venous thromboembolism between women with factor V Leiden mutation or prothrombin G20210A mutation using transdermal oestrogen and women with a mutation but not using oestrogen (OR= 4.4; 95%CI: 2.0-9.9) w30 (Figure 4).

The association of venous thromboembolism with hormone therapy in relation to elevated body-mass index has been investigated in both the WHI clinical trials w26 w27 and in a case-control study w32 . An elevated body-mass index (overweight or obesity) increased the risk of venous thromboembolism (pooled OR=2.6; 95%CI: 2.1-3.3). In addition, the combination of current oral oestrogen use and an increased body-mass index resulted in a further elevation of the risk of venous thromboembolism (pooled OR=5.4; 95%CI: 2.9-10.0). However, in one study, current use of transdermal oestrogen did not confer an additional risk on women with overweight or obesity w32 (Figure 5).

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Discussion

Principal findings

This meta-analysis of both observational studies and randomised controlled trials shows that current use of oral oestrogen increases two to three times the risk of venous thromboembolism. This elevation is higher within the first year of treatment and more pronounced for women at high thrombotic risk. Overall, with a baseline risk for venous thromboembolism of about 1 per 1000 women-years 28 29 , an additional 1.5 events per 1000 women each year would be expected. Combined analysis of observational studies shows no significant increase in the risk of venous thromboembolism among transdermal oestrogen users.

Strengths of the study

Previous reviews and meta-analysis regarding hormone therapy and risk of venous thromboembolism focused on oral oestrogen use and failed to take into account the route of oestrogen administration 7 11 13 15 . This report provides the first quantitative assessment of the thrombotic risk among oral and transdermal oestrogen users separately. Moreover, the present meta-analysis investigated the impact of hormone therapy by route of oestrogen administration among women at high thrombotic risk.

In two previous reviews 13 15 , the risk of venous thromboembolism among oral oestrogen users who carried prothrombotic mutations was assessed from two casecontrol studies w28-w29 . We updated this meta-analysis by adding data from four studies w26 w27 w30 w31 . With regard to women with overweight or obesity, our metaanalysis is the first to show a substantial increase in the risk of venous thromboembolism among oral estrogen users with elevated body-mass index (overweight or obesity) w26 w27 w32 .

Weaknesses of the study

In the present meta-analysis, assessment of the risk of venous thromboembolism among transdermal oestrogen was based on relatively few data w1 w5 w10 w11 .

Therefore, results should be interpreted with caution and further investigation of transdermal oestrogen is needed. Another limitation of the present report is the lack

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13/34 of data on the impact of progestogens. Although this meta-analysis showed similar risk of venous thromboembolism comparing oral oestrogen alone and opposed oral oestrogen, progestogens have recently emerged as a determinant of the risk of venous thromboembolism. One study reported that the risk of venous thromboembolism was higher in users of opposed oral oestrogen than in users of oral oestrogen alone w10 and the risk of venous thromboembolism was higher in the WHI oestrogen/progestogen clinical trial w18 than in the WHI oestrogen alone clinical trial w19 . In addition, among women recruited in the conjugated equine oestrogens plus medroxyprogesterone acetate versus conjugated equine oestrogens WISDOM trial, there was a suggestion in the opposed oestrogen therapy group of an increase in venous thromboembolism (RR=2.39; 95%CI: 0.62-9.24) w20 . Finally, recent data from one case-control study showed that norpregnane derivatives might increase the risk of venous thromboembolism whereas there was no association of venous thromboembolism with micronised progesterone and pregnane derivatives w11 .

Our meta-analysis of both observational studies and randomised controlled trials showed heterogeneity between studies among oral oestrogen users. An important source of heterogeneity between trials may arise from differences in the duration of treatment. The WISDOM trial, which was closed after a median follow-up of 11.2 months, reported an odds ratio for venous thromboembolism higher than those from other randomised controlled trials w20 . When analysis was restricted to randomised trials with a longer follow-up, heterogeneity between studies disappeared. Explanations for heterogeneity between observational studies include differences in the type of venous thrombotic event. Two studies included women with non-idiopathic venous thromboembolism w4 w9 . If analysis was restricted to idiopathic venous thromboembolism, heterogeneity between observational studies disappeared. There were also differences in results by study design. The association of venous thromboembolism with oral oestrogen use was lower in randomized controlled trials than in observational studies. This difference could be explained by inclusion of procedure-related venous thromboembolism in WHI trials, as well as the high degree of nonadherence to study medication in randomized controlled trials, resulting in an underestimation of hormone effects in randomized controlled trials.

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Biological explanations for results

Biological evidence lends support to the difference in the risk of venous thromboembolism between oral and transdermal oestrogen. Oral oestrogen administration results in a hepatic first-pass effect and may impair the balance between procoagulant factors and antithrombotic mechanisms [START_REF] Lowe | Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein--a cross-sectional population survey[END_REF] . Oral, but not transdermal, oestrogen increases plasma concentrations of prothrombin fragment 1+2 31 32 , which is a marker for in-vivo thrombin generation, and increases the fibrinolytic potential in postmenopausal women. A lower antithrombin concentration has also been shown in women using oral oestrogen but not in those using transdermal oestrogens [START_REF] Conard | Differential AT III-response to oral and parenteral administration of 17 beta-estradiol[END_REF] . In addition, an acquired resistance to activated protein C has been demonstrated in users of oral oestrogen 34 35 but two randomised trials recently indicated that these results did not apply to users of transdermal oestrogen 32 36 . Thus, transdermal oestrogen appears to have little or no effect on haemostasis.

Clinical implications

The findings of the present meta-analysis of studies by route of estrogen administration may have important clinical implications. Pulmonary embolism accounts for about one third of the excess incidence of potentially fatal events due to long-term hormone therapy [START_REF] Beral | Evidence from randomised trials on the long-term effects of hormone replacement therapy[END_REF] . Therefore, the risk of venous thromboembolism is an important determinant of the benefit/risk profile of hormone therapy, and differences in the risk of venous thromboembolism between types of hormone therapy may have important clinical implications. In addition, since recent guidelines recommend that women are prescribed the lowest effective dose of hormone therapy for the shortest time possible [START_REF]Estrogen and progestogen use in peri-and postmenopausal women: March 2007 position statement of The North American Menopause Society[END_REF] , pulmonary embolism becomes a main adverse effect due to oral oestrogen therapy within the first year of treatment. By contrast, there is little increase risk of stroke and breast cancer within the first year of treatment. Therefore, reducing venous thromboembolism risk by transdermal oestrogen use could improve the benefit/risk profile of hormone therapy, especially among women at high risk of venous thromboembolism (e.g. known prothrombotic mutation, elevated body-mass index).

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Future research

Future randomized trials of oral versus transdermal oestrogen will clarify this apparent lower risk. Clinical research should continue into genetic factors influencing the risk associated with hormone therapy, different oestrogen and progestogen formulations, different modes of delivery, lower-dose options and alternative regimens (e.g. selective oestrogen receptor modulators, phytooestrogens). Such research will assist patients and clinicians in making treatment decisions on the basis of an individual's benefits and risks [START_REF] Rexrode | Are some types of hormone therapy safer than others? Lessons from the Estrogen and Thromboembolism Risk study[END_REF] .

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Table1-Quality assessment of included randomised controlled trials (Appropriate=1

Legend of figures

Results of literature search for randomized controlled trials and observational studies of hormone therapy that reported venous thromboembolism.



  Postmenopausal oEstrogen/Progestin Interventions (PEPI) w12 PEPI was a multicenter, randomised, double-blind, placebo-controlled trial which examined the effects of hormone therapy on heart disease risk factors among 875 healthy postmenopausal women. Intervention was placebo or 0.625 mg per day conjugated equine oestrogens alone or combined with either cyclic Review BMJ Final version R4 7/34 medroxyprogesterone acetate or consecutive medroxyprogesterone acetate or cyclic micronised progesterone. During 3 years of follow-up, venous thromboembolism occurred in 4 women among pooled treated groups and none among the placebo group. Heart and oEstrogen/progestin Replacement Study (HERS) w13

  5 mg per day) or placebo. During 3.2 years of follow-up, venous thromboembolism occurred in 5 women, 2 women and one woman respectively.  Women's Oestrogen for Stroke Trial (WEST) w16 WEST was started in 1993 as a randomised, placebo-controlled trial of hormone therapy for the secondary prevention of cerebrovascular disease. This trial was conducted in 664 postmenopausal women (mean age, 71 years) who had recently had an ischaemic stroke or transient ischaemic attack. Women were randomly assigned to receive either 1 mg of 17-oestradiol per day or a placebo. Women were Review BMJ Final version R4 8/34 monitored for venous thromboembolism events. Venous thromboembolism occurred in 3 women in the hormone therapy group and in 4 women in the placebo group.  OEStrogen in the Prevention of ReInfarction Trial (ESPRIT) w17 ESPRIT was set up in United Kingdom to assess the effect of unopposed oestradiol valerate on the risk of coronary heart disease in postmenopausal women who had survived their first myocardial infarction. The study was a randomised, blinded, placebo controlled, secondary prevention trial among 1017 women aged 50-69 years. Women received either oestradiol valerate (2 mg per day) or placebo for 2 years. In this secondary prevention trial after a first myocardial infraction, 2 women in the hormone therapy group and 1 in the placebo group experienced venous thromboembolism.  Women's Health Initiative (WHI) w18 w19 w26 w27 The WHI focuses on strategies which could potentially reduce the incidence of coronary heart disease, breast and colorectal cancer, and fractures in postmenopausal women. Between 1993 and 1998, the WHI enrolled 161 809 postmenopausal women in the age range of 50 to 79 years into a set of clinical trials (trials of low-fat dietary pattern, calcium and vitamin D supplementation, and two trials of postmenopausal hormone therapy) and an observational study at 40 clinical centers in the United States.

  w21 , the risk of venous thromboembolism in relation to oral oestrogen use substantially increased (pooled OR=3.1; 95% CI: 2.3-4.1), whereas results for transdermal oestrogen use remained unchanged. Analysis by diagnosis of venous thromboembolism showed no significant difference in the risk of venous thromboembolism between deep vein thrombosis and pulmonary embolism in relation to oral oestrogen use. From observational studies, pooled OR (95% CI) was 2.8 (1.9-4.0) for deep vein thrombosis and 2.7 (1.1-2.5) for Review BMJ Final version R4 11/34 pulmonary embolism. This result was confirmed by data from randomised controlled trials (data not shown).

Figure 2 .

 2 Figure 2. Risk of first episode of venous thromboembolism by study design and route of oestrogen administration. Values are adjusted odds ratios (95% confidence interval). (NHS: Nurses' Health Study; Trans: transdermal; RCTs: randomised controlled trials).

Figure 3 .

 3 Figure 3. Risk of venous thromboembolism by characteristics of hormone therapy among users of oral oestrogen. Values are odds ratios (95% confidence interval).(O: oestrogen; O+P: oestrogen and progestogen; HT: hormone therapy).

Figure 4 .

 4 Figure 4. Risks of venous thromboembolism among hormone therapy users by route of oestrogen administration and presence of one of two prothrombotic mutations (Factor V Leiden mutation and/or prothrombin G20210A mutation). Values are odds ratios (95% confidence intervals) (O : oestrogen).

Figure 5 .

 5 Figure 5. Risks of venous thromboembolism among hormone therapy users by route of oestrogen administration and presence of an elevated body-mass index (overweight or obesity). Values are odds ratios (95% confidence intervals) (O : oestrogen).

Figure 5 Characteristics

 5 Figure 5 Characteristics Authors or Study, OR [95% CI]

  / No information or no appropriate=0)

	Study, years	Randomisation	Double-blinding	Dropout and withdrawals	Generation of random numbers	Allocation concealment		Score (0-5)
	PEPI w12 ,1995	Yes	Yes	3.0% withdrawal and dropout	Computer generated block randomisation	Active drug and identical forms placebo prepared in	5
	HERS w13 , 1998	Yes	Yes	0% dropout 2.1% withdrawal	Computer generated random numbers	Active drug and identical forms placebo prepared in	5
	EVTET w14 , 2000	Yes	Yes	23.6% dropout or withdrawal	Computer generated block randomisation	Active drug and identical forms placebo prepared in	5
							Each	women
	ERA w15 , 2000	Yes	Yes	14.0% dropout 4.0% withdrawal	Permuted randomisation	block	received two tablets and placebo tablets (active treatment	5
							or 2 placebo tablets)
	WEST w16 , 2001	Yes	Yes	0% dropout 1.4% withdrawal	Computer generated block randomisation	?		4
	ESPRIT w17 , 2002	Yes	Yes	?	Computer generated block randomisation	Active drug and identical forms placebo prepared in	4
	WHI I w18 , 2002	Yes	Yes	3.5% dropout	Permuted randomisation	block	Active drug and identical forms placebo prepared in	5
	WHI II w19 , 2004	Yes	Yes	2.2% dropout 3.0% withdrawal	Permuted randomisation	block	Active drug and identical forms placebo prepared in	5
	WISDOM w20 , 2007 Yes	Yes	0.01% dropout 13.2% withdrawal	Computer generated block randomisation	Active drug and placebo prepared in identical forms
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Table 2 -

 2 Quality assessment of included case/control studies (Yes=1 / No=0)

	Author or Study, year	Appropriate inclusion and exclusion criteria applied equally to cases and controls	Only first episode of venous thromboembolism	Objective diagnostic procedure	Adequate assessment of status menopausal	Accurate assessment of HT including the administration route of oestrogen	Adequate analysis and controlling for (adjustment) confusion	Score (0-6)
	Boston CDSP w21 , 1974	Yes	Yes	No	Yes	Yes	Yes	5
	Daly w1 , 1996	Yes	Yes	No	Yes	Yes	Yes	5
	Jick w3 , 1996	Yes	Yes	Yes	Yes	Yes	Yes	6
	Perez-Gutthann w5 , 1997	Yes	Yes	No	Yes	Yes	Yes	5
	Smith w9 , 2004	Yes	Yes	Yes	Yes	Yes	Yes	6
	Douketis w10 , 2005	Yes	Yes	Yes	Yes	Yes	Yes	6
	ESTHER Study w11 , 2007	Yes	Yes	Yes	Yes	Yes	Yes	6

Table 3 -

 3 Quality assessment of included cohort studies (Yes =1 / No =0)

	Author or Study, year	Appropriate method of subject selection	Only first episode of venous thromboembolism	Objectives diagnostic procedure	Adequate assessment of menopausal status	Accurate assessment of HT including the route of administration oestrogen	Overall low loss of follow-up	Adequate (adjustment) analysis and controlling for confusion	Score (0-7)
	Nurses' Health Study w4 , 1996	Yes	Yes	Yes	Yes	Yes	Yes	Yes

Table 4 -

 4 Characteristics of included observational studiesAuthor or Study, year

		Route of oestrogen administration	Clinical endpoint	Oestrogen type	Current users definition*	Exposed cases (n)	Adjusted risk ratio of VTE (95 % CI)
	Boston CDSP w21 , 1974	Oral	1 st episode of idiopathic VTE	Mainly CEE	NA	3	1.9 (1.4-7.8)
	Daly w1 , 1996	Oral Transdermal	1 st episode of idiopathic VTE	E2 / CEO E2	Less than 1	37 5	4.6 (2.1-10.1) 2.0 (0.5-7.6)
	Jick w3 , 1996	Oral	1 st episode of idiopathic VTE	CEE / EO Less than 6 21	3.6 (1.6-7.8)
	Nurses' Health Study w4 , 1996	Oral	1 st episode of PE	Mainly CEE	NA	68	2.1 (1.2-3.8)
	Perez-Gutthann w5 , 1997	Oral Transdermal	1 st episode of idiopathic VTE	E2 / CEO E2	Less than 6	20 7	2.1 (1.3-3.6) 2.1 (0.9-4.6)
	Smith w9 , 2004	Oral	1 st episode of VTE	CEO EO	NA	121 86	1.7 (1.2-2.2) 0.9 (0.7-1.2)
	Douketis w10 ], 2005	Oral Transdermal	1 st episode of idiopathic VTE	NA NA	Less than 1	36 3	1.9 (1.2-3.2) 0.8 (0.3-2.8)
	ESTHER Study w11 , 2007	Oral Transdermal	1 st episode of idiopathic VTE	E2 / CEO E2	Less than 3	57 67	4.5 (2.6-7.5) 1.1 (0.8-1.7)
	* Time duration between oestrogen use and VTE to be considered as current users (months)
	# 90% CI
	95 % CI: 95 % confidence interval
	VTE: venous thromboembolism
	PE: pulmonary embolism
	NA: not available
	E2: oestradiol or oestradiol valerate
	CEO: conjugated equine oestrogen
	EO: esterified oestrogen

Table 5 -

 5 Characteristics of included randomised controlled trials Study, years

		Total number of subjects *	Clinical background	Duration of the trial (years)	Number of events HT/placebo	Adjusted risk ratio of VTE (95 % CI)
	PEPI w12 ,1995	847	"Healthy"	3	4/0 §	1.9 (0.1-36.5) $ #
	HERS w13 , 1998	2763	History of CHD	4.1	34/12	2.9 (1.5-5.6)
	EVTET w14 , 2000	140	History of VTE	1.3	8/1	7.8 (1.0-60.5)
	ERA w15 , 2000	309	History of CHD	3.2	7/1 £	3.6 (0.5-28.9) $
	WEST w16 , 2001	664	History of stroke	2.8	3/4	0.8 (0.2-3.4)
	ESPRIT w17 , 2002 1017	History of CHD	2	5/4	1.2 (0.3-4.6)
	WHI I w18 , 2002	16608	"Healthy"	5.2	151/67	2.1 (1.6-2.7)
	WHI II w19 , 2004	10739	"Healthy"	7	77/54	1.3 (1.0-1.8)
	WISDOM w20 , 2007 5692	Possible history of arterial disease	0.99	22/3	7.4 (2.2-24.6)
	* Approximately equal number in placebo and active treatment group except in PEPI and
	ERA trials
	§ HT: n=682 Placebo: n=165

$

Risk was calculated from data reported in the study # To estimate the RR, number of events in placebo group was considered equal to 0.5 £ HT: n=204 Placebo: n=105 CHD : coronary heart disease 95 % CI : 95 % confidence interval

Pooled OR 5.4 [2.9-10.0]

	Articles identified by key words using MEDLINE database (n=1890) Figure 4 Figure 2 Figure 1 Boston CDSP, 1974 Daly, 1996 Jick, 1996 Design Oestrogen Authors or Study, OR [95% CI] 1.9 [0.4-7.8] 4.6 [2.1-10.1] 3.6 [1.6-7.8] Oral route Characteristics Authors or Study, OR [95% CI] years years Observational studies Rosendaal, 2001 3.8 [1.7-8.5] Herrington, 2002 3.3 [1.1-9.8] One of prothrombotic ESTHER, 2006 2.9 [2.1-4.0]	derived from [w26-w31]
	mutation	NHS, 1996 ESTHER, 2005 WHI I, 2004 Perez-Gutthann, 1997 Smith, 2004 WHI I, 2004 Douketis, 2005 WHI II, 2006 WHI II, 2006	2.4 [1.2-4.6] 3.9 [2.6-5.9] 2.2 [1.4-3.5] 2.1 [1.3-3.6] 1.6 [0.5-5.4] 1.7 [1.2-2.2] 1.9 [1.2-3.2] 2.2 [0.6-8.6] 2.6 [1.5-4.4]	•Articles not in English •Not related to the topic •On contraception
		ESTHER, 2007 Smith, 2006 Pooled OR 2.6 [2.1-3.3] 4.5 [2.6-7.5] 3.1 [2.2-4.1]	•Biological studies
	Pooled OR Test for homogeneity: ²=14.99 (p=0.03), I²=53.3 % 2.5 [1.9-3.4] Pooled OR 3.3 [2.6-4.1] Test for homogeneity: ²=0.94 (p=0.63), I²=0 %
	Test for homogeneity: ²=2.67 (p=0.75), I²=0 %
	Articles selected on titles and abstracts Daly, 1996 2.0 [0.5-7.6] Trans
		(n=111) Perez-Gutthann, 1997	2.1 [0.9-4.6]
	One of	Douketis, 2004 ESTHER, 2007 Rosendaal, 2003 ESTHER, 2006		0.8 [0.3-2.8] 1.1 [0.8-1.7] 11.0 [2.7-44.0] 13.1 [5.5-31.1]
	Pooled OR Test for homogeneity: ²=2.92 (p=0.40), I²=0 % 1.2 [0.9-1.7] PEPI, 1995 1.9 [0.1-36.5] Oral Herrington, 2003 14.1 [2.7-72.4] ESTHER, 2005 prothrombotic RCTs WHI I, 2004 4.7 [3.1-7.1] mutation and 25.5 [6.9-95.0] WHI I, 2004 5.2 [2.8-9.8] oral O WHI II, 2006 3.3 [1.9-5.6]	•Reviews •Did not assess VTE risk
		HERS, 1998 EVTET, 2000 WHI II, 2006		2.9 [1.5-5.6) 7.8 [1.0-60.5] 3.5 [0.2-11.1]
	ERA, 2000 Smith, 2006 Test for homogeneity: ²=7.01 (p=0.03), I²=71.5 % 3.6 [0.5-28.9] 9.1 [4.5-18.2]
	24 potentially appropriate studies WEST, 2001 ESPRIT, 2002 Pooled OR 8.0 [5.4-11.9] 0.8 [0.2-3.4] 1.2 [0.3-4.6] WHI I, 2002 2.1 [1.6-2.7] Test for homogeneity: ²=6.29 (p=0.28), I²=20.5 %
	15 observational studies 1 1.3 [1.0-1.8] 7.4 [2.2-24.6] Pooled OR WHI II, 2004 WISDOM, 2007 1 1 Test for homogeneity: ²=17.01 (p=0.03), I²=58.9 % 9 Randomised controlled trials transdermal O mutation and 2.1 [1.4-3.1] ESTHER, 2005 4.4 [2.0-9.9] One of prothrombotic ESTHER, 2006 3.5 [2.0-6.2]	10 10 10	100 100 100
				7 excluded studies because 31/34 33/34 34/34
					•Not only first VTE (n=4)
					•Without objective diagnostic
					procedures (n=3)
					•No adequate assessment of
					postmenopausal status (n=6)
					•No information on the route of
					estrogen administration (n=5)*
	9 randomised controlled trials	8 observational studies
	included in meta-analysis		included in meta-analyse

* n > 7 because excluded studies have more than one defect (low score of quality)

Funding: MC and PYS are funded by Inserm (Institut National de la Santé et de la Recherche Biomédicale). GPB is funded by AP-HP (Assistance Publique des Hôpitaux de Paris) and GDL is funded by the University of Glasgow.

"What this study add" box

What is already known on this topic Hormone therapy improves the quality of life but it is known to increase the risk of venous thromboembolism.

What this study adds

Transdermal oestrogen decreases the risk of venous thromboembolism when compared to oral oestrogen and it appears safe with respect to thrombotic risk.

Women with prothrombotic mutations or elevated body-mass index are at high risk of venous thromboembolism and should be discouraged from using oral oestrogen therapy.

Contributors: MC and PYS reviewed the studies and collected the data. MC, GPB and PYS performed statistical analysis. MC, GPB, GDL and PYS drafted the manuscript. MC, GBP, GDL and PYS revised the paper. PYS is guarantor.

Competing interests: All authors have declared no conflicts of interest.

Exclusive licence:

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its licensees, to permit this article (if accepted) to be published in BMJ editions and any other BMJPG products and to exploit all subsidiary rights, as set out in our licence. 32/34


G Lastras

M Canals

D Amblas

M Ivanov

B Dennielou

Laurence Droz

A Akhmetzhanov

  L'archive ouverte pluridisciplinaire

INTRODUCTION

Submarine landslides are widespread on ocean margins all over the world, both glacial and river-dominated, and in volcanic archipelagos [START_REF] Hampton | Submarine landslides[END_REF][START_REF] Canals | Slope failure dynamics and impacts from seafloor and shallow sub-seafloor geophysical data: case studies from the COSTA project[END_REF]). From a geological point of view, they are one of the most important processes in shaping continental margins, modifying the distribution pattern of canyon-channel systems and channel-levee complexes, and redistributing sediment from the shelf and upper slope to the base-of-slope and abyssal plains. Landslides pose a significant geologic risk, since they involve the release of large quantities of energy which can both directly and indirectly affect man-made structures. Direct impacts of submarine landslides on coastal structures, submarine power and telecommunication cables, pipelines, and oil platforms are associated with important economic losses [START_REF] Campbell | Deepwater geohazards: how significant are they?[END_REF]. Moreover, the generation of tsunami waves due to fast mobilisation of rocks and sediments can, and has caused severe damage onshore [START_REF] Tappin | The Sissano, Papua New Guinea tsunami of July 1998 -offshore evidence on the source mechanism[END_REF][START_REF] Smith | The Holocene Storegga Slide tsunami in the United Kingdom[END_REF]).

Consequently, major efforts have been made to study the occurrence, dynamics and impacts of seafloor failures, resulting in several overview publications in recent years (e.g., Locat and Mienert 2003;Mienert and Weaver 2003;[START_REF] Mienert | COSTA -continental slope stability: major aims and topics[END_REF]). Nevertheless, mass wasting processes are still poorly understood, mainly because the submarine environment is largely inaccessible, and their products occupy extensive areas which are difficult to cover in their entirety (cf. [START_REF] Haflidason | The Storegga Slide: architecture, geometry and slide development[END_REF]. Therefore, investigations of small-scale submarine landslides, such as the <0.2 km 3 Afen Slide in the Faeroe-Shetland Channel [START_REF] Wilson | The morphology, setting and processes of the Afen Slide[END_REF], are growing in importance. These, often displaying many of the characteristics of their larger counterparts, can be conveniently 4 characterised in detail over their full extent, using different geophysical methods without extensive ship time needs. This is the case for four small (<0.4 km 3 and 16 km 2 ) submarine landslides in the Eivissa Channel area, between the Iberian Peninsula and the Balearic Islands, western Mediterranean Sea (Fig. 1). These were first swath-mapped in 1995 and further surveyed in 2002 [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]). New high-resolution side-scan sonar data presented in this paper have been recently acquired ( 2004) with the aim of studying in higher detail the headwall scarps, with several detached and tilted slabs, and the depositional lobes, with compression ridges, of these slides.

STUDY AREA

Geological Setting

The Eivissa Channel, a slightly asymmetric, saddle-like north-to south-trending depression, separates La Nao Cape on the Iberian Peninsula, to the west, and the islands of Eivissa (Ibiza) and Formentera on the Balearic Promontory, to the east (Fig. 1). The channel represents the western end of this 348-km-long and 120-km-wide promontory, which consists of the Menorca, Mallorca and Eivissa structural blocks. Geologically, the Balearic Promontory is the prolongation of the external zone of the Betic Ranges from the Iberian Peninsula.

Three physiographic provinces can be distinguished within the Eivissa Channel: (1) the continental shelves off the town of Alacant to the west and the Eivissa-Formentera islands to the east, the shelf break being at around 100-130 m water depth; (2) the continental slopes down to 800 m; and (3) a wide, smooth central depression locally exceeding 900 m in depth, which is interrupted by the prominent, 200-m-high east-to west-trending Xàbia Seamount [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]).

Following the southward-oriented regional circulation along the Iberian Peninsula eastern margins, most of the sediment reaching the Eivissa Channel is thought to come from rivers to the north on the Iberian Peninsula (mainly Ebre, Túria and Xúquer; Fig. 1). The Balearic continental shelf east of the channel is dominated by patches of benthic carbonate-dominated sedimentation [START_REF] Canals | Production of carbonate particles by phytobenthic communities on the Mallorca-Menorca Shelf, northwestern Mediterranean Sea[END_REF]. The Eivissa Channel plays a major role in the exchange of water masses between the South Balearic Basin to the south and the Valencia Trough to the north (Fig. 1). The interaction between northwards-oriented near-bottom currents and the Xàbia Seamount has formed a typical contouritic ridge and an associated depression [START_REF] Faugères | Seismic features diagnostic of contourite drifts[END_REF][START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF].

Fluid escape features are present throughout the Balearic Promontory [START_REF] Acosta | Pockmarks in the Ibiza Channel and western end of the Balearic Promontory (western Mediterranean) revealed by multibeam mapping[END_REF], including in the Eivissa Channel [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]). Here, pockmarks have been identified to the north of the Xàbia Seamount, where their high abundance gives the seafloor an orange peel-like appearance, and on the Balearic continental slope where they are often aligned. In the latter region, pockmarks have been described as being similar in size, with diameters around 100 m and depths up to 15 m, occurring at water depths of approx. 500 m [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF].

Previous work

Four small slides are located on the Balearic continental slope of the Eivissa Channel, roughly aligned along the 0º48'E meridian, at water depths ranging between 600 and 900 m (Fig. 2a), namely (from south to north) the Ana, Joan, Nuna and Jersi slides [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]). Their areas range from 6.0 to 16.0 km 2 and their volumes from 0.14 to 0.40 km 3 (Table 1). They occur in segments of the continental slope where the slope varies from 1.6 to 3º. Their headwall scarps are as high as 50 m and display irregular, horseshoe-shaped morphologies (Fig. 2). Depositional lobes are characterized by areas of positive and rougher relief with respect to the surrounding seafloor.

However, this relief is much less than the thickness of the disturbed sediment, demonstrating that sediments were not evacuated from the source area, with the partial exception of the Jersi Slide [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]).

Seismic facies observed in very high-resolution acoustic profiles vary both between the slides and also, depending on the section surveyed, within individual slides. For example, the Jersi Slide displays broken stratified facies locally at the foot of the headwall scarp and transparent seismic facies along the slide deposit, whereas the Ana Slide displays three successive seismic facies (transparent, stratified and chaotic) from the headwall to the toe [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]). These different seismic signatures between slides are probably due to variations in the degree of disintegration of the original stratification of the sediment. The slip plane of the four slides is one and the same characteristic high-amplitude reflector within the seismically well-stratified slope deposits outside the slides [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]. The MAK-1M system is a deep-towed platform consisting of a 30-kHz side-scan sonar, yielding a total swath range of up to 2 km when positioned about 100 m over the seafloor. Towing was at about 2.5 knot, resulting in a variable resolution of about 7 to 1 m across track and along track. In addition, the system incorporates a very highresolution acoustic profiler operating at 5 kHz. Position was by means of a shortbaseline underwater navigation system. Vessel positioning was by means of an Ashtech GG24 GPS and a GLONASS receiver.

MATERIALS AND METHODS

Side

In the BALICAT survey area, side-scan sonar data cover 115 km 2 , and about 65 km of sub-bottom profiles were collected (Fig. 2) between 38º37' and 38º50'N and between 0º45' and 0º51'E. Onboard processing included slant-range correction of the sonographs, geometrical vertical correction of the sub-bottom profiles for the recovery of actual seafloor topography, and smoothing-average filtering of both types of record.

Ship track planning was based on data obtained onboard the R/V Hespérides in 1995 (BIG'95 survey) and 2002 (MARINADA survey), when 2,287 km 2 of Simrad EM-12S swath bathymetry data and 642 km of hull-mounted Simrad topographic parametric source TOPAS PS 018 very high-resolution acoustic profiles were obtained (Fig. 2a; [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]). This swath bathymetry data have a horizontal resolution of ~35 m at ~800 m water depth (0.043 times the depth; Simrad Subsea 1991). Because MAK-1M has a variable resolution of about 7 to 1 m across track and along track, most shadows observed in MAK-1M sonographs represent previously undetected features on the seafloor with the swath bathymetry.

RESULTS

Side-scan sonar

Three MAK-1M side-scan sonar lines completely cover the extent of the Ana and Jersi slides, and partially that of the Nuna and Joan slides (Fig. 2a). The slide deposits do not show a clearly contrasting backscatter compared with that of to the rest of the Balearic Margin of the Eivissa Channel, probably due to the presence of a thin regional sediment drape. Thus, changes in seafloor response are mainly due to the angle of insonification and, particularly, to shadows cast by positive relief.

In the Ana (Fig. 3), Joan (Fig. 2), Nuna (Fig. 4) and Jersi (Fig. 5) slides, the headwall scarps and sidewalls display sinuous morphologies, and they often look discontinuous, as if they were made of several, shorter scarp sections. The slide masses show, in their upper sections, i.e. close to the headwall scarps, many step-forming detached and tilted sediment slabs, giving a general staircase-like pattern. These slightly curved steps are generally up to 100 m long and 40 m wide, and are oriented perpendicular to the direction of slide motion (e.g., Fig. 4). In the uppermost part of the Jersi Slide, however, they are continuous from one edge of the slide to the other and attain lengths of up to 300 m (Fig. 5). Further downslope from the headwall scarp, steps are more discontinuous and degraded, their across-slide length decreasing but generally not their width (Figs. 4 and5).

Strikingly, the MAK-1M side-scan sonographs show that the depositional lobes of at least the Ana and Nuna slides (Fig. 6), which display chaotic seismic facies in very high-resolution acoustic profiles [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]) and are featureless in swath bathymetry maps (Fig. 2), have numerous arcuate ridges oriented normal to the direction of slide movement. These ridges are up to 800 m long and ~20 m in wave length, and have a much smoother relief than the step-forming slabs in the upper slide sections. The Joan Slide depositional lobe is not covered by the side-scan data (Fig. 2a), and the Jersi Slide depositional lobe, which is entirely made of transparent seismic facies, is featureless in the side-scan sonar images.

New data demonstrate that previously undescribed < 40 m in diameter pockmarks are widespread in the Balearic margin of the Eivissa Channel (Figs. 3 to 5). These were not detected before due to the lower resolution of the EM-12S swath bathymetry available.

They are located at greater water depths and are smaller in size than pockmarks observed in previous cruises [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF])

Acoustic profiles

Acoustic profiles (5 kHz), obtained by means of the MAK-1M acoustic system, show almost no penetration into the sediment in some sections of the slides. Where subseafloor reflectors can be observed, these are faint and difficult to follow. Nonetheless, the prominent slip plane (SP) reflector described by [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF] was recorded below the Nuna (Fig. 4) and Jersi slides (Fig. 5).

10

The acoustic profiles show the different morphological character of the smooth, undisturbed sections of the Balearic Margin, and the irregular negative relief of the headwall scarp areas (Figs. 3 and5) and the positive relief of the depositional lobes (Figs. 5 and6). In addition, the profiles reveal the presence of small pockmarks (less than 2 m in depth; Fig. 5) surrounding all the slides. These had previously not been detected on the swath bathymetry records.

DISCUSSION

Headwall scarps and structures in the upper part of slide masses are one of the features better imaged by MAK-1M side-scan sonar, and this is also the case for the four slides in the Eivissa Channel. The staircase geometry of the headwall scarp has been observed at a much larger scale, but also on sonographs, in the BIG'95 debris flow in the Ebre margin, north of the study area [START_REF] Lastras | Lessons from sea-floor and subsea-floor imagery of the BIG'95 debris flow scar and deposit[END_REF], and in the Storegga Slide in the Norwegian margin [START_REF] Haflidason | A weak layer feature on the Northern Storegga Slide escarpment[END_REF]. [START_REF] Lindberg | The Nyk Slide -morphology, progression, and age of a partly buried submarine slide offshore northern Norway[END_REF] described similar features in the Nyk Slide, a partly buried slide offshore northern Norway, and related these to extensional ridges formed as sediments moved downslope driven by gravity. These extensional ridges are commonly observed in the upper area of slides which are not fully evacuated [START_REF] Prior | Depositional characteristics of a submarine debris flow[END_REF], and consist of material which was not completely disintegrated before movement stopped. This is also the case of the Eivissa slides [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]). [START_REF] Lindberg | The Nyk Slide -morphology, progression, and age of a partly buried submarine slide offshore northern Norway[END_REF] pose the question as to whether these structures are developed by upslope retrogression of the headwall scarp or not. Although many factors are important in controlling the initiation point of a slide, such as zones of fluid escape, underlying structural controls and sedimentation rates, we consider these factors to be uniform or constant in slides as small as those in the Eivissa Channel. Thus, initiation should take place in areas with maximum gradients. However, the location of the headwall scarp is not coincident with the maximum gradient, located some hundreds of meters downslope. Therefore, we consider that the Eivissa Channel slides are retrogressive, and that the edge-to-edge, crescent-shaped detached and tilted slabs in the uppermost part of the Jersi Slide represent the last stages of retrogression. The initial slide scarp would be located in the area of maximum slope (Fig. 7, schema A) as would be expected from simple failure dynamics, and would retrograde (Fig. 7, schema B) when upslope sediments become unstable due to a lack of support. Each retrogression stage would create a series of steps, some of which could remain more or less intact within the slide mass, as seen, for example, in an acoustic profile across the Ana Slide (Fig. 4 in [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]). Since the slope angle decreases upslope, retrogression would cease when the driving force is not large enough to mobilize sediment, even if sediment partially lacks downslope support (Fig. 7, schema C). During retrogression, some of the pockmarks could be erased or their walls could become part of some scarps (Fig. 7, schema C), as suggested by [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF] for the Ana Slide.

Positive relief features perpendicular to the sliding direction observed in the depositional lobes of the Ana and Nuna slides have also been described before in other submarine slides, and are interpreted as compression ridges resulting from plastic deformation, similarly to those observed in the Nyk Slide [START_REF] Lindberg | The Nyk Slide -morphology, progression, and age of a partly buried submarine slide offshore northern Norway[END_REF]), which are typically found at the toe (i.e. in the most distal parts) of slides and debris flows [START_REF] Prior | Depositional characteristics of a submarine debris flow[END_REF]. Coincidently, the Ana and Nuna slides both display chaotic facies with internal reflections, whereas the Jersi Slide, which has no compression ridges, displays totally transparent facies. The absence of compression ridges in the Jersi Slide could be indicative of a higher degree of disruption of the material, which could have become less plastic and closer to the liquid limit after failure. Seeing that the granulometry, water content and, in general, the characteristics of the sediments should be essentially the same for all of these slides (cf. [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]), this higher disintegration of the internal structure could be related to a longer run-out distance (~3 km, Fig. 7 in [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF], in contrast to the modest run-out of the other slides (i.e. less than 1 km, Fig 4 . in [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]). Note also that the distance between the area of maximum slope and the headwall scarp in the Jersi Slide is much longer (Fig. 2; Fig. 7 in [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]).

These features are indicative of different stages of sediment disruption during landslide evolution. A first stage would involve the breakage, tilting and detachment of sediment slabs from the headwall scarp, above a certain slip plane, in this particular case the SP reflector [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]). Initially, these would preserve internal stratification, and thus would display stratified seismic facies similar to so-called rotated blocks within the Ana Slide (Fig. 4 in [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]). Retrogression pulses would form a series of these sediment slabs, creating the steps in the upper part of the slides (Fig. 7, schema B). A second stage would be linked to initial liquefaction and partial flowage of the sediment, involving plastic deformation and the disruption of internal stratification. This would produce compression ridges in the seafloor, yielding discontinuously stratified or chaotic seismic facies within the slide mass, as seen at the toe of the Ana and Nuna slides (Fig. 6;Figs. 4 and 6 in Lastras et al. 2004). The Jersi Slide, with a longer run-out, evolved in to the final disruption stage, related to total liquefaction of the sediment and yielding a deposit of transparent seismic facies (Fig. 7 in [START_REF] Lastras | Shallow slides and pockmark swarms in the Eivissa Channel, western Mediterranean Sea[END_REF]).

Last but not least, the widespread presence of pockmarks in the Eivissa Channel is clearly indicative that escapement of fluids from the sediment is a highly significant process on these slopes, and most probably heavily related to instability of shallow sediment. Furthermore, these data demonstrate that the study of small-scale landslides, which requires less ship time and, in general, lower effort, can help in the understanding of large-scale, margin-wide mass wasting processes.

CONCLUSIONS

  -scan sonar data were collected with the MAK-1M system during the BALICAT survey onboard the R/V Professor Logachev in August 2004, part of the 14th campaign of the Training-Through-Research (TTR) program promoted by UNESCO in collaboration with Moscow State University.

  MAK-1M side-scan sonar data show new features within four submarine landslides previously described in the Eivissa Channel based on swath bathymetry and highresolution seismic profiles. Step-forming detached and tilted slabs located in the uppermost part of the slides, and arcuate regular positive ridges in the depositional lobes of some of the slides, are interpreted as extensional ridges formed during retrogression of the headwall scarps upslope of the maximum gradient, and as compression ridges related to plastic deformation of the sediment during movement, respectively. The observation of these features, described earlier in both smaller and larger submarine landslides around the world, have important implications in the study of the post-failure dynamics of these four small slides, since they are indicative of different stages of sediment disruption.

Fig. 1

 1 Fig. 1 Bathymetric map of the Balearic Promontory region in the western

Fig. 4a

 4a Fig. 4a MAK-1M sonograph across the Nuna Slide headwall scarp and b 5-kHz

Fig. 5a

 5a Fig. 5a MAK-1M sonograph mosaic across the Jersi Slide sidewall and b 5-kHz

Fig. 6a

 6a Fig. 6a MAK-1M sonograph across the Nuna Slide depositional lobes, showing several

Fig. 7

 7 Fig. 7 Interpreted development of the Eivissa Channel slides, showing the formation of

Fig. 6

Fig. 7

ACKNOWLEDGEMENTS

This research was supported by the HERMES project, EC contract no. GOCE-CT-2005-511234, funded by the European Commission's Sixth Framework Programme under the priority Sustainable Development, Global Change and Ecosystems, by the projects SPACOMA (01-LEC-EMA14F) and WEST-MED (01-LEC-EMA22F) of the EUROCORES Program on EUROMARGINS of the European Science Foundation, the EURODOM Research Training Network (HPRN-CT-2002-00212) and the VFP project EUROSTRATAFORM (EVK3-2002-00079) of the European Community, and by the Generalitat de Catalunya Grups de Recerca Consolidats grant 2001 SGR-00076. The authors would like to thank the suggestions made by two anonymous reviewers and the Editor which greatly helped to improve this paper. The TTR-14 Leg 3 Shipboard Scientific Party also included E. Bileva, V. Blinova, C. Brönnimann, V. Catterall, K. Chumakova, S. Costa, D. Daudin, P. Ferrer, P. Golynchik, I. Gyr'ev, V. Kiselev, D. Korost, E. Kozlova, E. Logvina, V. Malin, A. Micallef, V. Osokin, A. Ovsjannikov, E. Sarantsev, A. Shoronova, A. Shuvalov, A. Sungurov, V. Tarasov, D. Titkova, O. Vidal and A. Zotova. The publication reflects only the views of the authors; the EC is not liable for any use which may be made of this paper.

Run-out values correspond to rough approximations of the actual travel distance of the centre of masses of each landslide, rather than the length of the slide from headwall to toe (Fig. 7)


X Sauvage
email: xavier.sauvage@univ-rouen.frgwilde@uni-muenster.de

G P Dinda

G Wilde

Non-equilibrium intermixing and phase transformation in severely deformed Al/Ni multilayers

Keywords: rolling, multilayers, nickel aluminides, three-dimensional atom probe, nanocrystalline

Al/Ni multilayers have been prepared by repeated folding and cold rolling (F&R) of elemental foils. The thickness of Al and Ni foils is reduced down to less than 50 nm after fifty F&R cycles. Three-dimensional atom probe analyses clearly reveal the presence of supersaturated solid solutions and give the evidence of deformation-induced intermixing. The formation of the solid solutions and their transformation into the Al 3 Ni phase upon annealing is discussed.

Phase transformations in thin metallic multilayer systems have been extensively investigated in the past. During heating of multiphase structures synthesized in thin multilayers, stable or metastable intermediate phases might appear as a result of interdiffusion and subsequent phase transformations. Aside from "static" microstructure features, interdiffusion or intermixing prior to phase transformation, and associated concentration gradients play a key role in determining the phase formation kinetics [1,2]. It is well known that severe plastic deformation can induce significant mixing, as in ball milled powders [3][4][5][6][7]. Similar features have also been reported for torsion under high pressure [8] and cold rolling [9]. Since this latter technique is also suitable for the preparation of metallic multilayers [9][10][11][12], it was used to prepare Al/Ni multilayers to clarify the influence of concentration gradients and the intermixing state on the phase transformation kinetics upon annealing. The Al-Ni system was chosen as a model system since it is both attractive for applications, e.g. in superalloys or as coatings of III-V semiconductors, and has also been studied thoroughly concerning the microstructure-and the phase evolution [10,11,[13][14][15][16][17][18][19][20][21]. In the studies reported so far, thin Al/Ni multilayers have mostly been deposited by sputtering [17,19,20] or electron-beam evaporation [16,[19][20][21], while repeated folding and cold rolling of Al and Ni foils was also applied as an alternative process to synthesize Al-Ni multilayer foils [10-12, 14, 18]. By this method, layers with thicknesses in the nanometer range were obtained and it was shown that such samples exhibit very similar phase transformation sequences and almost identical kinetic behaviour upon annealing compared to thin film multilayers that had been synthesized by deposition methods [12]. Yet, in the literature, different phase formation sequences have been reported for different nominal compositions and after different processing pathways. Under most conditions, the Al 3 Ni phase with an ordered D0 20 structure is the first phase to form. This is explained by the asymmetry of the interdiffusion coefficients, with Ni diffusing much more rapidly into Al than Al into Ni [22,23]. However, depending on the nominal composition of the multilayer and on the processing history, also different initial intermediate phases such as AlNi [19,20,[24][25][26], AlNi 3 [10] or a metastable Al 9 Ni 2 -phase [24,27] were observed. In this context, it is interesting to analyze whether the phase formation sequence is determined by the processing route, and especially by the presence of concentration gradients prior to annealing. Three-dimensional atom probe (3D-AP) analyses were performed to map out these concentration gradients at the atomic scale on F&R-processed multilayers prior and after thermal annealing. In particular, we have investigated how local modifications of the distribution of constituents and the presence of steep concentration profiles can change the kinetics of intermediate phase formation.

Al/Ni multilayer samples of nominal composition Al 80 Ni 20 were prepared from high purity foils of Ni (99.9%, thickness: 20μm) and Al (99.9%, thickness: 100μm) that were alternately stacked to form a 20 mm x 20 mm and 500 μm thick sandwich. This sample was then cold rolled (roll diameter 150 mm, 2 rotations per minute) to a thickness of 200μm in 10 passes, then folded to double the thickness and rolled again to a thickness of 200μm. This procedure was repeated 50 times. The final material was investigated in the as prepared state and after short time annealing in a differential scanning calorimeter (DSC, Pyris 1, Perkin Elmer) under Argon flow for 2 min at 250°C. This temperature was chosen because it is close to the onset for the Al 3 Ni formation [12,14,17,18], and the duration was sufficiently short to avoid significant grain growth. Phase identification was carried out using X-ray diffraction (Phillips X'Pert) with a Cu anode source operating at 50kV and 40 mA. The microstructure of the multilayer was examined in a FEI/Tecnai F20 ST transmission electron microscope (TEM) operating at 200kV and an extraction voltage for the field-emission gun of 4.1 kV, using a Philips double-tilt holder. TEM samples were prepared in cross section geometry by ion milling using a Gatan Precision Ion Polishing System (PIPS 691) operating at 3.5 kV and an angle of incidence of 4°. 3D-AP analyses were performed with a CAMECA tomographic atom probe detection system (TAP) and analyses were carried out at 80 K with a pulse fraction of 16 % in UHV conditions. 3D-AP samples were prepared by electropolishing (20°C, 10V, 2% perchloric acid in 2-butoxyethanol). During the cold rolling process, both Al and Ni foils are severely elongated in the rolling plane, resulting in a multilayer system with layer thickness in the nanometer range as indicated in Fig. 1. The average thickness of the layers is about 10 nm to 50 nm after 50 F&Rcycles. XRD data indicate that only the fcc Al and fcc Ni phases are present in the as-rolled multilayers, indicating further that no detectable phase formation reaction between Al and Ni occurred during the repeated deformation process (Fig. 2). Some pure Ni and pure Al regions were analysed by 3D-AP (not shown here), but a significant intermixing of Al and Ni was also revealed (Fig. 3). Regions containing between 15 at.% Ni and even up to 60at.% Ni were indeed detected, especially where the layer thickness was in the range of 10 nm or less (measured by field ion microscopy prior to 3D-AP analysis). Since both XRD and selected area electron diffraction in the TEM revealed only fcc Al and fcc Ni in the as prepared sample, these mixed regions are attributed to metastable orfor the highest Ni-content -even non-equilibrium supersaturated solid solutions. It is important to note that no impurity was detected on mass spectra, indicating that there was no contamination during the F&R process. Up to now it has been reported that cold rolled multilayers exhibit sharp interfaces [10-12, 12, 16], e.g. without significant mixing like deposited or sputtered multilayers [19,20]. However, in these earlier studies of F&R multilayers the local distribution of the constituents was not checked at the atomic scale. On the other hand, the formation of supersaturated solid solutions by ball milling was reported for Al-Ni powders [5,28], and for many different systems [6,7]. In the present case, it seems clear from the composition distribution in Fig. 3 that the mixing process is controlled by the diffusion of Ni in Al in agreement with ball milling data [5]. From the composition profile of Fig. 3, the effective diffusion distance R* is estimated as about 10 nm. Then, considering the roll geometry and the roll velocity, the total deformation time is τ d ≈ 30 s. This yields an effective diffusion coefficient D* = R* 2 / τ d = 1/3 10 -18 m 2 s -1 . Extrapolation of experimental thermal diffusion data shows that similar values are measured at temperatures above 600 K [29]. Such a temperature increase is unrealistic because of the low strain rate during rolling and the high thermal conductivity of rolls. Thus, thermal diffusion does not account for the observed mixing and other mechanisms like forced mixing [3] or deformation induced vacancies [8] may promote the atomic mobility. Yet, it is also revealing that intermixing was observed only in regions of the sample where the layer thickness is below 10 nm. This observation indicates that the intermixing is directly coupled with the plastic deformation. The regions with the smallest layer thickness after the repeated rolling deformation are regions of high stress concentration where "necking" [4] occurs. This phenomenon has been reported to occur in Al/Ni multilayer co-deformation and causes enhanced layer thinning in localized regions [10]. The observation also supports the presence of an intermixing mechanism that is not based on thermal diffusion.

The supersaturated solid solutions analysed in the present study are far away from the solubility limits and thus far away from equilibrium [START_REF] Massalski | Binary Alloy Phase Diagrams[END_REF]. One should also consider that both, mixed regions and concentration gradients up to 10 8 m -1 (Fig. 3(b)) can significantly modify the kinetics of phase formation and -more importantly -can prevent the nucleation of intermediate phases [32]. Thus, to clarify this point, samples have been annealed for a short time at a comparatively low temperature. In accordance with existing reports in the literature [11,12,14,17,18,22,23], the intermetallic Al 3 Ni phase formed first during the annealing treatment at low temperature, but the XRD data also show that -as intended -the reaction between Al and Ni was by far not completed after annealing for 2 min. at 250°C (Fig. 2). These three phases were also analysed by 3D-AP after annealing: essentially pure Ni regions (99.85±0.04 at.% Ni), regions with a composition that corresponds to the Al 3 Ni phase (25.5±0.35 at.% Ni) and almost pure Al regions (Ni concentrations in a range of 1 to 2 at.%).

Together with the results from XRD we can conclude that the regions with a composition close to 25 at. % Ni actually correspond to the intermetallic Al 3 Ni phase. As expected form the fine-scaled layer structure observed by TEM (Fig. 1), some interfaces between Al and Al 3 Ni were intercepted with 3D reconstructed volumes analysed by the atom probe (Fig. 4(a)) and data analysis reveals that concentration profiles across such interfaces are extremely sharp (Fig. 4(b)). The observed nucleation of the Al 3 Ni phase during short time annealing is consistent with published data showing that this phase is the first to grow in annealed Al/Ni multilayers [11,12,14,17,18,22,23]. It is however recognised that intermixing is a necessary initial process that needs to occur before any phase formation can proceed [17,21]. In cold rolled multilayers, this first step is not thermally activated but induced by the severe plastic deformation prior to annealing. This feature might explain why we measured an onset temperature of 468 K (DSC, 20K/min) for the Al 3 Ni phase formation, while for deposited multilayers, reported data obtained at a similar heating rate are higher (513K for a period of 11.42 nm [27] and 476K for a period of 10 nm [16]). Thus, the present results indicate that the nucleation of Al 3 Ni is kinetically favoured in Al-Ni mixed regions. However, limited preliminary redistribution of solute is still necessary, since mechanically mixed zones mostly do not have the Al 3 Ni stoichiometry. It is important to note that the Al 3 Ni-phase forms first, although the compositions of the intermixed regions are different in different parts of the sample and are partly even close to Al 50 -Ni 50 , i.e. the composition of the B2 ordered AlNiphase. Moreover, it is important to note that the same phase formation sequence was observed upon annealing as in most of the reports in the literature -keeping in mind that the sample processed by F&R has been intermixed at ambient conditions before the annealing Thus, the present results confirm that the Al 3 Ni-phase is kinetically favoured and that the competition in nucleation kinetics determines the evolution of the first phase to form from nanosize interface regions to microscopically observable volumes. These results also indicate the stability of the outcome of the kinetic competition in Al-Ni, indicating further that compositional variation might offer the only way to modify the phase formation sequence.

In conclusion, chemical analyses at the atomic scale of cold rolled Al/Ni multilayers clearly revealed significant intermixing induced by severe plastic deformation. This non-thermal diffusion leads to the formation of metastable or non-equilibrium solid solutions with various compositions. The analysis of the early stage of intermetallic phase formation shows that even if some atomic redistribution is needed prior to the nucleation of Al 3 Ni, the reaction is faster than in deposited multilayers where interfaces are sharp. The present work confirms that the Al 3 Ni phase is strongly favoured by nucleation kinetics so that even the presence of mixed regions with largely different compositions does not result in the initial formation of a different intermetallic phase.

Figure 1 :

 1 Figure 1 : TEM bright field image showing the cross sectional microstructure of the cold rolled Al/Ni multilayer.

Figure 2 :

 2 Figure 2 : X-ray diffraction results of the Al/Ni multilayer in the asprepared state and after short-time annealing, which causes the formation of the Al 3 Ni-phase as indicated by the additional Braggreflections.

Figure 3 :

 3 Figure 3 : (a) 3D reconstruction of an analysed volume in the as prepared Al/Ni multilayer (Ni green, Al red) ; (b) composition profile along the direction indicated by the arrow (sampling box thickness is 1 nm).

Figure 4 :

 4 Figure 4 : a) 3D reconstruction of an analysed volume in the Al/Ni multilayer annealed at 250°C for 2 min (Ni green, Al red) ; (b) composition profile across the Al / Al 3 Ni interface along the direction indicated by the arrow (sampling box thickness is 1 nm).

Acknowledgement

Dr. H. Roesner (Institute of Nanotechnology, Forschungszentrum Karlsruhe, Germany) is gratefully acknowledged for the TEM investigation of the Al/Ni multilayers.


Denis E Corpet
email: d.corpet@envt.fr.

Stefaan De Smet

Daniel Demeyer

Epidemiological evidence for the association between red and processed meat intake and colorectal cancer KEYWORDS: COLORECTAL CANCER, PROCESSED MEAT, DIETARY ADVICE, RED MEAT A perspective paper was synthesized during the workshop "How can we approach consensus on the healthiness of red meat?" held in Oslo, Norway, in November 2013 [START_REF] Oostindjer | The role of red and processed meat in colorectal cancer development: A review, based on findings from a workshop[END_REF]. DE. Corpet and S. De Smet had the honour to participate in this exciting and stimulating meeting and co-signed the article. D. Demeyer was acknowledged in the article for his comments on the draft. The leading authors of the paper probably had the intention to present a balanced view of the discussions, making clear that health issues associated with the consumption of red meat are manifold. However, reaching consensus on a number of critical issues was an ambitious task. The resultant article contains some very interesting information and focuses on the role of red and processed meat in colorectal cancer development. However, not all comments from the co-authors were taken into account in the final manuscript, resulting in a scientifically incorrect statement in the abstract:

"Epidemiological and mechanistic data on associations between red and processed meat intake and CRC are inconsistent…" Because of the high visibility of this abstract through many websites and journals we have to strongly object to that statement. Indeed, the work of the group led by DE Corpet supports the guidelines on intake of red and processed red meat set by the World Cancer Research Fund (WCRF/AICR, 2011). In Belgium, D Demeyer and S De Smet were part of aworking group that prepared an extensive report justifying the introduction of these guidelines in Belgium (Superior Health Council Belgium, 2013). Through extensive investigation of the literature the Belgian group confirmed the consistency of the epidemiological data, whereas indeed "underlying mechanisms are unclear" as reported elsewhere (Demeyer, Mertens, De Smet, & Ulens, in press). The major evidence supportive of "inconsistency" comes from the group working with DD. Alexander (e.g., [START_REF] Alexander | Processed meat and colorectal cancer: A quantitative review of prospective epidemiologic studies[END_REF] and was presented by DE. Weed at the Oslo workshop. However, as detailed elsewhere (Superior Health Council Belgium, 2013), the convincing power of these review articles suffers from some selectivity in references used, from their definition of processed red meats, and from conflicts of interest. In addition, [START_REF] Alexander | Processed meat and colorectal cancer: A quantitative review of prospective epidemiologic studies[END_REF] did not consider weak risk factors (less than 1.20) as relevant although they are significant, and would account for a large proportion of the disease burden at the population level [START_REF] Brenner | Colorectal cancer[END_REF]. Furthermore, each new study on meat and cancer adds to the evidence that the link is real (see e.g. Di [START_REF] Di Maso | Red meat and cancer risk in a network of case-control studies focusing on cooking practices[END_REF]. We are therefore convinced that "apart from some uncertainty related to age and ethnicity, epidemiological data are consistent, although the underlying mechanisms remain unclear".

To conclude, [START_REF] Oostindjer | The role of red and processed meat in colorectal cancer development: A review, based on findings from a workshop[END_REF] present a comprehensive summary of a workshop gathering a group of 23 scientists with sometimes widely different views on a problem not reflected in the main scientific background of the group. We understand that not all parts of the text can be fully accepted by all authors. However, these 23 authors doubting the overall consistency of the epidemiological evidence in the abstract seems to be "a bridge too far".