Dr Wojciech Piotr Oziminski

Ph.D Wojciech P Oziminski

Ph.D Wojciech P ; Oziminski

M Tadeusz

Professor Krygowski

CONH2, COOH, F, NH2, NMe2, NO, NO2, OCH3, OH, SiH3, SiMe3 Coch3

Tadeusz M Krygowski

Nh

Keywords: NBO, DFT, fulvene, substituent effect, pEDA NBO  DFT  Fulvene  Substituent effect  pEDA

Electronic structure of 22 monosubstituted derivatives of benzene and exocyclically substituted fulvene with substituents: B(OH)2, BH2, CCH, CF3, CH3, CHCH2, CHO, Cl, CMe3, CN,

occupations in a similar pairs of carbon atoms (ortho-and para-positions in benzene and 1-and averaged 3-,4-positions in fulvene are correlated, whereas it is not the case for ortho/meta pair in benzene (Fig. 17) and this is clearly resulting from scheme of resonance in Fig. 3. Finally, it was shown(Fig. 18) that aromaticity of the ring changes collinearly with substituent constants only for electron donating substituents, whereas for others there is no correlation. The conclusions at the end summarize these results. In principle, most important information results directly from figures, but despite of this fact, there is an explanation in the text.

For instance, the introduction is not to-the-point on the purpose of this research. Now we included some additional references, mostly for di-substituted aromatics, in which communication between substituents (one of them being fixed in a series and "working" as reaction or process site). We have also added some more explanation for using the term transmission.

The background and previous researches are lacking. Reply: This is now done. For non-alternant hydrocarbons there are not known any systematic works on transmission of the substituent effect in a classical meaning i.e. as a meaure of interactions between two substituents attached to the same molecular moiety. We intend to continue work in this direction but first step must be done first.

The description of the di-substituted species seems unnecessary. Reply: There are no data for di-substituted species presented in the MS.

The choice of the substituents is not explained. Reply: Of 22 substituents that are considered in the MS substituents with all kinds of typical interactions known for substituent effects are taken into account, cf. two examples: strongly electron donating by resonance e.g. OMe(σR=-0.63); with a substantial contribution of (electron accepting) inductive effects (σI=0. 31), or strongly electron donating by resonance NMe2,( σR=-0.94) with a moderate(electron accepting) inductive effects;( σI=0.11), then also strongly electron accepting by resonance with a strong inductive effect (also accepting)e.g. NO2 (σI=0.70 ) and strongly electron accepting by resonance( σR -= 0.40)[numerical data from: O.Exner, The Hammett Equation, chpt. 1 in Adv. In LFER, ed. N. Chapman and J. Shorter, Plenum Press 1972]. In this way 22 substituents ensure a variety of kinds of substituent effects, sufficient for getting reliable conclusions.

The description of results and discussion are unclear and insufficient. Reply: This is a general statement which does not help in any improvement of the MS.

Where are the substituent constants from? 0.269/0.184 seem not matching with the figures. Reply: The referee is right, we did not made reference, now it is done. The data were taken from[ Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165] and the ratio of ranges for σp/σm was done for all 223 substituents in Table V in the Taft review. That is why there is a disagreement observed by the Referee:. What is cc and what does "ortho-benzene" mean in the plots? etc. Reply: cc means correlation coefficient. Now it is explained. In figures:12, 13, 14, 15 and 17 ortho-, meta-, para-mean carbon atoms in benzene ring in positions ortho-, meta-and para-All these prevents a thorough review to be made. The manuscript in the current form is not appropriate for publication.

Reply: We hope that after revision made and replies to the criticism of the Referee our MS may be accepted for publication.

Reviewer #2

The manuscript by Oziminski and Krygowski is quite interesting and suitable for JMM. It provides a theoretical insight in the electronic structure of fulvene and benzene, and their D/A mono-substituted derivatives. The authors use a quite reliable approach (DFT) and find out interesting properties to be compared. However, there are some comments and questions that should be addressed by authors before publishing. The comments are as follows:

1)

The abstract contains too many details about methods and software used. That can be omitted there without loss in sense. Instead, it would be worth explaining some other details. For instance, it is unknown (without reading the article) what slopes are mentioned. The sentence starting from "Occupations in all positions…" seems confusing. What could it be "an occupation in a position"? The sense of the sentence erroneously looks like "Occupations … are … correlated with positive slopes…" The last sentence is not quite clear either. There are some abbreviations and notations that seem redundant in the abstract.

Reply: According to Reviewer suggestions the abstract is now completely rewritten.

2)

The authors set a question in the introduction: how the pi-electron structure looks like. However, a direct answer does not seem to be given in the paper.

Reply: We believe that we answered the question stated in the introduction. We described the pielectron structure of the fulvene and benzene rings by analysing electron occupations of ring carbon atoms, their interrelationships and relations to classical resonance structures.

3)

In the Results and discussion section it is said that Figs 2 and 3 present "the canonical structures". Meanwhile the figure captures state "Resonance structures". What are they and why do they (Fig. 2) contain one implicit H-atom less than the structure in Fig. 1? The authors mention also some "resonant interactions" in the sentence above Fig. 17.

Reply: By canonical and resonance structures we mean the sam -they can be also called "canonical resonance structures". By the names should be the same for figures and text so we changed it now in all places to "resonance structures". The structures in Fig. 1 and 2 contain the same number of hydrogen atoms. The difference is only in that the structures in Fig. 2 describe charge shifts from substituent to the fulvene ring. Thus, for electron donating substituents (like NH2 group) the charge is shifted from NH2 to one of the fulvene ring carbon atoms and this atom consequently has point negative charge and single bond to his neighbours. Resonance structures are a classical concept of organic chemistry recently quantitatively described by Natural Resonance Theory by Weinhold and coworkers. By the sentence above figure 17 by the lack of possibility of "resonance interactions" we mean that there is no possibility to construct a resonance structure for benzene where the charge is positioned at the meta-position.

4)

The first aspect just under the Fig. 3 capture mentions "these differences". What differences are meant? Reply: We mean the differences in substituent effect transmission for benzene and fulvene. The Referee is right that we should be more specific. Now this sentence reads: "how differences in substituent effect transmission through benzene and fulvene affect the overall electron structure of benzene and fulvene rings"

5)

A definition for sigma_p+ is given in the abstract. It should be defined in the text.

Reply: The sigma_p+ constant is defined similarly to classical Hammett substituent constant but it relates to interactons with positively charged "reaction site". Reply: We now added the sentence "Dependences plotted in Figures 4-18 are plotted for these substituents plus unsubstitueted compounds" at the end of Methods section.

7)

The ratio in the last paragraph on page 4 seems incorrect. The numbers 0.269/0.184 do not appear in the Figures. The authors, probably need to correct them to 0.245/0.1546 to make them consistent to Figs 4&6.

Reply: We thank the Referee for finding this error. Indeed the 0.269/0.184 values came from the different set of substituents and the correct ratio is 0.245/0.1546 = 1.58 This is now corrected in the paper on page 5.

8)

It would be interesting if the authors could give their comments on the numbers 1.44 and 0.06 entering the expression on page 5 above Fig. 4.

Reply: The explatation is already given on page 5:" When pEDA values for fulvene and benzene derivatives are plotted each other, (Fig. 8) the regression shows qualitatively the same picture: the substituent effect on the pi-electron population in fulvene is 1.44 times greater than for benzene ring (eqation 3). This difference in sensitivity on the substituent effect is caused by strong pi-electron accepting characteristics of fulvene ring, which contain 5 pi-electrons and tends to achieve the Huckel value 4N+2 electrons; in the case of benzene containing 6 electrons no such effect takes place". The free factor 0.06 in the equation ( 3) is just a random error and ideally should be zero. In the revised version of the manuscript it is ommited.

9)

The acronym "cc" standing for "correlation coefficient" is not defined in the text. How is it calculated?

Reply: We now added the explanatory sentence on page 5: "In the following figures CC means Correlation Coefficient". The correlation coefficient is calculated in the automatic way by the Microsoft Excel program.

10)

The sentence above Fig. 12 states: "… C1 position … is … more sensitive than…" Sensitive to what?

Reply: We mean sensitivity to substituent effect and this is now specified in the text.

11)

What does it mean: "averaged C2, C5 atoms" (see the caption to Fig. 13).

Reply: The Referee is right that this sentence is awkward. We changed it to "Averaged occupations of C2, C5 positions". We corrected it also in the caption of Figs. 10, 11 and 14.

12)

What is "HOMA" started to be mentioned from page 12.

Reply: HOMA means Harmonic Oscillator Model of Aromaticity and is a geometry-based aromaticity indiex. We now added two references on page 13.

13)

The axis's titles in almost all figures should be revised. See Fig. 15 for example. It should be something like that: "occupation of pi-orbitals of C in para-position in benzene".

Reply: We believe that short axis titles are easier to read so we leave our notation only slightly improved but full description is in the caption to figures..

14)

What is R^2 on the graphs?

Reply: R2 below the regression equation means the square of correlation coefficient. As the correlation coefficient is given we removed the R2 values in the revised manuscript.

There are a lot of typos, that the authors were able to correct themselves before submission. However, they did not do that. Some of the typos are listed below.

1)

The references in brackets should be reformatted to have a space in front of the opening backet.

Reply: This is now corrected

2)

The graphs should have white background.

Reply: This is now corrected 3) Third line of Introduction: "benzene is" should read "benzene it is".

Reply: We changed this sentence to "Fulvene is also chemically reactive, whereas benzene is rather inert"

4)

Next to the last sentence of the same paragraph: "monosubstituted substituted" reads bad.

Reply: This is now corrected 5)

Please, check the words with prefix "para", like parameters and comparable. You can find corresponding typos in the sentence atop Eq.( 2) and under Fig. 17.

Reply: This is now corrected

6)

The word "monosubstituted" in the first sentence of Results and discussion is written in two different ways. The second way is "mono-substituted".

Reply: We changed it now to: "Let us begin with a glimpse at the substituent effect in exo-cyclically monosubstituted fulvene and benzene presented by means of resonance structures"

7)

The same is about "electron -donating" and "electron accepting".

Reply: This is now corrected

8)

The last sentence on page 4: "… are plotted each other". Probably, the word "against" is missed.

Reply: This is now corrected

9)

The fonts in the Figs 2 -18 are too small.

Reply: We changed font size according to Reviewer suggestion 10)

The vertical axis in Fig. 4 is named "pEDA( 5)" instead of "pEDA(F)". The horizontal axis's name contains a redundant word "calc".

Reply: This is now corrected

11)

The vertical axes in Fig. 5 and 7 have 5 redundant zeroes after the decimal point.

Reply: This is now corrected

12)

The vertical axis in Fig. 7 is named "NICS" instead of "NICS(B)". The horizontal axis's name is "pEDAbenzene)", but it should be "pEDA(B)".

Reply: This is now corrected

13)

The first sentence on page 9: "Fig. 12 present …" should be "presents". The entire sentence should be revised anyway because it looks confusing. It should read "… dependence of pi-orbitals occupation of C1…".

Reply: This is now corrected

14)

The second sentence on page 10: "The slopes of C1atom …" This sounds strange.

Reply: This is now corrected

15)

Next to the last sentence of the first paragraph on page 13: "pi-electron sproperties".

Introduction

Fulvene, a non-alternant isomer of benzene differs from it by almost all possible characteristics. It is unstable, its ASE (aromatic stabilization energy) equals to -3.1 whereas for benzene is 32.4 kcal mol -1 [1]. Fulvene is also chemically reactive [START_REF] Lloyd | The Chemistry of Conjugated Compounds: To Be or Nor To Be Like Benzene[END_REF], whereas benzene is rather inert [START_REF] Smith | March's Advanced Organic Chemistry, Reactions, Mechanisms and Structure[END_REF]. Substituent effects influence the fulvene ring much stronger [START_REF] Stepień | [END_REF] than benzene [5]. In the case of benzene, typical approaches concern the di-substituted species, in which one group is fixed (so called "reaction site", Y) and another one, X, varies [6][7][START_REF] Exner | Correlation Analysis of Chemical Data[END_REF][START_REF] Krygowski | [END_REF][10]. Thus, the charge transfer in benzene derivatives takes place between X and Y and is transmitted by the aromatic ring [11]. In these cases a classical measure of transmission is just reaction constant  which compared for two systems indicates in which of them the transmission is easier, or in other words which of them is more sensitive for substituent effect [START_REF] Exner | Advances in Linear Free Energy Relationships[END_REF][START_REF] Godfrey | Similarity models in organic chemistry, biochemistry and related fields[END_REF]. Transmission depends on nature of the reaction, medium in which it is carried out and obviously on the distance between the substituent and the reaction site [START_REF] Hammett | Physical Organic Chemistry[END_REF][START_REF] Krygowski | [END_REF]. In cases where there is no experimental study in which the Hammett-like approach is applied to physicochemical properties but instead some quantum-chemically derived quantities, a similar understanding of the transmission can be in use e.g. linear regression between 2p occupations for two atoms in a ring may indicate which of them is stronger influenced by a substituent. In the case of fulvene, most studies and interpretations of the substituent effects on structural and other properties are related to the exocyclic substitution [16][17][18][19][20][21]. Most aromatic indices exhibit strong variability and intercorrelate for 6-substituted derivatives of fulvene [21] which is not the case for monosubstituted benzene derivatives [11,22]. Moreover, in the case of strongly electron donating substituents, fulvene exhibits clearly aromatic properties [21]. Due to these differences in response to substituent effects, a comparison of substituent effects influence on electron structure of fulvene and benzene seems to be interesting and therefore is subject of this paper. Some questions arise: how the pi-electron structure looks like for the ring of fulvene and for the linking bond between the ring and the substituent (C1C6 bond, see Fig. 1). Then, how in detail the substituents affect pi-electron population for individual carbon atoms in 6substituted fulvene derivatives. Finally, we intend to show a difference between the substituent effect in alternant hydrocarbon exemplified by benzene and non-alternant onefulvene.

<Figure 1>

Methods

All calculations were performed at the B3LYP/6-311+G(d,p) level of theory using Gaussian 03 suite of programs [23]. Geometry optimizations were followed by frequency calculations to prove that the obtained stationary points are true minima on the potential energy surface.

Natural Bond Orbital [24] analysis was performed by NBO 5.G program interfaced to Gaussian03. NICS [25] aromaticity index was calculated as a shielding constant of a ghost atom located at the geometric center of the ring.

The pEDA [acronym from: pi Electron Donor-Acceptor] index was calculated by summation of the occupations of 2p z natural atomic orbitals (NAOs) of benzene ring carbon atoms and subtracting number 6as for the ideal sextet (Eq. 1). This definition is slightly modified comparing to the original one [26]. where j index runs over all six benzene carbon atoms and  benzene is the occupation of the j-th 2p z NAO.

For the fulvene ring the definition is similar (Eq. 2) with the exception that the summation runs over only five atoms of the ring and to obtain pEDA(F) as relative value to the unsubstituted fulvene molecule we subtract the number 5. In this way the pEDA(F) parameter is comparable with that for benzene derivatives. All regressions presented in Fig. 9-11 have acceptable correlation coefficients and hence their regression slopes may be subject of further analysis. As we see, the slope for dependence of 2p z occupation at C1 is 2.8 times greater than for mean value for 2p z occupations at C3 and C4 and 5.7 times greater than mean value for 2p z occupations at C2 and C5 despite of the longer distance from substituent to C3 and C4 atoms. Now, let us look at the direct comparison of substituent effect on pi-electron population at individual carbon atoms in benzene and fulvene. Fig. 121314show the occupations at carbon atoms which are distant from the substituent by one, two and three CC bonds. Fig. 12 presents the dependence of pi-orbital occupation of C1 in fulvene on pi-orbital occupation of orthocarbon atom in benzene. The slope of the regression is 1.45 and shows that occupation of carbon atom C1 in fulvene is 1.45 times more sensitive to the substituent effect than the ortho-carbon atom in benzene.

<Figure 12-14>

A direct comparison reveals a very important difference between changes in 2p z occupation at carbon atoms in benzene and fulvene rings. The slopes of the regression of pi-occupation of C1 atom of fulvene vs. occupation of carbon atoms in ortho-position of benzene and of averaged occupations of C3, C4 atoms of fulvene vs. occupations of carbon atoms in paraposition of benzene are positive and with relatively high correlation coefficients. Completely different is the regression of occupations of averaged C2, C5 atoms of fulvene vs. metaposition of benzene. Its slope is negative and correlation coefficient is very low. How to interpret this strange result? As presented in Fig. 2 and3, in the case of fulvene, all carbon atoms in the ring may communicate with the substituent by resonance effect, withdrawing or donating pi electrons from the substituent if it is donating/withdrawing in nature. That is not the case of benzene, where only two ortho-positions and one para-are able to communicate with the substituent by means of resonance effect. The meta-position is stronger influenced by inductive/field effect than by resonance [28,[START_REF] Exner | Chapt 1[END_REF]. The inductive/field effect is mostly electrostatic in nature and acting through the space [START_REF] Bowden | [END_REF][31][32]. Thus, the pi-occupation at carbon atoms in meta-position of benzene has weak contribution from resonance effect, react via different mechanism on substituent effect than it is the case of fulvene in 2,5 positions. This point is well supported by a direct comparison of slopes of the regressions of pi-electron occupation for pairs of resonance accessible carbon atoms in benzene and fulvene derivatives, shown in Fig. 15 and 16 <Figure 15-16> Despite the fact that there are two ortho-carbon atoms in benzene ring and only one paracarbon atom, the substituent effect acts in ortho-position much stronger than in para-as documented by the slope of regression shown in Fig. 15 which is equal to 1.44 with correlation coefficient 0.991. In the case of the fulvene (Fig. 16) the slope for the regression of occupation at C1-vs. averaged values of occupation at C3 and C4 atoms is even larger -2.67 and the correlation coefficient amounts to 0.959. It seems reasonable to relate this difference to much stronger withdrawing ability of 4N+1 ring of fulvene than that of benzene fulfilling the Hückel rule.

To support the conclusion dealing with a different mechanism presented in discussion of results shown in Fig. 12-14, we plotted the pi-electron occupation of carbon atoms in orthoagainst meta-position in benzene shown in Fig. 17. There are two important differences when compared with the picture in Fig. 15 and 16. The slope in Fig. 17 is negative and the correlation coefficient much lower. Additionally, it is also shown that the range of occupation changes in the case of carbon atoms in meta-position is only 0.02e whereas for atoms in para-position it is 0.16e. This is in excellent agreement with the simple reasoning that results from Fig. 2 and3: carbon atoms in meta-position in benzene is not accessible for resonance interactions (as far as only single excited resonance structures are concerned) [33] and other effects may play important role.

<Figure 17>

Another aspect of changes in pi-electron structure of 6-substituted fulvene derivatives is a relation of parameters describing the C1C6 bond, the transmitter of the substituent to the ring, and the ring itself. Fig. 18 presents the dependence of HOMA aromaticity index [34,35] on the C1C6 bond lengths.

<Figure 18>

It is clear that for pi-electron donating substituents (NMe 2 , NH 2 , OMe, OH and F in Fig. 18), parameters of the ring (HOMA) and of the bond (bond length) vary in line with a very high correlation coefficient (cc = 0.970) indicating strong cooperation of pi-electron structure in the ring and in the bond. This agreement is dramatically broken for electron accepting substituents, which form a cluster of points below the line HOMA = 0. For the latter case it may be interpreted as follows: both parts of molecules, the ring and the substituent from the point of view of -electron properties, are the electron withdrawing moieties. Thus, there does not exist one dominant effect, but rather a composition of many effects, which contribute to the changes in geometry of both kinds of fulvene derivatives and hence lead to irregular changes.

Conclusions

(i) pi-electron population at carbon atoms of the ring -pEDA in fulvene and benzene correlates well with substituent constant  p + and with aromaticity index NICS indicating that pEDA may serve in some cases as a useful indicator of aromaticity.

(ii) pi-electron occupations of carbon atoms in benzene and in fulvene rings are mutually well correlated for positions orthoand parain benzene and 1 and 3,4 positions in fulvene with positive regression slopes, whereas for position meta-vs. 2,5 in fulvene correlation is much worse and with a significant negative slope.

(iii) Direct comparison by means of linear regression of pi-electron occupation at ortho-vs. metacarbon atoms in benzene gives negative regression slope and weak correlation coefficient. This is explained by different mechanism of substituent effect on orthoand metacarbon atoms: the dominant resonance effect in the case of ortho-atoms and dominant inductive/field effect in the case of metapositions.

(iv) The difference between substituent effect in benzene and fulvene is not only quantitative (greater effects in fulvene) but also in that, that in fulvene all carbon atoms in the ring communicate by resonance with the substituent whereas in benzene ring only orthoand para-positions can do that.

Figure captions

Fig. 1 The numbering scheme for the substituted fulvene molecule

  runs over all five fulvene ring carbon atoms and  fulvene is the occupation of the jth 2p z NAO. 22 substituted species span a wide range of substituents with varying donor-acceptor properties: B(OH) 2 , BH 2 , CCH, CF 3 , CH 3 , CHCH 2 , CHO, Cl, CMe 3 , CN, COCH 3 , CONH 2 , COOH, F, NH 2 , NMe 2 , NO, NO 2 , OCH 3 , OH, SiH 3 , SiMe 3 and all of them plus an unsubstituted compound are taken into account in Figs. 4-18. <Figure 4-8> Next, let us consider how the population of pi electrons on the individual carbon atoms in fulvene ring depends on substituent constants. Figs. 9-11 present appropriate dependences. <Figure 9-11>

Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 Fig. 16 Fig. 17 Fig. 18

 23456789101112131415161718 Fig. 2Resonance structures of the fulvene molecule

  Figure 1 Click here to download high resolution image

  Thus it is appropriate for describing the interactions of the substituent with electron deficient fulvene ring. The values of sigma_p+ constants are taken from Ref20 [Stepień BT, Cyrański MK, Krygowski TM (2001) Chem Phys Lett 350:537.] and the proper citation is now included in the text.

6)

It is missed in the text that points on the graphs in Figures are plotted for original compounds and 22 derivatives.

Acknowledgments

Computational Grant G31-10 from the Interdisciplinary Centre of Mathematical and Computer Modelling (ICM) at Warsaw University is gratefully acknowledged.

16)

The first sentence of the Conclusions: "correlate" should be corrected to "correlates".

Reply: This is now corrected I do not think I have listed all of misprints and unclear sentences. The manuscript needs to be read critically and corrected accordingly.

Reply: We have done our best to correct remaining mistakes.

Results and discussion

Let us begin with a glimpse at the substituent effect in exo-cyclically monosubstituted fulvene and benzene presented by means of resonance structures. There are three aspects to be considered: (i) how differences in substituent effect transmission through benzene and fulvene affect the overall electron structure of benzene and fulvene rings, (ii) how they operate for individual carbon atoms in the rings and (iii) how the changes in the ring correlate with those in the transmitter of the substituent effect: C1=C6 moiety.

First, let us consider the overall effects observed in fulvene and benzene derivatives. In both cases pEDA [26] correlate well with Hammett  p + [20,27] and aromaticity index NICS [25] as shown in Fig. 4 through 7. The first observation is that -electron populations at carbon atoms of the ring in fulvene and benzene, pEDA(F) and pEDA(B) plotted against  p + differ dramatically in values of the slopes of the regressions. Sensitivity of fulvene and benzene rings on substituent effect estimated by ratio of the slopes for fulvene and benzene derivatives is 0.245/0.155 = 1.58. It means for fulvene is 1.58 times greater than in benzene derivatives.

Alike is a situation for scatter plots of pEDA against NICS. When pEDA values for fulvene and benzene derivatives are plotted against each other, (Fig. 8) the regression shows qualitatively the same picture, the substituent effect on the pi-electron population at carbon atoms in fulvene is 1.44 times greater than for benzene ring (Eq. 3). This difference in sensitivity on the substituent effect is caused by a strong pi-electron accepting characteristics of fulvene ring, which contains 5 pi-electrons and tends to achieve the Hückel value 4N+2 electrons; whereas in the case of benzene containing 6 electrons no such effect takes place.

pEDA(F)= 1.44 * pEDA(B)

In the following figures cc means correlation coefficient.


M.D Stuart Skoutelis

M.D. Johnson

M.D. Ioannis G ; Baraboutis

P Eleftheria

M.D.; Jeanette L Tsagalou

R N Lepinski

M.D.; Ilias Papakonstantinou

M.D Vassilios ; Papastamopoulos

T Athanasios

Keywords: Staphylococcus aureus, urinary tract infection, primary staphylococcus aureus urinary tract infection, Escherichia coli urinary tract infection, urinary tract catheterization

Primary urinary tract infection: the role of undetected hematogenous seeding of the urinary tract

ANSWER. We tried to avoid studying just bacteriuria by using quite strict criteria to define "urinary tract infection" (ending up this way with 20 patients only). Those are described in the "materials and methods" section. Besides a positive urinalysis and urine culture, we required at least 4 pertinent symptoms (out of the following: dysuria, frequency, hematuria, fever more than 38oC, suprapubic tenderness, costovertebral area tenderness to percussion) AND documentation in the chart of a clinical impression of urinary tract infection by the responsible physicians. Since 1. there is significant symptom overlap between cystitis, prostatitis and pyelonephritis and 2. the diagnosis written in the patient charts was, in the majority of cases, just "urinary tract infection" without further specification, we feel we do not have data accurate enough to discriminate between upper and lower UTI in the 2 groups. So, we think that "symptomatic urinary tract infection" is the best description we can come up with (we have made appropriate corrections in the "materials and methods" section). Also, we have put a pertinent comment in the "limitations of the study" section.

INTRODUCTION

Staphylococcus aureus (S. aureus, SA) is the causative factor of a great variety of infections in outpatients as well as in hospitalized patients. It is considered one of the commonest causes of nosocomial infection in US hospitals and in many European countries [1]. On the other hand, urinary tract infections (UTI) are one of the commonest types of infections encountered in clinical practice, while they constitute the most common type of nosocomial infection in the US [1]. Up to 95% of nosocomial UTIs may be associated with indwelling urinary catheters [1].

Despite the above, S. aureus has been known for years to be a relatively rare urinary isolate [START_REF] Arpi | The clinical significance of Staphylococcus aureus bacteriuria[END_REF]. Older studies, involving outpatients or inpatients or mixed populations, report a percentage of 0.5% to 6% of all positive urine cultures [START_REF] Blazevic | Organisms encountered in urine cultures over a 10-year period[END_REF][START_REF] Demuth | Staphylococcus aureus bacteriuria[END_REF][START_REF] Pead | Staphylococci as urinary pathogens[END_REF][START_REF] Jepsen | Urinary-tract infection and bacteremia in hospitalized medical patients-a European multicentre prevalence survey on nosocomial infection[END_REF]. Newer reports mention a 13.1% contibution of S. aureus in a bacteremic UTI case-series involving mostly elderly people in a large community hospital [START_REF] Ackermann | Bacteremic urinary tract infection in older people[END_REF].

The clinical significance of a positive urine culture for SA has been long debated. Traditionally S. aureus has been considered to invade the kidney from the hematogenous route, resulting in intrarenal or perinephric abscesses [START_REF] Jepsen | Urinary-tract infection and bacteremia in hospitalized medical patients-a European multicentre prevalence survey on nosocomial infection[END_REF][START_REF] Sobel | Urinary tract infections (Chapter 66)[END_REF]. S. aureus bacteriuria may occur in 7% of patients with S. aureus bacteremia and in 13% of cases of S. aureus endocarditis according to an older study [START_REF] Lee | The association between Staphylococcus aureus bacteremia and bacteriuria[END_REF], although more recent data doubt this association [START_REF] Ekkelenkamp | Quantifying the relationship between Staphylococcus aureus bacteremia and S. aureus bacteriuria: A retrospective analysis in a tertiary care hospital[END_REF].

On the other hand, some investigators of S. aureus bacteremia include the urinary tract as the portal of entry, although infrequently [START_REF] Arpi | The clinical significance of Staphylococcus aureus bacteriuria[END_REF]. In vitro, S.

aureus is able to attach to and aggregate onto uroepithelial cells through glycoproteins found in bladder mucin, like GP51, which is significantly increased in the presence of urinary tract infection [START_REF] Byrne | Interaction of bladder glycoprotein GP51 with uropathogenic bacteria[END_REF]. This retrograde pattern of S. aureus UTI (or primary SA UTI) has been mostly documented in elderly men with presence of important predisposing factors in the urinary tract. These include presence of indwelling catheters, obstruction or other abnormalities, instrumentation or surgery [START_REF] Arpi | The clinical significance of Staphylococcus aureus bacteriuria[END_REF][START_REF] Demuth | Staphylococcus aureus bacteriuria[END_REF]. Rates of secondary bacteremia in these groups of patients have been reported to range from 2.3% to 8.3% [START_REF] Arpi | The clinical significance of Staphylococcus aureus bacteriuria[END_REF][START_REF] Demuth | Staphylococcus aureus bacteriuria[END_REF][START_REF] Jepsen | Urinary-tract infection and bacteremia in hospitalized medical patients-a European multicentre prevalence survey on nosocomial infection[END_REF][START_REF] Muder | Isolation of Staphylococcus aureus from the urinary tract: Association of Isolation with symptomatic urinary tract infection and subsequent staphylococcal bacteremia[END_REF].

Even more puzzling and also much less studied is the clinical significance of SA bacteriuria without documented bacteremia before or after the positive S. aureus urine culture date. A study of SA bacteriuria without documented bacteremia from 1997 speculates a transient unidentified bacteremic state, at least for some of these patients [START_REF] Sheth | Clinical significance of Staphylococcus aureus bacteriuria without concurrent bacteremia[END_REF]. The above speculation of a transient bacteremic state leading to S. aureus urine colonization or even UTI (which, if existed, would possibly be another candidate for the definition of "primary SA UTI" besides the already known UTI via the ascending route) could potentially apply to some clinical observations we made in our clinical practice.

 Case-report A: Young woman with eosinophilic meningitis and prolonged hospital stay was seen in f/up with a superficial phlebitis at the site of a previous intravenous catheter in her wrist/forearm. The site was not warm or fluctuant and she had no systemic symptoms so she was treated conservatively with warm compresses. The following visit she mentioned symptoms of a UTI so a urinalysis (UA) and a urine culture (UC) were sent and she was started on trimethoprim-sulfamethoxazole empirically. The UC yielded >10 5 colonies/ml of S. aureus (pure growth).

 Case report B: 42 year-old patient with advanced AIDS and HIVrelated dementia was hospitalized briefly for mental status changes.

During his hospital stay, he received a brief course of intravenous anti-CMV therapy. The hospital course was uneventful, he improved and was discharged home after 8 days. There was no urinary tract (UT) manipulation during his hospital stay or later and there was no history of UTI or UT abnormality. Four weeks later, he was evaluated as outpatient. He had no systemic symptoms but reported new-onset urinary frequency, dysuria and suprapubic pain.

UA showed significant pyuria and UC revealed pure growth of >10 5 colonies/ml of S. aureus.

We hypothesized that the ``primary S. aureus UTI`` identified in those two patients was blood-borne in origin. In the first case, it could be related to transient bacteremia related to intravenous site thrombophlebitis, while in the second case there was no obvious primary focus but the patient had been recently hospitalized, received intravenous therapy and was significantly immunocompromised. Several reports of increased rates of S. aureus bacteremia in the HIV/AIDS population are now available [START_REF] Senthilkumar | Increased incidence of Staphylococcus aureus bacteremia in hospitalized patients with acquired immunodeficiency syndrome[END_REF][START_REF] Jacobson | SAB and recurrent Staphylococcal infection in patients with acquired immunodeficiency syndrome and AIDS-related complex[END_REF].

MATERIALS AND METHODS

To put our hypothesis in perspective we wanted to further evaluate the occurrence of this phenomenon/syndrome, should it exist. Our study was approved by the Institutional Review Board (IRB) of Northwestern University and Lakeside Lakeside Veterans Affairs (VA) Hospital. We used the Infection Control records of the VA hospital for the purposes of our research. We reviewed the infection control line listing of patients with S. aureus infections of the time period between March 2000 and September 2001 and we identified patients with positive urine cultures for S. aureus without documented concurrent S. aureus bacteremia. Then, we used the computerized medical record system of our hospital to search the charts of those patients for clinical and microbiological data to support the diagnosis of "SA symptomatic UTI without concurrent bacteremia".

The diagnosis of "symptomatic UTI" was present when all the following criteria were present: 1. positive urine culture for S. aureus in pure growth and >10 5 CFU/mL, 2. more than 10 white blood cells per highpower field on urinalysis, 3. positive test for nitrates or leucocyte esterase, 4. at least 4 out of the following 6 symptoms/signs: dysuria, frequency, hematuria, fever more than 38 o C, suprapubic tenderness, costovertebral area tenderness to percussion and 5. diagnosis of urinary tract infection by the responsible physicians. "Concurrent bacteremia" was defined as at least one blood culture positive for S. aureus in the 2 weeks preceding or the 72 hours after the first urine culture yielding S. aureus. By using the above-described definitions, we finally came across with a list of 20 patients eligible for further study.

For those 20 patients, we collected demographic and medical history data about pre-existing illnesses (with attention to conditions predisposing to UTI). We recorded data about prior hospitalization within the last six months and inpatient or outpatient status when the urine culture (UC) was obtained. Paper chart notes were also reviewed looking for history of recent hospitalization at another facility possibly not recorded on electronic VA chart.

Dates of prior vascular procedures (peripheral line and/or central venous catheter placement) that took place during the last month before the positive UC date were also recorded. Subsequently, we carefully reviewed all the medical and nursing notes up to 1 month prior to the positive UC date looking for any sign of local inflammation at the site of the peripheral or central catheter entry. We included recordings about local redness, swelling, induration and presence of pus.

Additionally, we looked for data on any kind of UT manipulation during the same time-period. Those included placement and presence of Foley catheter up to 48 hours before the positive UC date and also other urologic procedures.

To compare that patient group ("SA group" or "cases") with other primary UTI cases in which retrograde infection is usually the norm, we looked for a control group of E. coli UTI cases without concomitant bacteremia. The exclusion of bacteremic E. coli UTI cases may not have been critical as most E. coli bacteremias are thought to be secondary to E. coli UTI and much less likely due to other primary foci of infection.

We reviewed our microbiology laboratory records for E. coli urinary isolates and identified cases of positive UCs for E. coli without documented concurrent bacteremia for the same time period (March 2000 through September 2001). We went through the exact same procedure as for the SA group (review of computerized medical charts to support the diagnosis of "E. coli symptomatic UTI without concurrent bacteremia" based on identical definitions to the ones for SA UTI). After eliminating from our list patients not fitting the pre-specified criteria, we created our control group (almost double in number than the SA cases) by selecting every third eligible case from the modified microbiology list. Finally, we went back to computerized and paper medical charts and collected similar data for our control group as for the SA patients.

RESULTS AND DISCUSSION

We were finally able to compare 20 cases of S. aureus symptomatic UTI with a control group of 43 E. coli symptomatic UTI cases. Characteristics of the S. aureus group and the E. coli control group are included in table 1.

Cases (n= 20) and controls (n= 43) were similar in respect to age (71.15±11.6 vs. 67.9±13.5 yrs, mean±SD), diabetes mellitus (35% vs. 31%), prostatic hypertrophy (50% vs. 48%), previous UTI (25% vs. 26%), and other UT abnormality (15% vs. 21%). However, cases were more likely than controls to have had recent hospitalization (within the last 6 months) and recent urinary catheterization (p values of 0.012 and 0.0001 respectively). Additionally, cases exhibited a trend, as a group, for having had central line placement the month before the positive UC date (p 0.075) and also more likely to have exhibited signs of inflammed peripheral intravenous line within the same time period (p 0.008). In multivariate analysis, recent urinary catheterization and history of admission during the last 6 months for outpatients remained significant predictors of SA UTI (p 0.000 and 0.006 respectively).

We then attempted to compare each of the 2 subgroups of the SA UTI cases (MRSA and MSSA) with the control cases in a similar manner (table 1).

MRSA cases. Cases of MRSA UTI (n= 15) did not differ from controls in terms of age, diabetes mellitus, prostatic hypertrophy, previous UTI and other UT abnormality (15% vs. 21%). Strong differences again arose between MRSA cases and controls when assessed for hospitalization within the last 6 months (p 0.013) and recent urinary catheterization (p 0.000). Additionally, MRSA cases were more likely to have been inpatients on the date of the positive culture collection (p 0.05) and to have exhibited signs of inflammed peripheral intravenous line within the last month before the positive culture dates as opposed to E.coli controls (p 0.049). Both differences in recent urinary catheterization and recent hospitalization for outpatients were predictors of MRSA UTI in regression analysis (p 0.001 and 0.027, respectively).

MSSA cases. That small subgroup again did not differ from controls in terms of age, diabetes mellitus, prostatic hypertrophy, previous UTI and other UT abnormality. Also, no significant differences were noted in any parameter which differed in the previous group analyses, possibly due to low numbers, at least in part.

Even though several types of infectious syndromes caused by S. aureus are common in clinical practice and adequately well studied, urinary tract involvement by this pathogen is probably not one of them. The presence of S. aureus in urine cultures is not always easy either to explain or to appreciate its significance in order to evaluate and treat accordingly. The long-standing concept of SA bacteriuria as a common reflection of SA bacteremia has been cast doubt, even for patients without recent indwelling urinary catheter placement, in terms of cost-effectiveness of extensive source investigations [START_REF] Ekkelenkamp | Quantifying the relationship between Staphylococcus aureus bacteremia and S. aureus bacteriuria: A retrospective analysis in a tertiary care hospital[END_REF][START_REF] Sheth | Clinical significance of Staphylococcus aureus bacteriuria without concurrent bacteremia[END_REF]. The authors of the 1997 report do not think an extensive evaluation for an occult focus of S. aureus infection is warranted for patients with SA bacteriuria, although it should be considered with community-acquired SA bacteriuria, pure growth of >10 8 organisms /L in culture and absence of urinary tract predisposing conditions (mentioned above) [START_REF] Sheth | Clinical significance of Staphylococcus aureus bacteriuria without concurrent bacteremia[END_REF].

On the other hand, S. aureus seems to be an infrequent but definite colonizer of the urinary tract, especially in people with urinary catheters, and, in a minority of those, a cause of symptomatic urinary tract infection [START_REF] Muder | Isolation of Staphylococcus aureus from the urinary tract: Association of Isolation with symptomatic urinary tract infection and subsequent staphylococcal bacteremia[END_REF]. Although urinary S. aureus may be the source of subsequent staphylococcal bacteremia, the proportion of patients with chronic S. aureus bacteriuria who subsequently become bacteremic is unknown [START_REF] Muder | Isolation of Staphylococcus aureus from the urinary tract: Association of Isolation with symptomatic urinary tract infection and subsequent staphylococcal bacteremia[END_REF]. The results of our study were in agreement with other reports that urinary catheterization is probably the strongest predisposing factor for colonization and/or infection of the UT by S. aureus. Besides that, it did bring up-in our opinion-some interesting hints that other factors related to exposure to the healthcare system may be participating in the process, possibly through transient unrecognized bacteremia, at least in some instances. The SA group had higher rates of recent hospitalization, recent central venous catheter placement and recent line-related peripheral thrombophlebitis. The noticed trend was largely driven by the MRSA patients. There were significantly more inpatients included in the MRSA subgroup than in the control group and they did have higher rates of intravascular device placement preceding the UTI by S. aureus.

Additionally, recent hospitalization maintained its significant difference in multivariate analysis between that subgroup and the E.coli control group, the latter not without significant exposure to both UT manipulations and the healthcare system.

Transient, sometimes asymptomatic and spontaneously resolving S. aureus bacteremia, is a well known phenomenon.to experienced clinicians but not adequately studied. Any attempt to further study that phenomenon in a prospective way would be probably unethical, especially when thinking of how devastating S. aureus bloodstream infection can be to the point that even the finding of colonization of a removed intravascular catheter without documented bacteremia may warrant immediate antistaphylococcal therapy [START_REF] Ekkelenkamp | Bacteremic complications of intravascular catheters colonized with Staphylococcus aureus[END_REF]. Nevertheless, some studies have touched on that issue from different angles. In an older prospective study of sources and outcome of MRSA bacteremia and septicaemia (total of 82 episodes), circulation access sites were the commonest source of the bacteremia with non-surgical wounds including burns, varicose ulcers and bed sores as the next most common [START_REF] Cafferkey | Sources and outcome for methicillin-resistant Staphylococcus aureus bacteraemia[END_REF]. The authors categorized 15 of those episodes of bacteremia as transient and, even though they did not provide exact details, they mentioned that 14 of the 82 episodes resolved without antimicrobial therapy. Patients with transient bacteremia were relatively younger than patients with septicaemia. The 2 groups had, although, similar rates of serious underlying diseases and recent surgery. In 10% of cases, there was no obvious source for bacteremia. In 3 of those, there had been recent surgery, while in 4 of the remaining 5, patients had been recently receiving intravenous fluids. Staphylococcus aureus can be an infrequent cause of transient bacteremia after tooth surgery [START_REF] Tomás | Prevalence of bacteraemia follwing third molar surgery[END_REF] and also after both upper and lower gastrointestinal endoscopy, where it has been long realized that bacteremia is usually transient and asymptomatic [START_REF] Nelson | Infection control during gastrointestinal endoscopy[END_REF].

Interestingly, the small MSSA UTI group seemed also to have had its share of healthcare and intravascular device exposure despite no detected difference in inpatient status on the culture date. Also, no difference arose in urinary catheterization rates when compared with the E.coli group.

More definite conclusions about that group were precluded by its small size.

Strengths of the study. We have not found any prior studies addressing this specific question. We tried our best to apply strict criteria for patient enrollment in the study. The study group derived from a significantly homogeneous population in terms of demographics and underlying illnesses. A significant degree of homogeneity also holds true about completeness of medical care data for the population, based on the almost exclusive care at the VA hospital, computerized medical records and full availability of nursing records. Additionally, we carefully created a control group of E.coli UTI cases based on the same criteria for more accurate comparison purposes. Finally, although we can only speculate that our hypothesis may be true under certain circumstances and in certain patients, we believe in our results since they seem to be making physiologic sense in terms of what is known about epidemiology and clinical behavior of S. aureus.

Limitations of the study. There was obviously no definite conclusion of a new pathogenetic pathway for S. aureus symptomatic urinary tract infection from our retrospective study. Despite our efforts for completeness, we definitely had missing data about hospitalization events, urinary tract instrumentation and and intravascular device use.

Still, we believe that if data were even more complete, that would have augmented possible differences between the study groups. In the same line, we did not assess other risk factors for S. aureus bacteremia (surgery etc). Additionally, since a. there is significant symptom overlap between cystitis, prostatitis and pyelonephritis and b. the diagnosis documented in the patient charts was, in the majority of cases, just "urinary tract infection" without further specification, our data were not accurate enough to discriminate between upper and lower UTI in the 2 groups.

That is why we maintained the general term "symptomatic urinary tract infection" throughout. Furthermore, we did not obtain outcome data of our study patients. A recent well-designed study reported worse outcomes in those cases of S. aureus bacteremia accompanied by bacteriuria [START_REF] Huggan | Concomitant Staphylococcus aureus bacteriuria is associated with poor clinical outcome in adults with S. aureus bacteraemia[END_REF].

Finally, patient numbers were small, especially that of the MSSA UTI subgroup.

We conclude that even though urinary tract catheterization is probably the strongest predisposing factor for primary S. aureus UTI, some cases may be mediated through another pathogenetic mechanism, i.e., unrecognized preceding bacteremia related to intravascular device exposure or other healthcare-related factor. We are not sure if a larger,

  Statistical analysis. Collected data were entered into a Microsoft Excel spreadsheet and version 13 of SPSS software was used for data processing. We used Student's t-test for independent samples for comparison of continuous variables and Pearson's chi-square test for categorical variables [or Fisher's exact test in cases of low (<5) cell numbers]. Factors of statistical significance on univariate analysis were used for logistic regression analysis [backward stepwise (Wald)]. A p value of 0.05 or less was used for clinical significance.

Our 2

 2 clinical cases prompted us to investigate another-probably-piece of the puzzle: the circumstances of development of symptomatic urinary tract infection by S. aureus in the absence of documented bacteremia. Our hypothesis was that these circumstances could involve, besides prior urinary tract manipulation leading to SA colonization, a transient bacteremic state, at least for some of the cases, like Sheth et al speculated in 1997. We carefully identified patients with the diagnosis of SA UTI without documented preceding or concomitant bacteremia based on strict predefined criteria and we compared them with a control group of E.coli UTI patients in terms of predisposing factors for ascending SA UTI as well as predisposing factors for preceding SA bacteremia, especially focusing on exposure to healthcare system and recent presence of intravascular devices.

  prospective study could clarify this issue. Still, we believe that clinicians treating patients with S. aureus UTI should thoroughly inquire both about recent UT instrumentation and recent hospitalization with intravascular device use. Note: Part of this work was presented as a poster at the 42th annual IDSA meeting, 30 Sep-3 Oct, Boston, MA (paper 533, page 143 of abstract book).

Table 1 . Comparison of cases of Staphylococcus aureus Urinary tract Infections (UTIs) with Escherichia coli UTIs (controls) with subgroup analysis for methicillin-resistant and methicillin-sensitive isolates.

 1 Footnote. MRSA: methicillin-resistant Staphylococcus aureus, MSSA: methicillinsensitive Staphylococcus aureus.OR: odds ratio, CI: confidence intervals, NA: not applicable.

	Characteristics	Escherichia	All cases of	p /OR (95% CI)	MRSA	p/OR (95%	MSSA	p/OR (95%
	/microorganism	coli(n=43)	Staphylococcus		(n=15)	CI)	(n=5)	CI)
			aureus (n=20)
	Age	67.9±13.5	71,15±11,6	0,348/NA	73.1±9.9 0.176/NA	65.2±15.2	0.677/NA
	Diabetes mellitus	14/43	7/20	0,85/1.11(0.36-	5/15	1.00/1.03(0.29-	2/5	1.00/1.38(0.21-
				3.41)		3.61)		9.22)
	History of	6/43	4/20	0,71/1.54(0.38-	4/15	0.262/2.24(0.53-	0/5	1.00/0.88(0.78-
	genitourinary			6.21)		9.39)		0.98)
	procedure (more than
	6 months ago)
	Benign prostatic	20/43	10/20	0,79/1.15(0.38-	9/15	0.37/1.72(0.52-	1/5	0.37/0.28(0.03-
	hypertrophy			3.32)		5.69)		2.78)
	History of urinary	16/43	5/20	0,67/0.77(0.23-	4/15	1.00/0.84(0.22-	1/5	1.00/0.57(0.06-
	tract infection			2.56)		3.13)		5.67)
	Other urinary tract	9/43	3/20	0,73/0.67(0.16-	2/15	0.71/0.58(0.11-	1/5	1.00/0.94(0.094-
	abnormality			2.78)		3.06)		9.52)
	Inpatient on culture	10/43	8/20	0,17/2.2(0.70-6.88) 8/15	0.05/3.77(1.09-	0/5	0.57/0.87(0.77-
	date					12.99)		0.98)
	If outpatient,	4/43	8/20	0,012/6.5(1.66-	6/15	0.013/6.5(1.51-	2/5	0.11/6.5(0.82-
	admission last 6			25.14)		27.93)		51.2)
	months
	Inpatient on culture	14/43	16/20	0,000/8.28(2.33-	14/15	0.000/29.0(3.46-	2/5	1.00/1..38(0.20-
	date or recent			29.44)		243.22)		9.22)
	admission
	Presence of	8/43	14/20	0,0001/10.21(2.99-	13/15	0.000/28.44(5.3	1/5	1.00/1.09(0.11-
	indwelling urinary			34.81)		2-151.84)		11.52)
	catheter more than 48
	hours before culture
	date
	Genitourinary	5/43	2/20	1.00/0.84(0.15-	2/15	1.00/1.17(0.20-	0/5	1.00/0.88(0.79-
	procedure last 6			4.78)		6.77)		0.98)
	months
	Any intravenous line	15/43	11/20	0,13/2.28(0.77-	9/15	0.089/2.8(0.84-	2/5	1.00/1.24(0.18-
	last 30 days			6.72)		9.37)		8.28)
	Peripheral	15/43	7/20	0,99/1.005(0.33-	6/15	0.72/1.24(0.37-	1/5	0.65/0.46(0.05-
	intravenous line last			3.05)		4.16)		4.55)
	30 days
	Central venous	2/43	4/20	0,075/5.12(0.85-	3/15	0.10/5.12(0.76-	1/5	0.28/5.12(0.37-
	catheter last 30 days			30.78)		34.31)		69.75)
	before positive
	culture date
	Any sign of	1/43	4/20	0,032/10.5(1.09-	3/15	0.049/10.5(0.99-	1/5	0.19/10.5(0.54-
	intravenous line			101.19)		110.35)		201.71)
	inflammation last 30
	days before positive
	culture date

Table

We thank the Editorial Office and the reviewers for their time and effort On behalf of the authors Ioannis G. Baraboutis

Electronic Supplementary Material

Click here to download Electronic Supplementary Material: SA UTI COVER LETTER REVISED.doc

PRIMARY STAPHYLOCOCCUS AUREUS URINARY TRACT INFECTION : THE ROLE OF UNDETECTED HEMATOGENOUS SEEDING OF THE URINARY TRACT


Marc Demeuse
email: marc.demeuse@umons.ac.benathanael.friant@umons.ac.

Nathanaël Friant

School segregation in the French Community of Belgium

est destinée au dépôt

Introduction

In the French Community of Belgium, education is compulsory and free of charge for a period of twelve years starting at the age of 6 and ending at the age of 18. Pre-primary (not compulsory but free of charge and of a period of three years) and primary (between the ages of 6 and 12), are called fundamental education. Secondary education has three stages of two years each [START_REF] Eurydice | Organisation of the education system in the French Community of Belgium[END_REF]. For the first stage of two years, pupils have access to a common curriculum (Demeuse & Lafontaine, 2005). From the second stage on, secondary education is spread into different curricula1 with different objectives and outlets, and each curriculum attracts distinct social and academic populations [START_REF] Demeuse | Parcours scolaire et inégalités de résultats [School experience and inequalities in results[END_REF]Demeuse et al., 2007). According to the curriculum followed, pupils will get access to higher education (after general or certain technical and vocational curricula), or a "vocational aptitude" certificate (after vocational or certain technical curricula). The Belgian education system is based on the principle of freedom of education, proclaimed in the Belgian Constitution. This principle of freedom is found at two levels. The first one concerns the freedom given to pupils and parents to choose the school that suits them (law of 1959). This freedom of choice was initially given in order to respect individual philosophical beliefs but nowadays this criterion is less and less important in families" choices. The second one regards the freedom of school management. This freedom in education led to a system spread into "réseaux" (networks), each having its own educational plan within which each school (and teachers) has its (his/her) own pedagogical freedom. In practice, education is structured in three main networks: Public schools run and financed by public authorities (the French Community); Public grant-aided schools run by the provinces or by municipalities and subsidised by the French Community, and Private grant-aided schools (denominational, nondenominational) run by private associations (non profit, diocese or congregation) or persons and subsidised by the French Community. The public financing is based on the same rules whatever the network except for school buildings.

The freedom of choice, combined with public financing of education -including private schools -and a method of calculating the financing of each institution according to the number of students registered, leads to a school quasi-market [START_REF] Vandenberghe | L"enseignement en Communauté française de Belgique: un quasimarché [Teaching in the French Community of Belgium: a quasi-market[END_REF]Delvaux, Demeuse and Dupriez, 2005).

From the school"s point of view, pupils have not only a "financial" value, because their numbers determine the subsidies awarded to each institution (first-order competition), but also a "pedagogical" value based on their more or less desirable personal traits (second-order competition) [START_REF] Maroy | Ecole, régulation et marché -une comparaison de six espaces scolaires locaux en Europe [School, regulation and market -a comparison of six local school zones in Europe[END_REF]. Schoolchildren that conform to school norms will be that much easier for the school to manage. Numerous authors have in addition demonstrated that peers play an important role in a pupil's learning [START_REF] Slavin | Achievement effect of ability grouping in secondary schools: A bestevidence synthesis[END_REF][START_REF] Duru-Bellat | La constitution de classes de niveau dans les collèges: Les effets pervers d"une pratique à visée égalisatrice [Constituting level-based classes in secondary schools: The counterproductive effects of a practice that is intended to equalize[END_REF][START_REF] Vandenberghe | L"enseignement en Communauté française de Belgique: un quasimarché [Teaching in the French Community of Belgium: a quasi-market[END_REF][START_REF] Crahay | L'école peut-elle être juste et efficace? De l'égalité des chances à l'égalité des acquis [Can school be fair and efficient? From equal opportunities to equal acquisition[END_REF][START_REF] Ireson | Ability Grouping in Education[END_REF][START_REF] Dupriez | Classes homogènes versus classes hétérogènes: les apports de la recherche à l"analyse de la problématique [Homogenous classes versus heterogenous classes: what research brings to the question[END_REF][START_REF] Monseur | Composition académique et sociale des établissements, efficacité et inégalités scolaires: une comparaison internationale [Academic and social composition of schools, effectiveness and inequalities: an international comparison[END_REF]: while learning, a pupil is influenced by the characteristics of the other pupils in his class or school. In fact, teachers are also influenced by the composition of the group of pupils in their classroom and adapt the demands of the curriculum and the evaluation to these pupils [START_REF] Thrupp | Schools making a difference: let"s be realistic[END_REF][START_REF] Thrupp | School composition and peer effects[END_REF][START_REF] Dumay | Effet établissement: effet de processus et/ou effet de composition [The school effect: a process effect and/or a composition effect[END_REF].

The school hopes to respond appropriately to parents' choices by providing quality education and in turn cultivate a certain demand from parents. A school that does not satisfy the most demanding parents will see them withdraw their children, taking with them the funds that allow the school to operate and thus reducing the resources available. In light of this, it is understandable that schools are not only in competition but also interdependent. This is what [START_REF] Delvaux | Les espaces locaux d'interdépendance entre écoles : étude de cas en Belgique francophone [Local areas of interdependence between schools : case study in French speaking Belgium[END_REF] have called competitive interdependence between institutions: "the distribution of pupils, mainly determined by the free choice of parents but also by the relegation processes that exist between institutions, produces hierarchical positions among schools and these influence the strategies and actions that headmasters develop in their institutions and that are "formally" in their zone of autonomy. Schools located in the same local space are interdependent insofar as the workings of a school depend on its position in the local school hierarchy and indirectly on the workings of the other institutions in this space"2 . These particularities of the educational system in French-speaking Belgium foster segregation of schools and create several "types" of schools on a continuum from "ghetto" schools to "sanctuary" schools. Different examples of segregation have been observed in numerous studies [START_REF] Crahay | L'école peut-elle être juste et efficace? De l'égalité des chances à l'égalité des acquis [Can school be fair and efficient? From equal opportunities to equal acquisition[END_REF]Demeuse et al., 2005;[START_REF] Baye | A set of indicators to measure the equity of the 25 educational systems of the European Union[END_REF][START_REF] Delvaux | Les espaces locaux d'interdépendance entre écoles : étude de cas en Belgique francophone [Local areas of interdependence between schools : case study in French speaking Belgium[END_REF][START_REF] Demeuse | Measuring and Comparing the Equity of Education Systems in Europe[END_REF][START_REF] Eurydice | Organisation of the education system in the French Community of Belgium[END_REF][START_REF] Friant | Les liens entre recherche prospective, description du système éducatif et pilotage: un exemple en Communauté française de Belgique [Ties between prospective research, description of the educational system and "pilotage": an example from the French Community of Belgium[END_REF]. Not only are there great socio-economic disparities between schools, related to the type of programmes they offer, but also, when we look at the institutions on the extreme ends of this continuum, we see that the situation is worsening: the most privileged institutions dispose of their most underprivileged pupils, whereas the most underprivileged schools cannot keep their most privileged pupils (Friant et al., 2008).

Numerous studies [START_REF] Dupriez | Inequalities in school systems: effect of school structure or of society structure?[END_REF][START_REF] Monseur | Composition académique et sociale des établissements, efficacité et inégalités scolaires: une comparaison internationale [Academic and social composition of schools, effectiveness and inequalities: an international comparison[END_REF] have shown that the quasi-market of the Belgian education system results in significant inequalities in school results because of the related segregation. PISA 2000 and 2003 from OECD revealed a strong score discrepancy between the 25% of 15-year-old pupils with the most favourable socioeconomic background and the 25% of pupils with the least favourable one. These assessments also underlined the importance of the average socioeconomic level of schools themselves on differences on pupils" performances (Baye et al., 2006).

Types of segregation

With [START_REF] Delvaux | Ségrégation scolaire dans un contexte de libre choix et de ségrégation résidentielle [School segregation in a context of free choice and residential segregation[END_REF], we define segregation as "the expression of social differences in space. It appears as soon as individuals classified by society into distinct social categories, endowed with a differentiated social value, are separated in space and thus do not mix with each other"3 . In the French Community of Belgium, as in other systems, several types of segregation occur. It is worth clarifying this, because there is not the same amount of information or political attention, which together lead to specific policy interventions, for each type of segregation.

From this definition, one can say that segregation can be characterized by two factors: the social categories and the type of spatial separation. Without the pretention of being exhaustive, we identify 3 possible social categories, and 3 possible types of separation. This gives us 9 types of segregation, about which we have varying amounts of information. A major part of the research is focussed on socioeconomic segregation in secondary education, that is to say the separation of pupils according to their socioeconomic status, measured by indicators such as answers to survey questions (as in the PISA studies) or a composite indicator characterizing their home district4 . The latter indicator is used, among other things, in priority education policy: in the rest of this document, we will refer to it with the abbreviation "SES". Socioeconomic segregation between curricula and between schools (somewhat linked given the varying training programs offered by schools) is well documented. However, we know very little about segregation within schools, as the available data do not go to such detailed level (except for curricula).

Since the PISA studies and the acknowledgement of the huge differences in pupils" results, notably between schools, academic segregation is quite well documented. Again, there is not so much information regarding segregation within schools, as the available data does not go to such detailed level. However, some studies using external evaluations (e.g. [START_REF] Demeuse | Mise au point d'un dispositif d'évaluation des performances « objectives » des établissements scolaires dans l'enseignement fondamental de la Communauté française[END_REF], have explored this dimension.

Finally, there is a lack of data about "ethnic" segregation in the French Community of Belgium (Jacobs et al., 2009). One source of information is the PISA dataset, using the birthplace of the pupils" parents [START_REF] Demeuse | Measuring and Comparing the Equity of Education Systems in Europe[END_REF][START_REF] Eurydice | Organisation of the education system in the French Community of Belgium[END_REF][START_REF] Jacobs | Performances des élèves issus de l'immigration en Belgique selon l'étude PISA: une comparaison entre la Communauté française et la Communauté flamande[END_REF]Jacobs et al., 2009). Another consists in local studies using indirect indicators such as the pupils" first name [START_REF] Demeuse | Analyse critique des fondements de l'attribution des moyens destinés à la politique de discrimination positive en matière d'enseignement en Communauté française de Belgique[END_REF], or the feeling of being a person with immigrant background (Jacobs & Rea, 2007). However, we do not have much information about the segregation of Belgian pupils with an immigrant background (grandparents born in another country). This situation is certainly due to the lack of data resulting from the philosophical position of the government of the French Community of Belgium that "ethnic" and immigration categorization is not desirable [START_REF] Friant | En Belgique. Deux modes de régulation des effets d"une logique de quasi-marché [Priority education policies in Belgium: two modes for regulating the effects of a market logic[END_REF]Jacobs et al., 2009).

The following sections will present what we know about segregation and the specific policy intervention aimed at tackling it. We will keep in mind that, given the available data, this picture is not complete and shall mainly focus on socioeconomic and academic segregation between schools in secondary education, with a brief mention of ethnic segregation.

Segregation between schools

An empirical approach to the mechanisms fostering segregation requires that researchers work on empirical data. Unfortunately, this type of data is almost inexistent in the French Community of Belgium. Thus researchers tend to use information coming mainly from international studies, in order to build segregation indicators. Certain authors who have used this method reviewed several calculation modes (Baye et al., 2006;[START_REF] Demeuse | Measuring and Comparing the Equity of Education Systems in Europe[END_REF]. One of the chosen segregation indicators is the proportion of pupils from the target group (for example, pupils whose parents were born outside of Belgium) that should change schools in order to constitute an equivalent proportion of these pupils in each school (Gorard & Taylor, 2002).

Table 2, computed with the PISA 2003 dataset (Baye et al., 2006, p.42;[START_REF] Demeuse | Measuring and Comparing the Equity of Education Systems in Europe[END_REF][START_REF] Eurydice | Organisation of the education system in the French Community of Belgium[END_REF], shows several segregation rates according to specific target groups and makes it possible to compare the French Community of Belgium with other countries. Columns 1 to 4 of this Table illustrate the academic segregation between schools. For example, we can read from column 3 that in the French Community of Belgium, about six pupils out of ten from the group of the 10% of the weakest pupils in mathematics should change schools in order to attain an equivalent share of this group of pupils in each school, that is to say 10% in each school (segregation indicator of 58.9%, column 3). This indicator is only of about 28% in Finland. Columns 1 and 2, regarding literacy, show very similar results.

Columns 5 to 8 show indexes of segregation between schools according to the pupils" personal characteristics: socioeconomic segregation (column 5), segregation according to linguistic origin (column 7) and to parents" country of birth (column 8). The socioeconomic segregation index according to parents" profession is one of the highest in Europe (36%, versus 30% in France or 21% in Luxembourg). Given the different patterns of language origin and immigration in European countries, indexes of segregation regarding linguistic origin (49%) and the parents" place of birth (23%) are difficult to interpret.

Regarding "ethnic" segregation, from a more local point of view, [START_REF] Medhoune | L"école face à la diversité sociale et ethnique [School in view of social and ethnic diversity[END_REF] showed that in Brussels, where 40% of pupils came from an immigrant background, one primary school out of three enrolled 70% of pupils with an immigrant background. Furthermore, at the secondary education level, pupils with an immigrant background were overrepresented in the relegation curricula and schools, and underrepresented in the curricula and schools with a good reputation.

Segregation within schools

In the French Community of Belgium, as a tradition, there is a trend to put pupils with similar performances in the same classes [START_REF] Rey | Hétérogénéité des classes: une construction historique [Classes heterogeneity : a historical construction[END_REF]. As a result, there is a sort of "ability-grouping" within schools. According to the IEA Reading-Literacy (1991), the aggregation effect linked to the class is of about 20% in primary education, and 45% in the first stage of secondary education [versus10% in Finland, but 60% in the Netherlands [START_REF] Monseur | Gérer l"hétérogénéité des élèves. Méthodes de regroupement des élèves dans l"enseignement obligatoire [Managing heterogeneity of pupils. Grouping pupils in compulsory education[END_REF]]. In the French Community of Belgium, this aggregation effect increases when passing from the primary to the secondary level, whereas in other educational systems, such as in Finland, it decreases. Moreover, the practice of grade repetition, which is highly present in the French Community of Belgium, fills the role of managing heterogeneity: it contributes to the constitution of homogeneous classes [START_REF] Delvaux | Orientation et redoublement: recomposition de deux outils de gestion des trajectoires scolaires [Orientation and grade repetition : recomposition of two tools to manage school trajectories[END_REF][START_REF] Monseur | Gérer l"hétérogénéité des élèves. Méthodes de regroupement des élèves dans l"enseignement obligatoire [Managing heterogeneity of pupils. Grouping pupils in compulsory education[END_REF].

Other mechanisms can only be studied at a very local level. For example, [START_REF] Demeuse | Analyse critique des fondements de l'attribution des moyens destinés à la politique de discrimination positive en matière d'enseignement en Communauté française de Belgique[END_REF] observed the characteristics, in terms of birthdate and first names, of pupils from two classes of a primary school during two years. We can see in Table 3 that, in school year 1, all the pupils of the class A are "on time", whereas only half of those in the class B are. In school year 2, the composition of the class A stay unchanged, but the class B has lost 4 of its pupils, who are replaced by 4 newcomers, of whom 3 are grade repeaters. Moreover, the analysis of the pupils" first names, a method used by [START_REF] Felouzis | La ségrégation ethnique au collège et ses conséquences [Ethnic segregation in secondary education and its consequences[END_REF] in France, shows ethnic segregation between these two classes (the majority of the first names in the class A are common in French Speaking Belgium, while the majority of the first names in the class B show an immigrant background).

Segregation between curricula

Options and school curricula in the secondary education play a major role in the mechanisms of segregation. At 14-15 years old, pupils who have just completed a common core curriculum, have to choose or are oriented to a specific curriculum in their third year of secondary school. In reality, we observe that pupils are oriented negatively, less successful pupils being directed to less and less valued curricula (Demeuse & Lafontaine, 2005[START_REF] Discry-Theate | A l"aube de l"enseignement secondaire, quelle connaissance les jeunes ont-ils de l"arborescence des filières scolaires [What do pupils know about school tracks before secondary education[END_REF].

Focusing on the curricula only, Figure 1 shows that the average socioeconomic index (SES) is significantly different from one curriculum to another [START_REF] Demeuse | Parcours scolaire et inégalités de résultats [School experience and inequalities in results[END_REF][START_REF] Friant | Les liens entre recherche prospective, description du système éducatif et pilotage: un exemple en Communauté française de Belgique [Ties between prospective research, description of the educational system and "pilotage": an example from the French Community of Belgium[END_REF]. Academic curricula have a higher average SES than others. Inversely, technical and, above all, vocational curricula, have a lower SES.

There is thus a divide between academic curricula, with privileged pupils, and vocational ones, with underprivileged pupils. The SES seems to increase during secondary education, in all curricula. This surprising evolution actually translates the mechanisms that come into play between curricula: pupils from the academic curricula with non satisfactory school results tend to switch to technical or vocational curricula. These pupils are at the same time among the less privileged from their original curriculum, but also among the more privileged from their arrival curriculum. That is how a certain hierarchy of curricula is established, according to a social status that is linked with school success for some and school failure for the others.

Such a mechanism is also observed at the level of schools: those offering technical or vocational education draw pupils that have been pushed out from general education, with a lower socioeconomic status [START_REF] Delvaux | Les espaces locaux d'interdépendance entre écoles : étude de cas en Belgique francophone [Local areas of interdependence between schools : case study in French speaking Belgium[END_REF][START_REF] Friant | Les liens entre recherche prospective, description du système éducatif et pilotage: un exemple en Communauté française de Belgique [Ties between prospective research, description of the educational system and "pilotage": an example from the French Community of Belgium[END_REF][START_REF] Friant | Designing school level indicators in French Speaking Belgium[END_REF]. Some segregation according to immigrant background is also observed between curricula. In a survey led in secondary schools of the municipality of Brussels, Jacobs & Rea (2007) observed that 40% of the pupils General education had a mother or father born abroad, compared with 80% in technical and vocational education.

Specific policy interventions tackling segregation between schools

Acknowledging the major segregation in the educational system, the Government of the French Community of Belgium5 set out to encourage social mixing within schools, in particular through the "Contrat pour l"Ecole" (2005). To do this, two complementary lines of action were proposed: regulating enrolment in the secondary education and differentiating financing. In the first case, the motivation is to ensure that all parents receive truly identical treatment (setting up an enrolment record in all schools, managing enrolment according to common and identical rules avoiding favouritism). In the second case, by balancing the recruitment of more "difficult" schoolchildren with a larger school staff, the legislator aims to compensate for these difficulties by increasing funding and manpower.

Interventions affecting school enrolment procedures

In 2007, on the initiative of the Minister of Education Marie Arena, the government set up a simple system of enrolment regulation, known as the "enrolment law" (French Community of Belgium, 2007). The idea was to apply a "first-come, first-served" principle. The secondary schools had to keep a register of the available spots and the requests for enrolment, by keeping a track of each request in order of arrival starting from a date know to everyone. Every pupil requesting enrolment was accepted, until there were no more spots available. Pupils arriving later were placed on a waiting list. The purpose of this procedure, set up for the school year 2007-2008, was to tackle possible discrimination at enrolment, such as unjustified rejection, or the use of legally inacceptable criteria for rejection (such as former school results). Changing of schools during the same cycle as well as the expulsion of pupils were also made more difficult.

Even though these measures were modest and somehow only reinforced the possibility of monitoring the application of existing rules, this law was very badly received by a part of the public. According to [START_REF] Galand | Inscriptions scolaires et mixité sociale : beaucoup de bruit pour rien ?[END_REF], there are two reasons for this. First, the application of the law brought to light problems that have always existed, but that stayed hidden in the past: divergences between parents about the role of school, and differences between schools according to their popularity with students and parents (with queues before envy-inspiring, high SES schools). Second, these measures were received with a certain anxiety by some parents who made multiple registrations, which then undoubtedly increased competition for the most envied spots. This "enrolment law", whose aim was simply to make transparent the enrolment process for secondary education, thus had modest objectives in terms of social mixing. It nonetheless produced spectacular effects in the media, fuelled by some school principals and groups of parents denouncing a situation that had previously been favourable for them. An in-depth analysis of the media effects of enrolment regulation can be found in [START_REF] Delvaux | Débat sur la régulation des inscriptions scolaires en Belgique francophone: où se situent les désaccords? [Debate on regulating school registration in French speaking Belgium : where are the disagreements?[END_REF].

Following these negative reactions, a new law was prepared by Christian Dupont, the Minister of Education who succeeded Marie Arena, and replaced the old one in the school year 2008-2009 (Communauté française de Belgique, 2008). At the same time more ambitious (it is called the "social mixing law") and a priori more acceptable in public opinion (no more queues), the measures were also much more complex. The social mixing law kept some ingredients of the enrolment law (enrolment from a given date and accounting for available spots) but the principle of "first-come, first-served" was abandoned. Instead, priority rules were instituted and a random factor was applied when the demand still surpassed the supply.

In practical terms, in some very desirable schools where the demand surpassed the number of available spots, a number of rules were to be applied, in order to manage the surplus of demand and to encourage social mixing within these schools. Without going into the details, the pupils living near the school and those with a lower SES than the average of the school had more a greater chance of being enrolled. For the other pupils, independently from their order of arrival, the process had the characteristics of a random drawing.

The social mixing law was applied in November and December 2008 for the start of the school year 2009-2010 and, just like the previous one, made the headlines. As a result, the Minister of Education announced already in December 2008 that it had to be changed (Christian Dupont on the RTBF, December 10, 2008). One of the reasons is once again to be found in the criticisms of some of the parents for whom this law unacceptably undermined their freedom of choice. But above all, multiple registrations caused major problems and dramatically reduced the chances of satisfying parents" preferences.

After the June 2009 elections, the new Minister of Education, Marie-Dominique Simonet, prepared the changes and implemented the new law (French Community of Belgium, 2010).

In order to correct the issues of the previous version, the random drawing is abandoned.

Parents" preferences are maximised by asking them to rank several schools, and the management of enrolment is centralized by a commission in order to avoid multiple registrations6 . It is still contested by some parents, but its application at the start of the school year 2010-2011 went without major problems.

Have these interventions on school enrolment procedures had an effect of desegregation? It is too soon to say, but this should be the case in the near future. There is little doubt, however, that if a desegregation effect is observed, it will not be spectacular.

Interventions on school funding

While actions aimed at greater social mixing by regulating school enrolment have been implemented and greatly criticised, the idea of instating differentiated financing is following another path, initially inspired by a compensatory approach. The "Contrat pour l"École" (Contract for School) initiated this project by studying the efficiency and feasibility of directly linking the calculation of the number of teaching hours to the socio-economic background of each pupil in the school (Government of the French Community of Belgium, 2005, p. 46). An interuniversity research project commissioned by the Government to be performed by the universities of Mons and Liège had the goal of setting up new measures to fight school segregation thanks to a modulation of the financing of primary and secondary schools (Demeuse et al., 2007). The Government received the research report in March 2007 and pursued its reflections in this way.

This study envisages the setting up of a general school funding formula that encompasses all the components determining school funding (currently the numbers of pupils, their grade and curriculum), plus other parameters, particularly the socioeconomic composition of the school.

The interuniversity team tested several scenarios linking the schools" SES with extra staff by a continuous function.

The idea was the following [START_REF] Demeuse | Differentiated financing of schools in French speaking Belgium: prospectives for regulating a school quasi-market[END_REF]): if we accept that any school, personified by its head, tries to maximise its teaching staff, we can assume that rational choices will be made in order to attain this goal. The means that the school head can use to this end will depend upon the implementation of a policy of social mixing among schoolchildren in view of obtaining optimal financing from the public authorities if the compensatory mechanisms are sufficient with respect to the supposed difficulty that this social mixing may engender. Accordingly, the dissemination of information related to financing measures must be guaranteed at least for schools.

However, in the workings of the French-speaking Belgian school quasi-market, the maximisation of the "quality" of the public recruited also plays an important role, so that schools do not get any "profit" in having an underprivileged public. Because it is easier, for school workforces of the same size, to educate a certain type of public, institutions in a high position in the local school hierarchy [START_REF] Delvaux | Les espaces locaux d'interdépendance entre écoles : étude de cas en Belgique francophone [Local areas of interdependence between schools : case study in French speaking Belgium[END_REF] select pupils with a privileged background. In this sense, the use of a formula that weights school staff funding according to the social status of pupils could make it possible to favour the recruiting of underprivileged pupils, as long as the supplementary means are considered sufficient and the supposed results (because they are not measured effectively via national examinations, for example) remain acceptable in terms of client expectations -parents who wish to entrust their children to institutions that take the risk of modifying their recruitment policy.

The financing measures implemented in the French Community of Belgium at the beginning of the 2009 school year abandoned this idea of incentive for social mixing, and focussed only on a compensatory approach. They are characterised by an increase in the budget (from €22 million -0.45% of the total budget -it goes to €62 million -1.35% of the total budget -for all levels of education) and a desire to concentrate supplementary funds in schools with an underprivileged population. The distribution of these funds is illustrated in Figure 2 After the election in June 2009, the new government had to implement this law for the start of the 2010-2011 school year with a lower budget than was foreseen at the time of its adoption. This was done by proposing a reallocation of funds from the most privileged schools to the most underprivileged ones. This idea was probably inspired from a scenario described in the research report, but neglected the underlying principle of the scenario, which was to add an effect of incentive redistribution by penalising schools whose pupils are on average privileged and that have little socio-economic mixing. The reactions that ensued demonstrated the political impossibility of such a reallocation of funds.

Conclusions and reflection

Segregation, particularly socioeconomic segregation between schools, is a major issue in the French Community of Belgium. The functioning of the quasi-market tends to foster this. Acknowledging this phenomenon, the government is trying to tackle the problem. However, in the context of this Community, it is very difficult to set up specific interventions that have a desegregation effect.

Interventions on enrolment procedures in the French Community of Belgium generally cause great turbulence. The freedom of school choice is indeed considered a basic right that is difficult to question. However, the last law regulating enrolment procedures was implemented without major problems. The key is that it tries to maximise parents" preferences by asking them to rank several schools, and that these preferences are treated by a centralized commission. Moreover, a great effort has been made to provide information by creating a website where parents can find specific details and useful tools7 .

Interventions on school funding are less unpopular. However, in order to have an effect of desegregation, these interventions must be broad enough, and include an incentive effect that penalizes schools that will not play the desegregation game. Such a mechanism has been politically impossible to implement, at least as it has been presented so far.

Another possibility that has been studied but not applied is worth noting. In a research project commissioned by the government, Delvaux et al. (2005) studied the feasibility of creating "school catchment areas" in which the schools could work together no matter what network they belong to, especially from the point of view of courses offered. It also proposed a system of collective treatment of preferences in choosing schools, in order to regulate the quasimarket even more while still respecting parents' freedom of choice. The authors believed that such actions could limit the phenomenon of segregation between schools. The various tensions arising from these proposals did, however, make it difficult to continue along this path.

There is no evaluation of the effectiveness of policy interventions yet but it should come in the near future. Indicators making it possible to evaluate the potential social mixing resulting from these new measures should be built at the micro level, i.e. at the level of each school (average socio-economic index score, evolution of this score, standard deviation of the score, etc) and/or at the system level [START_REF] Demeuse | Measuring and Comparing the Equity of Education Systems in Europe[END_REF][START_REF] Eurydice | Organisation of the education system in the French Community of Belgium[END_REF] in order to evaluate the attainment of the goals and, if necessary, to end these measures once the goal of social mixing is reached. However, there is little doubt that the desegregation effects of the policy interventions will not be spectacular in a near future.

Finally, the production of such indicators could be a means of promoting schools" autonomy, by making them able to know their situation in terms of segregation and relegation. In this case, the schools would be regarded as real units, and not simply operators undergoing a certain number of educational policies [START_REF] Ross | Needs-based resource allocation in education[END_REF]. Each school could therefore be characterized by a set of indicators that could be used by the school principals in their pursuit of quality. Indicators such as grade repetition treatment [START_REF] Demeuse | Differentiated financing of schools in French speaking Belgium: prospectives for regulating a school quasi-market[END_REF]Friant et al., 2008;2010) could inform the school principals about the school level mechanisms that have a systemic impact and create academic and socioeconomic segregation between schools. Therefore, they could help them to determine and to implement actions. However, it is not advisable that this autonomy of the schools prevent the public authority"s right to oversee them, especially by the means of external evaluations of the pupil"s outcomes, which give full meaning to indicators such as grade repetition rates.

Figure 1 :

 1 Figure 1: Average SES by curriculum and grade in the school year 2005-2006(Friant et al., 2008)

Figure 2

 2 Figure2-illustration of the school workforce and financing according to the Government of the French Community(French Community, 2009)

Table 1 -Types of segregation and possible interventions Social categories Socioeconomic Academic "Ethnic" Separation Between curricula

  Table 1 illustrates this with an example of research results for the French Community of Belgium and places the specific policy interventions on this grid.

		Research		Interventions	Research Interventions Research	Interventions
		Friant, Demeuse and Derobertmasure (2008)		Baye et al. (2006)	Jacobs & Rea (2007)
				 Interventions
				on school
	Between Schools	Demeuse Baye (2007)	and	enrolment procedures  Interventions	Demeuse and Baye (2007)	Medhoune (1998)
				on school
				funding
	Within				Demeuse	Demeuse
	schools				(1996)	(2002)

Table 2 -

 2 Indices of segregation between schools (adapted from[START_REF] Demeuse | Measuring and Comparing the Equity of Education Systems in Europe[END_REF]

			literac
		literacy	y	math	math				parents
		(10%	(under	(10%	(unde	parents'			'
		weakest	level	weakest	r level	occupationa	gende	linguisti	country
	Country*	)	2)	)	2)	l status	r	c origin	of birth
	Finland	25	32,9	27,7	33,7	30,8	7,5	65,4	45,3
	Island	26,2	19,3	26,1	21,5	**	8,4	65,3	30,7
	Sweden	31,4	26,8	32,3	24,5	29,3	8,5	57,9	31,6
	Norway	31,8	24,1	29,9	21,1	**	8,4	51	35,7
	Poland	34,5	27,7	31,8	23,3	42,5	7,8	95,5	93,9
	Denmark	38,3	30,5	36,5	29,7	29,2	9,4	60,9	34,1
	UK	38,4	33,7	40,7	32,8	33,9	14,9	64,5	32,4
	Latvia	39	30,2	40,9	28,5	28,8	9,1	86,7	37
	Luxemburg	39,6	32,7	39,3	32,9	21,2	13	26,2	14,2
	Ireland	40,8	39,8	37,4	30,5	30,9	28,3	83,1	21,6
	Spain	42,6	30,5	43,7	30,3	30,9	11,4	74,7	38,6
	Greece	50,3	36,2	51	28,2	31,1	10,5	70,2	37,7
	Turkey	50,8	30,6	49,5	22,9	**	13	85	67,5
	Slovak Republic	52	37	52,4	40,8	35,9	17,4	81,3	32,4
	Belgium (German
	Community)	52,1	46,5	56,2	46,4	27,4	15,3	44,6	21,2
	Portugal	54,3	41,5	52,5	34	29,4	9,2	71,5	35
	Czech Republic	55,3	42,6	55	46,1	40	18,8	83,7	36,8
	Netherlands	56,2	54,2	56,6	55,9	33,9	10,8	55,8	33,9
	France	56,3	48,3	57,5	50,4	30,8	15	57	31
	Italy	56,5	43,6	57,6	38,1	33,6	23,5	72,2	38
	Belgium (Flemish
	Community)	57,6	54,2	59	56,5	39,4	20,5	60,2	33,6
	Austria	59,9	50,4	55,9	47,7	31,5	28,3	47	34,6
	Belgium (French Community)	60,2	44,2	58,9	42	35,9	14,7	49	22,8
	Hungary	60,2	47	60,6	44,9	36	18,5	84,2	33,9
	Belgium (As a country)	61,1	49,9	59,2	50,4	38,4	17,9	55,8	34,7
	Liechtenstein	63	62,9	63,6	61,8	**	5,9	17,6	16,2
	Germany	64,7	48,7	62,9	49,8	36,8	12,4	52,3	37,9
	* No data available for Cyprus, Lithuania, Malta, Slovenia, Estonia, Bulgaria and Romania.
	** No data available

Table 3 -

 3 Evolution of the composition of two classes during two school years (adapted from[START_REF] Demeuse | Analyse critique des fondements de l'attribution des moyens destinés à la politique de discrimination positive en matière d'enseignement en Communauté française de Belgique[END_REF]

			School year 1			School year 2
					on
		on time "Belgian" first name quitting	time "Belgian" first name newcomers
	Class A	9/9	8/9	0/9	9/9	8/9	0/9
	Class B	5/9	3/9	4/9	3/8	2/8	4/8

Table 4 -

 4 Average SES according to the type of secondary school (school year 2005-2006)(Friant et al., 2008)

		General Mixed (academic + technical-vocational) Technical -vocational
	Average SES 0.38	-0.04	-0.23
	% of pupils	27.3%	60.1%	12.6%

Secondary education is structured in three main curricula: general, technical or vocational education, artistic education being included either into technical or vocational one.

Our translation.

Our translation.

The socio-economic index is based on the student's district of origin (the notion of district is a statistical division of the territory(Demeuse, 2002, p. 219). A synthetic socio-economic index score is assigned to each district in Belgium, on the basis of 11 variables within the framework of 6 domains (income per inhabitant, level of the certificates, unemployment rate, employment rate and proportion of people receiving welfare, professions, comfort of housing). Thus each student is assigned the socio-economic index score of the district where he lives and somehow brings this index score to the level of the institution. From a statistical point of view, this is a normal distribution metric variable that varies between -3.5 and 3.5. It is recalculated every three years on the basis of the latest statistics available

The French Community of Belgium has been governed during the considered period by a centre-left coalition, providing several ministers of education.

Such a system of collective treatment of preferences in choosing schools had first be mentioned in a research report commissioned by the Government[START_REF] Delvaux | Les bassins scolaires : de l'idée au projet. Propositions relatives aux domaines d'intervention, aux instances et aux territoires [School districts: from idea to plan[END_REF], on the basis of a description of school choice systems in several countries.

http://www.inscription.cfwb.be

Acknowledgements

The authors would like to thank Ramona Shelby, from the University of Mons, for her help in translating this chapter from French to English.