Relationship between radiological grading and clinical status in knee osteoarthritis. a multicentric study

RESEARCH ARTICLE Open Access Rela ionship be ween adiological g ading and clinical s a us in knee os eoa h i is. a mul icen ic s udy Daniel He nández-Vaque o 1* and José Manuel Fe nández-Ca ei a 2 Abs ac Backg ound: Con o e sy exis s ega ding he ela ionship be ween adiog aphic indings and clinical s a us in knee os eoa h i is. Al hough he su gical indica ion o o al knee a h oplas y (TKA) should be based on pain, clinical s a us, and he de e io a ion o quali y o li e, he adiog aphic s udy is he mos commonly used c i e ion o p eope a i e e alua ion. The objec i e o his s udy is o ind ou he ela ionship be ween he Ahlbäck classi ica ion and clinical s a us in pa ien s unde going TKA. Me hods: 1329 p o ocols we e collec ed om p eope a i e s udies in ou mul icen ic wo king g oups ( he In e ax, Du acon, Sco pio, and T ia hlon Spanish g oups) in 30 Spanish hospi als. Mean age was 70.4 yea s (SD: 6.8; ange: 35 o 98); 76.3% o pa ien s we e women. Pa ien s en e ed he s udy whene e he su geon ound ha medical ea men was insu icien o con ol pain and unc ional limi a ion. Da a we e collec ed using elec onic Case Repo Fo ms, and included Ahlbäck g ading sco es, Hospi al o Special Su ge y Knee Sco e (HSS), SF-12, and o he clinical and epidemiologic a iables. Resul s: Acco ding o he Ahlbäck g ading sys em, pa ien s we e di ided as ollows: 243 g ade I (18.3%), 358 g ade II (26.9%), 416 g ade III (31.3%), 241 g ade IV (18.1%), and 71 g ade V (5.3%). As o HSS, he ollowing sco es we e ob ained: <60 poin s in 925 pa ien s (69.6%), 60 o 69 poin s in 286 pa ien s (21.5%), 70 o 84 poin s in 112 pa ien s (8.4%) and 85 o 100 poin s in 6 pa ien s (0.5%). Sco es showed a s a is ically signi ican di e ence depending on Ahlbäck g ade, wi h a clea endency owa ds dec ease in HSS sco es as he Ahlbäck g ade inc eases (p<0.001). Howe e , he HSS sco e di e ence be ween Ahlbäck g ades I and V was o 9.56 poin s only. Compa ing he s a us o he pa ien s a he s a (1994) and a he end (2010) o he da a collec ion p ocess, we obse ed ha pa ien s who unde wen su ge y in he las yea s we e olde and showed a lowe Ahlbäck g ade. Conclusions: We ound a ela ionship be ween Ahlbäck g ading and he p eope a i e clinical sco e. The ange o a iabili y o he HSS sco e be ween he di e en Ahlbäck g ades is small. Backg ound Knee Os eoa h i is (OA) is a equen p ocess especially a ec ing women o e age 50. Among Uni ed S a es adul s, he p e alence o knee OA and symp oma ic knee OA is 37.4% and 12.1%, espec i ely (4.3 million olde US adul s). Al hough i may a ec all kinds o people, i is mo e equen in indi iduals wi h g ea body mass index (BMI ≥30), g ea e age, aces/e hnici ies such as non- Hispanic Blacks, and among men wi h manual labo occupa ions [1]. Con o e sy exis s ega ding he ela ion- ship be ween adiog aphic and clinical s a us in knee OA [2]. S anda d adiog aphs o he knee a e an in eg al pa o he p ima y assessmen o os eoa h i is. Al hough he Ahlbäck classi ica ion [3] o knee os eoa h i is is o e 50 yea s old, i is s ill commonly used in heuma ology and o hopedics o he ollow-up o disease p og ession, and as a classi ica ion c i e ion in clinical ials and epi- demiological s udies. The Ahlbäck classi ica ion is p ob- ably he mos quo ed classi ica ion in he li e a u e on p eope a i e s udies and is also used o su gical indica- ions such as o al knee a h oplas y (TKA) o unicom- pa men al knee a h oplas y, a h oscopic deb idemen , * Co espondence: [email p o ec ed] 1 School o Medicine, Uni e si y o O iedo, Julian Cla e ia, 6, 33006 O iedo, As u ias, Spain Full lis o au ho in o ma ion is a ailable a he end o he a icle © 2012 He nández-Vaque o and Fe nández-Ca ei a; licensee BioMed Cen al L d. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/2.0), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. He nández-Vaque o and Fe nández-Ca ei a BMC Musculoskele al Diso de s 2012, 13:194 h p://www.biomedcen al.com/1471-2474/13/194 ibial os eo omy, e c. The Ahlbäck sys em is used o en be- cause i is a he simple and ough, and hus a good ep o- ducibili y can be expec ed e en when obse e s a e no pa icula ly skilled wi h i s use [4]. TKA is a equen ly used p ocedu e o knee a h i is when conse a i e measu es do no wo k. Al hough he su gical indica ion o TKA should depend on clinical s a us, a adiog aphic e alua ion — ollowing he Ahlbäck c i e ia—is he mos commonly used g ading sys em o p eope a i e assessmen . Some publica ions by scien i ic socie ies [5] ha e acknowledged he Ahlbäck classi ica- ion as a alid aid o he selec ion o he su gical p o- cedu e. The Hospi al o Special Su ge y Knee-Ra ing Sco e (HSS) [6] is one he mos egula ly used ques ion- nai es o assess knee s a us, bo h p eope a i ely and a e TKA. This classi ica ion sys em assigns a maximum o 100 poin s, which a e subdi ided in o six ca ego ies: pain, unc ion, ange o mo ion, muscula s eng h, lexion con ac u e, and s abili y. Among he ools o assessing quali y o li e, he Sho Fo m 12 (SF-12) —mo e p ecisely, i s men al and physical componen s—is one o he mos widely used, and has been alida ed in se e al popula ions and coun ies. I is easy o sel -comple e and i has been employed o ollow he changes in heal h- ela ed quali y o li e a e a su gical p ocedu e, such as a TKA [7]. An ad an age o mul icen e s udies is ha hey po - ay he ac ual si ua ion o he medical p ac ice, as opposed o o he ypes o s udies which may come om high-le el, specialized cen e s. The he e ogenei y o he su geons' le el o aining, age, wo king si ua ion, and he ac hey wo k a di e en cen e s, en ich he esul s and may in o m he heal h au ho i ies abou he usage o a gi en p ocedu e. The aims o his wo k a e: 1. To analyze he ela ionship be ween he Ahlbäck g ade and he HSS and SF-12 sco es in a se ies o knees unde going TKA included in a mul icen ic s udy o e a 17-yea pe iod. 2. To disco e whe he he e exis s any a ia ion in such ela ionships depending on he pa ien 's gende and age. 3. To ind ou i he e had been any changes in he Ahlbäck g ade and he clinical- unc ional s a us o TKA pa ien s o e he 17-yea pe iod. The ul ima e goal o ou s udy is o de e mine whe he classi ying pa ien s acco ding o he Ahlbäck g ading scale co ela es wi h he clinical and unc ional s a us o he pa ien s. Me hods Du ing a 17-yea pe iod (1994–2010), clinical and adio- g aphic ques ionnai es o pa ien s wi h knee a h i is accep ed o TKA ea men in ou mul icen e wo king g oups (In e ax, Du acon, Sco pio and T ia hlon Spanish g oups) in 30 gene al hospi als we e collec ed. Fo y-one su geons we e in ol ed in he s udy. Di e en su geons had di e en le els o aining, and hospi als a ied eno mously in e ms o size, le el, and a ea o in luence. Pa ien s en e ed he s udy whene e he su geon ound ha physical and medical ea men s (NSAIDs and analgesics in ake o a leas six mon hs) we e insu i- cien o con ol pain and a se e e unc ional limi a ion was p esen . Besides a he p eope a i e assessmen , he ques ionnai e was illed in wi h da a on he in e en ion and he clinical and adiog aphic s a us a six mon hs a e TKA and hen annually. Pa ien s we e excluded om he s udy i hey needed e ision su ge y o i hey did no a end he scheduled appoin men s. All pa ien s signed an in o med consen o m which desc ibed he sugges ed su gical p ocedu e, he o eseeable isks, any po en ial complica ions, and he possibili y o abandon- ing he s udy olun a ily. P eope a i e and ollow-up da a we e enc yp ed wi h a s udy-speci ic nume ic se . The s udy was app o ed by he San Agus ín Hospi al Resea ch Commi ee. Da a collec ion s a ed when he pa ien was included in he su ge y wai ing lis ; a ha momen , a clinical and adiog aphic p eope a i e assessmen was ca ied ou . The su geon illed in he HSS ques ionnai e, whe eas he pa ien comple ed he SF-12 o m. Any adiological indings in he adiog aphic s udy we e eco ded. Two p ojec ions we e examined: on al and la e al, wi h he knee ully ex ended in weigh -bea ing posi ion. The Ahlbäck g ade [3] o each case was ag eed upon by he su geon who added he case o he s udy and he adiologis who pe o med he adiog aphic assess- men . Pa ien s who could no achie e ull ex ension o he knee wi h es ing limb we e disca ded o his s udy. Ou o he o al 1717 ques ionnai es ob ained, 1329 cases we e assessed; hey all had gone h ough he ull p eope a i e clinical and adiog aphic assess- men . In 577 cases, he men al (MCS) and physical (PCS) componen sco es o he SF-12 o m we e also ob ained. Mean age o he pa ien s was 70.4 yea s (SD: 6.8, ange: 35 o 98) (Figu e 1), and 76.3% we e women. Table 1 shows he s udy g oup in which he pa ien s we e included, and Figu e 2 shows hei dis- ibu ion h oughou he yea s o he s udy. Da a we e collec ed using elec onic Case Repo Fo ms (eCRF), and included Ahlbäck g ading, HSS, and o he clinical and epidemiologic a iables. S a is ical analyses we e pe o med wi h he SPSS 19 so wa e. Desc ip i e s a is ics was ca ied ou o all a iables. The di e ences in HSS sco es be ween he i e Ahlbäck g ades we e analyzed wi h analysis o a iance (ANOVA) and he S u- den 's - es when Ahlbäck g ading was g ouped (g ades I He nández-Vaque o and Fe nández-Ca ei a BMC Musculoskele al Diso de s 2012, 13:194 Page 2 o 8 h p://www.biomedcen al.com/1471-2474/13/194 o IV e sus g ade V). The Mann–Whi ney non- pa ame ic es was used o analyze he Ahlbäck g ade, compa ing he i s 50 wi h he las 50 cases. The gene al linea model was used o analyze he ela ionship be ween Ahlbäck and HSS, aking gende as an in e ac ing a iable, he HSS sco e as a dependen a iable, and Ahlbäck and gende as ixed ac o s. S a is ical signi icance was achie ed when he p alue was <0.05. Resul s Ahlbäck g ading [3] was dis ibu ed in o i e g oups (Table 2). Mo e han 75% o he pa ien s we e classi ied as ei he g ade II, III o IV, and 18.3% we e classi ied as g ade I. Rega ding HSS, we ound an a e age sco e o 53.12 poin s (SD: 12.56): 925 pa ien s showed an HSS sco e <60 poin s (69.6%); 286, be ween 60–69 (21.5%); 112, be ween 70–84 (8.4%); and 6, be ween 85–100 (0.5%) (Figu e 3). The e was a s a is ically signi ican di - e ence in he HSS sco es depending on he Ahlbäck g ade, wi h a clea endency owa ds dec ease in HSS sco es as he Ahlbäck g ade inc eases (p<0.001, ANOVA) (Table 3). Howe e , he HSS sco e di e ence be ween Ahlbäck g ades I and V was o only 9.56 poin s (Figu e 4). No ela ionship was ound be ween he MCS p o ile o SF-12 and he Ahlbäck g ade, bu a signi ican di e ence (p=0.006, - es o Equali y o Means) was disco e ed when analyzing he PCS p o ile di e en ia ing g ades I-IV (558 pa ien s) and g ade V (19 pa ien s). While s udying he ela ionship be ween Ahlbäck g ade and HSS sco es aking in o accoun he gende o he pa ien s, we ound ha ou comes di e ed depending on gende (p=0.042), especially in Ahlbäck g ade III: men sco ed 55.2 poin s and women, 50.9 (mean alues) (Figu e 5). Ahlbäck g ade dis ibu ion was compa ed be ween he i s 50 cases (en e ed in o he s udy be ween 1994 and 1996) and he las 50 cases (2009 and 2010). As Figu e 6 shows, he e is a di e ence in dis ibu ion acco ding o he Ahlbäck g ade: hose pa ien s who en e ed he s udy in he la e yea s had knees wi h lowe Ahlbäck g ades (P=0.007, U Mann–Whi ney). Simila ly, he e we e di - e ences be ween he mean ages o he pa ien s included a he beginning o he se ies (68.43; SD: 6.321; ange: 52–81) and hose en e ed a he end (70.29; SD: 5.567; ange: 59–80) (p=0.038). Analyzing bo h se s o da a allowed us o deduc ha pa ien s unde going TKA su - ge y in he las yea s we e olde and hei knees exhib- i ed lesse deg ees o adiog aphic in ol emen . Discussion I can be s a ed ha he adiog aphic classi ica ion o knee a h i is is based ei he on he deg ee o join space na owing, as wi h he Ahlbäck g ading [3], o on he Figu e 1 Age dis ibu ion by gende . Table 1 G oups and numbe o TKAs N% Du acon 70 5.3 In e ax 751 56.5 Sco pio 426 32.1 T ia hlon 82 6.2 To al 1329 100.0 He nández-Vaque o and Fe nández-Ca ei a BMC Musculoskele al Diso de s 2012, 13:194 Page 3 o 8 h p://www.biomedcen al.com/1471-2474/13/194 p esence o os eophy es, such as he classi ica ion p o- posed by Kellg en and Law ence [8]. Some au ho s de- end he la e [9], a guing ha ma ginal os eophy es a e he mos sensi i e adiog aphic ea u e o he de ec ion o os eoa h i is, mo e han join space na owing, sub- chond al scle osis, and subchond al cys s. Bo h classi i- ca ions show a good co ela ion [10] and he Ahlbäck sys em seems easy o apply and sui able o he assess- men o medial compa men a h i is o he knee, he mos equen ly a ec ed compa men in knee a h i is; hus, i appea s o be pa icula ly use ul o he o ho- pedic ea men o knee diso de s [11]. Al hough he ela ionship be ween adiog aphic knee OA and he need o TKA is no ye ully es ablished, se- e e os eoa h i is and ange o mo ion es ic ion e en- ually necessi a e su gical in e en ion. I should be men ioned ha in ou s udy mo e han 18% o he pa ien s in he wai ing lis o TKA had OA o he knee g ade I acco ding o he Ahlbäck classi ica ion [3], and in g ade I cases, he adiog aphic images we e close o no mali y. On he o he hand, i we ake in o accoun he HSS sco e a he s a o he s udy, 112 pa ien s showed a sco e >70 poin s, which ansla es as a mild clinical and unc ional in ol emen . Thus, he i s ind- ing o ou s udy was he asce ainmen ha he e is a g oup o pa ien s showing no ele an adiog aphic ind- ings which a e included in o he wai ing lis o TKA implan a ion. I is possible ha o he ac o s such as he social en i onmen , a subop imal communica ion be- ween he pa ien and he physician, he di icul y o assessing pain o he lack o o he esolu i e he apeu ic measu es may modi y he demand o TKA. Figu e 2 Yea o inclusion by g oup. Table 2 Ahlbäck g ade in he se ies Ahlbäck g ading N% I Na owing o he join space (wi h o wi hou subchond al scle osis) (*) 243 18.3 II Obli e a ion o he join space 358 26.9 III Bone de ec /loss <5 mm 416 31.3 IV Bone de ec /loss be ween 5 and 10 mm 241 18.1 V Bone de ec /loss >10 mm, o en wi h subluxa ion and a h i is o he o he compa men 71 5.3 To al 1329 100.0 (*) Join space na owing is de ined by a space in e io o 3 mm o in e io o hal o he space in he o he compa men (o in he homologous compa men o he o he knee). He nández-Vaque o and Fe nández-Ca ei a BMC Musculoskele al Diso de s 2012, 13:194 Page 4 o 8 h p://www.biomedcen al.com/1471-2474/13/194 We ha e obse ed a good co ela ion be ween Ahlbäck g ade [3] and he HSS: whene e he o me inc eases, he HSS sco e dec eases. We ha en' ound in he li e a- u e any publica ions which may suppo o con adic his conco dance. The e a e se e al s udies ha do no ind any ela ionship be ween knee pain and adio- g aphic changes. La sson e al. [12] s a e i is di icul o co ela e ch onic knee pain, he diagnosis o adio- g aphic OA, and unc ional capaci y. In his a icle, he p opo ion o pa ien s wi h knee pain ound o ha e adiog aphic OA anged om 15–76%, whe eas in he case o hose wi h adiog aphic knee OA he p opo ion wi h pain anged om 15–81%. Conside able a ia ion occu ed wi h x- ay iew, pain de ini ion, OA g ading and demog aphic ac o s. Bedson and C o [13] men- ion ha he esul s o knee x- ays should no be used in isola ion when assessing indi idual pa ien s wi h knee pain, and conclude ha knee pain is an imp ecise ma ke o adiog aphic knee os eoa h i is, al hough he mo e se e e he adiog aphic os eoa h i is, he mo e likely he e a e o be accompanying symp oms. The HSS scale we used does no assess only pain, bu also unc ion and ange o mo ion. Al hough i canno be desc ibed as a "quali y o li e scale", i does analyze some ac i i ies (such as s ai climbing, he need o assis i e walking de ices, e c.) which a e pa o daily li e. On he o he hand, we ha e obse ed ha he e is only a e y small di e ence in HSS sco e be ween Ahlbäck g ades I and V (only 9.56 poin s). This would suppo he idea ha he HSS scale does no disc imina e adiologic in ol emen , meaning ha a sca ce numbe o adiog aphic lesions, o small ones, may ne e heless al e he clinical and unc ional s a us o he pa ien . The Ame ican Knee Socie y Sco e (AKSS) has been alida ed and is esponsi e and ep oducible. Howe e , i also su - e s om high in e - and in aobse e a ia ion when he Figu e 3 HSS sco e in o e all se ies. Table 3 Ahlbäck g ade and HSS sco e Ahlbäck g ade N Mean HSS SD S anda d E o Mean 95% con idence in e al o mean Min Max Lowe limi Uppe limi I 243 56.91 10.750 0.690 55.55 58.27 32 82 II 358 55.64 12.019 0.635 54.39 56.89 22 95 III 416 51.86 12.966 0.636 50.61 53.11 3 95 IV 241 49.44 12.699 0.818 47.83 51.05 18 94 V 71 47.35 12.322 1.462 44.44 50.27 12 73 To al 1329 53.12 12.596 0.346 52.44 53.80 3 95 He nández-Vaque o and Fe nández-Ca ei a BMC Musculoskele al Diso de s 2012, 13:194 Page 5 o 8 h p://www.biomedcen al.com/1471-2474/13/194 assessmen s a e pe o med by less expe ienced doc o s and nu ses [14]. E en hough we could no ge he SF-12 ques ionnai es om all he pa ien s in ou se ies, we obse ed ha he e was no ela ionship be ween he g ade o adiog aphic in ol emen and he men al heal h componen scale sco es o he SF-12. No did we ind such a ela ionship wi h he physical componen scale, ex- cep i we g ouped pa ien s wi h g ades I-IV e sus pa ien s wi h g ade V acco ding o he Ahlbäck classi ica- ion. By pe o ming his associa ion, we did ind a Figu e 4 HSS sco e and Ahlbäck classi ica ion ela ionship. Figu e 5 Rela ion be ween HSS sco e and Ahlbäck g ade by gende . He nández-Vaque o and Fe nández-Ca ei a BMC Musculoskele al Diso de s 2012, 13:194 Page 6 o 8 h p://www.biomedcen al.com/1471-2474/13/194 s a is ically signi ican di e ence. Acco ding o hese ind- ings, i seems ha he e is no ela ionship be ween adio- g aphic classi ica ion and quali y o li e wi h he excep ion o he physical appea ance o pa ien s wi h mo e ad anced adiog aphic a h i is. We ha e no ound di e ences in HSS sco es be ween Ahlbäck g ades when aking in o conside a ion he age o pa ien s. As o gende , di e ences we e only p esen be ween men and women wi h g ade III. We did no ound any explana ion o his inding. In he s udy by Mu aki e al. [15] knee pain was s ongly associa ed wi h join space na owing, especially in men, while women ended o expe ience knee pain e en wi hou adio- g aphic OA. The p e alence o knee pain was age- dependen in women, bu no in men. When compa ing he s a us o pa ien s who en e ed he s udy in 1994 and in 2010, we obse ed ha nowadays pa ien s a e added o he TKA wai ing lis wi h lesse Ahl- bäck g ades and ha hei age has inc eased. The easons behind hese changes may ha e o do wi h an ea lie indi- ca ion o TKA bo h on he pa o he su geon and he pa ien , since i is known his p ocedu e leads o posi i e esul s. The g ea e mean age may be due o he highe su i al a e o he pa ien s. In any case, bo h indings would equi e a mo e speci ic analysis. Ou s udy has some limi a ions. I s mul icen ic na u e has he ad an age o p o iding an o e iew o he ac ual clinical p ac ice in hospi als and o a he e ogeneous g oup o su geons, al hough his may also become a dis- ad an age, o i could al e he homogenei y o he esul s and in oduce bias in he measu emen c i e ia. E en hough all he pa icipa ing su geons we e amilia wi h bo h he Ahlbäck classi ica ion [3] and he HSS scale and used hem on a egula basis, he e is no way o gua an eeing he da a ha e been p ope ly collec ed. In ou se ies, he adiog aphic s udies we e ca ied ou homogeneously wi h ull ex ension o he knee and es - ing limb. E en hough some deg ee o lexion is ecom- mended, since his is a mul icen ic s udy in ol ing many su geons, ull ex ension seemed o be easie o e- p oduce and s anda dize. Since all adiog aphs we e aken in his posi ion, he o e all esul s should no be comp omised no al e ed. I he s udy had been ocused on knee OA p og ession, i would ha e been indispen- sable o pe o m he adiog aphic s udy wi h he knee sligh ly lexed [16]. Knee OA assessmen and g ading is a om sol ed. We did ind a ela ionship be ween Ahlbäck g ades and he p eope a i e clinical sco e. Ne e heless, he ange o a iabili y o he HSS sco e be ween he di e en Ahl- bäck g ades is small, a ac ha educes i s use ulness in clinical p ac ice. Besides he scales analyzed in his s udy, o he echniques a e needed o disc imina e he a h i ic knee in ol emen aking in o accoun he Figu e 6 Ahlbäck g ade o i s and las cases included. He nández-Vaque o and Fe nández-Ca ei a BMC Musculoskele al Diso de s 2012, 13:194 Page 7 o 8 h p://www.biomedcen al.com/1471-2474/13/194 commonness o his p ocess and he socioeconomic imb ica ions he apeu ic decisions ha e on hese pa ien s. Conclusions We ound a ela ionship be ween he Ahlbäck classi ica- ion scale and he p eope a i e clinical sco e, bu he ange o a iabili y o he HSS sco e be ween he di e- en Ahlbäck g ades is small. One i h o he pa ien s who ecei e a TKA p esen a g ade I in he Ahlbäck scale and o e 9.5% exhibi only a mild in ol emen in he HSS clinical unc ional scale. Pa ien s added o he su ge y wai ing lis o his ype o in e en ion in he las yea s show a lesse adiog aphic in ol emen and a e olde han hose pa ien s added 17 yea s ago. Compe ing in e es s The au ho s decla e ha hey ha e no compe ing in e es s. Au ho s’con ibu ions DHV concei ed o he s udy, pa icipa ed in i s design and helped o d a he manusc ip . JMFC pa icipa ed in he design o he s udy, in he da a collec ion p ocess and pe o med he s a is ical analysis. Bo h au ho s ead and app o ed he inal manusc ip . Au ho s’in o ma ion Spanish G oups o Knee A h oplas y Spanish Hospi als ha pa icipa ed in da a collec ion: Axa quía, Vélez-Málaga; Bell i ge, Ba celona; Cabueñes, Gijón; Cen al Uni e si a io, O iedo; Cen o ICOT, Las Palmas; Clínico, Málaga; Complejo Hospi ala io, Albace e; Complejo Hospi ala io, León; Cos a del Sol, Ma bella; Dos de Mayo, Ba celona; Espí i u San o, San a Coloma; F ancisco de Bo ja, Gandía; Gene al, Cas ellón; Gene al, Je ez de la F on e a; G ego io Ma añón, Mad id; Hospi al Clínico, Ba celona; Hospi al de la P incesa, Mad id; Hospi al de Mo il, Mo il; José T ue a, Ge ona; Juan G ande, Je ez de la F on e a; La Paz, Mad id; La Za zuela, Mad id; Molle , Molle ; Mu ua de Ta asa, Ba celona; Pa c Tauli, Ba celona; San Agus ín, A ilés; San Be nabé, Ve ga; San Camil, Ba celona; Uni e si a io de Tene i e, Tene i e; Vi gen de la Cin a, To osa. Acknowledgemen The company S yke Ibe ia con ibu ed o he acquisi ion and analysis o da a. 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