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Ultrasound in Medicine & Biology (38), 2012. FIRST APPLICATION OF AXIAL SPEED OF SOUND TO FOLLOW UP INJURED EQUINE TENDONS Claudio Vergari*,†, Philippe Pourcelot†, Bérangère Ravary-Plumioën†, Anne-Gaelle Dupays†,‡, Jean-Marie Denoix†,‡, David Mitton§, Pascal Laugier# and Nathalie Crevier Denoix† Ultrasonography is an established technique to follow up injured tendons, although the lesions' echogenicity tends to become normal before the tendon is ready to sustain the stresses imposed by exercise. Normalized axial speed of sound (SOS) has been found to correlate with an injured tendon's stiffness; therefore, the purpose of this study was to establish whether SOS would be a useful tool in tendon injury follow-up. Axial SOS was measured in 11 equine superficial digital flexor tendons during a 15 weeks follow-up period, and compared with an ultrasonographic grading system. SOS significantly decreased 2 weeks after the surgical induction of a core lesion, showing a minimum between 7 and 10 weeks; ultrasonographic grade showed a minimum at 3 weeks and increased thereafter. The ultrasonographic grading at 15 weeks was correlated to normalized SOS. These results suggest that axial SOS provides complementary information to ultrasonography that could be of clinical interest. Keywords: Soft tissue; Tendon; Injury; Quantitative ultrasound; Speed of sound; Ultrasonography.
† Université Paris Est, Ecole Nationale Vétérinaire d'Alfort, USC 957 BPLC, F-94700 Maisons-Alfort, France ; INRA, USC 957 BPLC, F-94700 Maisons-Alfort, France. ‡ Université Paris Est, Ecole Nationale Vétérinaire d'Alfort, CIRALE, F-14430 Goustranville, France § Université de Lyon, F-69622, Lyon, France; IFSTTAR, LBMC, UMR_T9406, F-69675, Bron ; Université Lyon 1, Villeurbanne. # UPMC Université Paris 6, UMR CNRS7623, LIP, Paris, F 75005 France. *Corresponding author: [email protected] (C.Vergari) Ultrasound in Medicine & Biology (38), 2012. tendon SOS). However, the progression of SOS during the 3.5 months follow-up was not reported in this previous study, and the clinical Tendon lesions are the most investigated and relevance of this technique has not been most common equine musculoskeletal injuries investigated yet. (Thorpe et al. 2010); they present a high rate of The objectives of the present study were (i) to recurrence and their outcome is often negative report the axial SOS measured during a 15 (Dyson 2004; Marr et al. 1993; van den Belt et weeks follow-up of 11 injured tendons, (ii) to al. 1994). Training and competing are both compare these SOS values with the semi- responsible of these injuries (Ely et al. 2004; quantitative ultrasonographic assessment of the Murray et al. 2006; Pinchbeck et al. 2004). They same tendon lesions made by clinicians and (iii) often require long periods without full training to verify if SOS could provide complementary and they represent one of the major reasons of information for the evaluation of tendon status. horse athletes retirement (Lam et al. 2007). Ultrasonography is a widely spread technique 2. Materials and methods for tendon lesions diagnosis, follow-up and a tool to establish a prognosis (Denoix et al. 1990; Genovese et al. 1986). Although qualitative in 2.1 Subjects and timing Eleven French Trotters (2-4 years old) were ultrasonographic images of a tendon lesion (e.g. included in the present study. They were size, echogenicity and architecture) can be semi- participating in a clinical trial testing the quantitatively assessed by grading (Genovese et efficiency of a regenerating agent on SDFT al. 1990; van den Belt et al. 1993). This lesions. Six horses were thus bilaterally treated operator-dependant technique relies on the with this molecule, while a placebo was clinician's experience; this aspect is critical administered to the other 5. The evaluation of during the follow-up, when the echogenicity of this molecule, however, is beyond the scope of healing tendons progressively increases up to its the present paper. normal level (Fig. 1). In order to stimulate The trial (approved by the Ethical Committee collagen production and optimize fibres ComEth Afssa/Ecole Nationale Vétérinaire alignment (Alves et al. 2001; Kingma et al. 2007) d'Alfort/Université Paris-Est Créteil) required without applying unnecessary stresses to a still the bilateral surgical induction (SI) of a tendon fragile tendon, a reliable prognosis is required to core lesion in the middle metacarpal area of the determine the most appropriate time to start forelimb SDFT. The lesion was induced with a controlled exercise and its intensity (Dowling et specially designed amagnetic pin, 30 cm long al. 2000; Gillis 1997). and ending with a 4 edged arrowhead of 10 mm, Quantitative ultrasound is being applied to non- using a previously described surgical technique invasively evaluate tendon load (Crevier-Denoix (Schramme et al. 2010; Vergari et al. In Press). et al. 2009; Pourcelot et al. 2005; Roux and The lesions were about 7 cm in length and included about half of the tendon cross-section. demonstrated that axial speed of sound (SOS) in Ultrasonographic images of the SDFT were tendon varies with the tendon loading acquired before the SI and 3, 7, 10 and 15 weeks (Pourcelot et al. 2005). Recently, SOS has been after it (subscripts from 0 to 4). Axial tendon measured in healthy equine superficial flexor SOS was measured before SI and 2, 7, 10 and tendons (SDFT) and 3.5 months after the 15 weeks after it (subscripts from 0 to 4). induction of a core tendon lesion (Vergari et al. Horses were weighted before the SI (437 ± 27 In Press). SOS significantly decreased after the kg average body mass) and 15 weeks after it induction and, while SOS values were not (437 ± 28 kg), finding a non-significant correlated to injured tendon's elastic modulus, a correlation was observed between the latter and normalized SOS (the ratio of injured on normal Ultrasound in Medicine & Biology (38), 2012. 2.2 Ultrasonographic images ultrasonographic grade (UG) from 0 for normal tendon to 10 for maximal lesion severity, Trained clinicians acquired ultrasonographic according to: UG = 10 – score*10/16. Each images (with an Aloka Alpha-10 Prosound, tendon was independently graded at each stage using a 7.5 MHz linear probe with a standoff (UG to UG ). A reduced ultrasonographic pad) of both forelimbs SDFT of each horse in grade (RUG) was also calculated by summing the metacarpal area. Both longitudinal (with the and normalizing only the two scores relative to ultrasound beam parallel to the tendon fibres) the lesion's echogenicity and transversal and transverse images (with the ultrasound architecture (RUG = 10 – score*10/8). beam perpendicular to the tendon fibres) were acquired. The ultrasonographic machine's 2.4 Speed of sound measurements magnification, contrast and luminosity were standardised, while for each image the gain was SOS in the right SDFT of each horse was adapted, in order to optimize the brightness of measured with a previously described technique the SDFT, and the focus was placed in the (Pourcelot et al. 2005) and protocol (Crevier- middle of the lesion. Denoix et al. 2009; Vergari et al. In Press). The The ultrasonographic examinations included the probe was composed by a 1 MHz broadband entire metacarpal area, where the lesions were pulse emitter and two receivers, which are 1 cm targeted. Three weeks after the SI, a region of spaced. The received ultrasonic signals (400 per interest (ROI) for a given horse was defined as second) were digitized at 10 MHz and the time the tendon cross-section where the maximal of flight of the first arriving signal was estimated lesion severity was observed. using the first zero crossing criterion (Bossy et al. 2002); the speed of this first arriving signal 2.3 Ultrasonographic scoring was calculated as the distance between the two receivers divided by the corresponding signal Different ultrasonographic scoring systems have time-of-flight difference. been previously used to semi-quantitatively SOS measurements were performed during 6 evaluate injured tendons in veterinary practice series of walk (about 5 strides each) on an (Genovese et al. 1986; Saini et al. 2002; Van den asphalt pavement. The maximal SOS value Belt et al. 1993). In the present study, four semi- measured in each stride, corresponding to the quantitative ultrasonographic criteria were tendon's maximal load, was selected, then these defined (score 0 – 4): a. lesion echogenicity (0 maximal values were averaged to obtain the mean maximal SOS. This quantity was anechogenic tissue), b. transversal lesion extent measured before the SI (SOS ) and 2, 7, 10 and (0 no extension - 4 lesion area > 50% of the 15 weeks after it (SOS to SOS ). SOS was cross-sectional area), c. transversal lesion measured in the middle palmar metacarpal area architecture (0 normal - 4 pathologic (the expected location of the lesion) while SOS hypoechogenic tissue) and d. longitudinal lesion through SOS were measured in the ROI. architecture (0 sane tendon - 4 complete Considering SOS variability among sane disorganization of fibres pattern). Criteria a to c tendons (Crevier-Denoix et al. 2009) and the were defined on the images corresponding to influence of the initial severity of the lesion on the ROI. Although a score was assigned to each its evolution, two normalized values of SOS ultrasonographic criterion on each examination, were calculated to quantify the impact of the the definitive scoring was reassessed for each lesions on SOS: SOS / SOS (i.e. relative to horse during a longitudinal blind collegial review the SOS in normal tendon) and SOS / SOS of all images. The clinicians who examined the (i.e. relative to the SOS measured in the recently ultrasonographic images did not have access to injured tendon). the SOS measured values. The four scores were summed (yielding scores from 0 to 16) and normalized to give a final

Ultrasound in Medicine & Biology (38), 2012. 2.5 Statistical analysis UG were significantly lower. The grade was at its lowest 3 weeks after the SI (average UG = Normality was tested with the Lilliefors test. 1.6 ± 0.7). It started increasing thereafter up to Pearson's correlation coefficient was calculated half of its original value (UG = 5.2 ± 0.6) 15 for normally distributed variables while weeks after the SI (Fig. 2). Horses #5 and #9 Spearman's rank correlation coefficient was were the only two horses whose grade remained used for the non-normally distributed ones. constant between 3 and 7 weeks (UG = 2.5 and Differences between measurements at different 3.1, respectively). Average UG in each stages were statistically analyzed with Wilcoxon measurement session was significantly different signed-rank test. Significance level was set at p from the previous one. RUG presented a similar variation in time (i.e. a minimum 3 weeks after The short term precision of the SOS the SI followed by a steady increase), but measurement, as defined by Gluer et al. (1995), showed a higher range of variation (from RUG was calculated separately for each stage. For this = 0.9 ± 1.0 to RUG = 6.1 ± 0.9). precision evaluation, it was considered that the average of each series of walk (about 5 strides 3.2 Speed of sound each) corresponded to one SOS measurement; thus, SOS measurement was repeated 6 times Table 1 reports the average SOS of each for each horse and each exam. measurement session. Averaged SOS in healthy tendons was 2178.8 ± 32.8 m/s (before SI). SOS significantly decreased after two weeks (2096.6 ± 49.7 m/s) and seven weeks (2041.8 ± 62.6 m/s) after SI. Then, a stabilization was 3.1 Ultrasonographic grade observed from week 7 to 10 after SI (2041.5 ± 67.5 m/s). Finally, a significant increase was Figure 1 shows an example of transverse measured at week 15 after SI (2072.4 ± 66.2 ultrasonographic images in normal tendon and m/s, Fig. 2). While at the end of the study no during its lesion follow up. Table 1 reports the tendon had regained its initial SOS, two tendons average value for each variable and each exam. (#3 and #10) reached similar or higher SOS UG was 10 for all horses (since all the tendons values than those measured 2 weeks after SI. were initially healthy), while grades from UG to Figure 1. Transverse ultrasonographic images of tendon #5, acquired in normal tendon (a), 2 (b), 7 (c), 10 (d) and 15 weeks (e) after the surgical induction of a core lesion. Ultrasound in Medicine & Biology (38), 2012. Table 1. Ultrasonographic evaluation and speed of sound measured before and during the injured tendons' follow-up UG: ultrasonographic clinical grade; RUG: reduced ultrasonographic clinical grade; SOS: speed of sound. The short term precision of the technique for each stage was inferior or equal to 0.3 % ultrasonographic grades, but SOS /SOS and (corresponding to about 6 m/s). SOS /SOS were both correlated to UG (Table 2). The ratios SOS /SOS and SOS /SOS were also significantly correlated both to UG (r = 0.72, p = 0.01) and RUG (r = 0.63, p = 0.04). UG was found correlated to several SOS However, the ratio SOS /SOS was not relative variations (Table 2); in particular, the correlated to the clinical ultrasonographic grade. best predictor of UG was SOS /SOS (r = 0.78, p = 0.005, Fig. 3). A similar correlation was found when considering RUG (r = 0.79, p = 0.004). SOS values at other stages were not This study represents the first application of axial SOS in the monitoring of surgically induced tendon lesions. SOS was compared with the ultrasonographic assessment all along the tendons healing process, performed by trained clinicians. Six horses were bilaterally treated with a regenerating agent, while the other 5 were bilaterally administered a placebo; the evaluation of this regenerating agent, however, was beyond the scope of the present paper. The precision error of the technique was found lower than 6 m/s at all stages; Crevier-Denoix et al. (2009) previously evaluated the precision of SOS measurements in normal tendons during in-vitro tension cycling, finding an error inferior to 1 m/s for loads between 600 and 4050 N (the loads expected at walk being in this range). Although six times higher than the error found in vitro, the precision error evaluated ultrasonographic in this study was still below 0.3%; the difference measured 15 weeks after lesion induction) and is likely due to the variability of in-vivo dynamic the speed of sound (SOS) measured 7 (black (i.e. at walk) measurements contrary to dots) and 15 weeks (gray dots) after lesion controlled laboratory testing. induction, both normalized on the initial speed SOS is clearly showing an important of sound, in 11 equine superficial digital flexor interindividual variability (Crevier-Denoix et al. 2009), most likely because of the different Ultrasound in Medicine & Biology (38), 2012. Table 2. Correlation coefficient describing the relation of normalized speed of sound values with the ultrasonographic clinical grade and reduced clinical grade († p < 0.05; ‡ p < 0.01). SOS: speed of sound; UG: ultrasonographic clinical grade; RUG: reduced ultrasonographic clinical grade; subscript 0: measurements in normal tendon; subscripts from 1 to 4: measurements performed 2, 7, 10 and 15 weeks, respectively, after the surgical induction of core tendon lesions. mechanical properties that affect ultrasound should be investigated further before being propagation (i.e. elastic modulus, density and applied in the clinical context. Poisson's ratio). Normalized SOS values were The clinical grading by ultrasonography expected to account for this variability and thus evaluated four lesion features: echogenicity, better reflect the effects induced by the tendon transversal extent, transversal architecture and injury, so it is not surprising that those values longitudinal architecture. While normalized SOS were significantly correlated with the clinical values were in agreement with the clinical assessment by ultrasonography. The correlation assessment by ultrasonography at 15 weeks, between SOS /SOS and UG suggests that normalized SOS at a late stage (relatively to the complementary information. In fact, the latter present study) is capable of quantifying the show a minimum between 7 and 10 weeks after clinical ultrasonographic assessment, which the induction, while the clinicians observed that relies on the examiner's experience. Normalized the ultrasonographic characteristics of the SOS measured 7 and 10 weeks after induction lesions started recovering from 3 weeks. This were already correlated with this final clinical difference between ultrasonographic evaluation assessment, which was performed several weeks and SOS might reflect two different aspects of later, suggesting that normalized SOS values the injured tendon; while the former evaluates may be capable of predicting the tendon status a its structure and architecture (i.e. lesion extent, few weeks in advance. This result was alignment of newly formed fibres), the latter is unexpected and the predictive capacity of related to tendon elastic modulus (Vergari et al. normalized SOS values should be confirmed In Press). Still, normalized SOS is probably with a larger cohort and, possibly, on a longer affected by the tendon's architecture, as suggested by its correlation with the reduced Values of SOS normalized on SOS offer an ultrasonographic grade. In fact, the latter is advantage on those normalized on SOS , since based on the lesion's echogenicity (injured in normal clinical practice a SOS reference of tendon's mean echogenicity has been reported normal tendon (i.e., before the lesion's to be correlated to tendon's elastic modulus insurgence) is rarely available; nevertheless, the (Crevier-Denoix et al. 2005)), and transversal lack of a significant correlation between architecture; other combinations of grading SOS SOS and UG casts doubts on the were not correlated with normalized SOS. relevance of this normalization. A reference for Tendon healing can be divided in three or four normal tendon SOS might be obtained in the overlapping phases (Patterson-Kane and Firth contralateral limb. However, as a SOS 2009; Sharma and Maffulli 2005). The first difference of about 10 m/s between two normal reaction to the injury, lasting about 4 days and tendons coming from the same horse has been often accompanied by haemorrhage, is an previously reported (Crevier-Denoix et al. inflammatory process characterised by swelling 2009), normalization on the contralateral limb and infiltration of inflammatory cells, which after a few days are replaced by new blood Ultrasound in Medicine & Biology (38), 2012. vessels and fibroblasts. This early repair tissue is gelatinous and contains randomly oriented fibres (Watkins et al. 1985). After 6 weeks, the The present study did not last enough to thoroughly test the ability of SOS measurements maturation) commences and, between 8 and 12 to help in the establishment of a reliable weeks, the newly-produced collagen fibres start prognosis of tendon lesions. Moreover, the aligning along the stress direction. Ten weeks tested lesions were not spontaneous, and the after the injury, the fibrous tissue is gradually sample was too small to positively define substituted by scar-like tendon tissue. The SOS technique's power to characterise them. Still, it in injured tendon seems to roughly follow these was observed that SOS is affected both by the phases, with a decrease that begins with the presence of a lesion and by its evolution in time, injury occurrence and continues until the and that SOS variations (i.e., the normalized beginning of the remodelling phase. A values) are related to the lesion status as significant SOS increase was then observed assessed by trained clinicians. While the during the supposed formation of scar tissue functional meaning of axial SOS has yet to be (after 10 weeks from induction). The follow up investigated, the presented results suggest that ended 15 weeks after the lesion induction, so it SOS measurements, as indicative of tendon's is not known how the SOS would have changed later; however, since the mechanical properties information to the ultrasonographic exam. of healed tendons rarely match their original These results confirm the potential clinical quality (Crevier-Denoix et al. 1997), it can be interest of axial SOS measurements in the supposed that eventually SOS would have not follow-up of tendon lesions. regained its original value. It can be hypothesized that the SOS decrease Conflict of interest statement observed during the first weeks was due to the swelling induced by the inflammatory state and The authors have no conflicts of interest to to the decreased injured tendon's elastic modulus (Crevier-Denoix et al., 1997). The SOS increase observed between 10 and 15 weeks probably coincided with the beginning of the fibres realignment. Numerical simulations could The authors are grateful to the Direction be used to assess the factors affecting the SOS Générale de l'Enseignement et de la Recherche progression in healing tendon, as it was recently (French Ministry of Agriculture), the Région done for healing bones (Machado et al., 2010). Basse-Normandie, the Institut National de la However, this would require more information Recherche Agronomique and the Agence on the mechanical and acoustic local properties Nationale de la Recherche (Programme ANR- of injured tendon. 08-BIOT-021 RGTAtendon) for financial support. The authors would also like to thank Elodie Paumier-André for her precious help. Ultrasound in Medicine & Biology (38), 2012. Alves ALG, Rodrigues MAM, Aguiar AJA, Thomassian A, Nicoletti JLM, Hussni CA, Borges AS, Effects of beta-aminopropionitrile fumarate and exercise on equine tendon healing: Gross and histological aspects. J Equine Vet Sci 2001;21:335-40. 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Fda drug safety communication: fda modifies monitoring for neutropenia associated with schizophrenia medicine clozapine; approves new shared rems program for all clozapine medicines

FDA Drug Safety Communication: FDA modifies monitoring for neutropenia associated with schizophrenia medicine clozapine; approves new shared REMS program for all clozapine medicines Safety Announcement [09-15-2015] The U.S. Food and Drug Administration (FDA) is making changes to the requirements for monitoring, prescribing, dispensing, and receiving the schizophrenia medicine clozapine, to address continuing safety concerns and current knowledge about a serious blood condition called severe neutropenia. Severe neutropenia is a dangerously low number of neutrophils, white blood cells that help fight infections. Severe neutropenia can be life-threatening. Treatment with clozapine may improve the symptoms of schizophrenia in patients who do not respond adequately to standard antipsychotic treatments. Symptoms of schizophrenia include hearing voices, seeing things that are not there, and being suspicious or withdrawn. Clozapine is also effective in reducing the risk of repeated suicidal behavior in patients with schizophrenia or schizoaffective disorder. We previously communicated safety information associated with clozapine i There are two parts to the changes in the requirements for treating patients with clozapine. First, we have clarified and enhanced the prescribing information for clozapine that explains how to monitor patients for neutropenia and manage clozapine treatment. Second, we approved a new, shared risk evaluation and mitigation strategy (REMS) called the Clozapine REMS Program. The revised prescribing information and the Clozapine REMS Program will improve monitoring and management of patients with severe neutropenia. The shared REMS is also expected to reduce the burden and possible confusion related to having separate registries for individual clozapine medicines. The requirements to monitor, prescribe, dispense, and receive all clozapine medicines are now incorporated into the Clozapine REMS Program. The Clozapine REMS Program replaces the six existing clozapine registries maintained by individual clozapine manufacturers. The shared REMS requires prescribers, pharmacies, and patients to enroll in a single centralized program. Patients who are currently treated with clozapine will be automatically transferred to the Clozapine REMS Program. In order to prescribe and dispense clozapine, prescribers and pharmacies will be required to be certified in the Clozapine REMS Program according to a specific transition schedule starting October 12, 2015 (see Additional Information for Prescribers section and Additional Information for Pharmacies section for more details). The monitoring recommendations for neutropenia caused by clozapine treatment have changed. Clozapine can decrease the number of neutrophils in the blood, in some cases causing severe