S0.2), 40 (S0.4), 60 (S0.6), and 80% (S0.8) of maximal voluntary torque (TMVC). CMJ was not correlated with strength indices but was positively correlated with MRTD/BM, S0.4/BM. The slope α2 and intercept β2 of the torque-stiffness relationships from 40 to 80% TMVC were correlated negatively (α2) and positively (β2) with CMJ. The different stiffness indices were not correlated with MRTD. The prediction of CMJ was improved by the introduction of MRTD in multiple regressions between CMJ and stiffness. CMJ was also negatively correlated with indices of curvature of the torque-stiffness relationship. The subjects were subdivided in 3 groups in function of CMJ . There was a downward curvature of the torque-stiffness relationship at high torques in group H or M and the torque-stiffness regression was linear in group L only. These results suggested that torque-stiffness relationships with a plateau at high torques are more frequent in the best jumpers.The relationships between ankle plantar flexor musculotendinous stiffness (MTS) and performance in a countermovement vertical jump (CMJ) and maximal rate of torque development (MRTD) were studied in 27 active men. MTS was studied by means of quick releases at 20 ( Pmax) and vertical jump [Pmax is not accurate which suggested that the performances in vertical jump tests also depend on other factors than the maximal power of the lower limbs.Since its presentation in 1921 by Sargent as “the physical test of a man” [cal jump . HoweverThe rise in the force exerted on the ground depends on the rate of force development by the lower limb muscles. Therefore, CMJ should be positively correlated with maximal rate of torque development (MRTD) by these muscles. As the rate of force development depends on the series elastic component , CMJ shoIn the present investigation, it was hypothesized that ankle plantar flexor MTS and maximal rate of torque development (MRTD) were factors influencing performance in CMJ. The relationship between countermovement vertical jump performance and ankle plantar flexor MTS was estimated from the results of quick releases during plantar flexion and CMJ.Twenty-seven male subjects participated in this study (22.41 ± 1.98 years). They were all healthy active male physical education students. In order to study the relation between MRTD, MTS, and CMJ, they were subdivided in 3 groups (3 × 9) in function of their results in the vertical jump test: high (group H), medium (group M), and low performers (group L). Body mass (BM) and body height (BH) are presented in −1 that required a tachometer. Torque was obtained by means of a strain gauge torque transducer. All mechanical data were sampled at 1 kHz. A dual beam oscilloscope gave the subjects visual feedback about the procedure in progress.Ankle plantar flexor MTS was studied by means of the ankle ergometer designed by the University of Technology of Compiègne (France) for the measurement of ankle plantar flexor MTS before and after long-term spaceflights . This anMaximal countermovement vertical jump (CMJ) was performed with the device described by Vandewalle et al. , Driss eThe subjects were comfortably lying on an adjustable table with the left foot attached rigidly to the actuator of the ankle ergometer by a cyclist shoe with a rigid sole . DiffereTMVC).In first test, the maximal torque under isometric conditions was determined during a maximal voluntary contraction of the plantar flexors. The subjects were instructed to develop a maximal contraction as fast as possible against the actuator and to maintain this contraction during 2 seconds. Three contractions with 90-second recovery intervals were carried out, and the best performance was considered as the torque at maximal voluntary contraction  . Quick release movements from the neutral position were achieved by sudden releasing of the moving parts of the device while the subjects were instructed to maintain submaximal plantar flexion torques of around 20% 40%, 60%, or 80% of Finally, the maximal rate of torque development (MRTD) was measured according to Sahaly et al. . The subThe vertical jump test was a countermovement jump which is probably a much more natural jumping movement than a squat jump and one advantage of a countermovement is that the leg muscles attain a higher level of activation and force before they start to shorten . As in tThe reliability of CMJ performance is high when measured with this device and this protocol. In a study on 31 subjects , the intraclass coefficient was 0.98, the test-retest coefficient of correlation was 0.978, and the differences between the first and second sessions ranged only from −1 to 1 cm in 21 from the 31 subjects.S between variations in angular acceleration (Θ′′) and angular displacement (Θ) within a time lapse of 20 ms , as expressed byIn quick and control release methods, MTS is estimated by recording the decline in moment as a function of joint rotation and is expressed in newton-meters per radian. These methods do not require knowledge about the lengths of the tendon moment arms of the individual muscles. However, the translation of the rotational measure of MTS into linear measures of MTS of the individual muscles (the different ankle plantar flexors) needs information about tendon dimensions, tendons moment arms, and force sharing. In quick release methods, the decline in moment is measured from the decline in acceleration. MTS is calculated as the ratio T) equals dynamic torque and acceleration is maximal:In this equation, inertia is assumed to be constant. This can be verified easily by considering the transition between the static phase and the dynamic phase. At this moment static torque . Then, tionship , 22:  have been tested but none of them could fit the experimental data in all the subjects. Indeed, the value of S extrapolated for zero torque must be positive but S at zero torque was negative in some subjects. Moreover, a curvilinear model could not accurately fit the experimental data in the subjects whose T-S relationships were linear and the difference between observed and predicted data was high in some subjects. Therefore, the T-S curve was approximated by two linear segments S1=α1 = α2 and β1 = β2 and ratio α2/α1 = 1 if the T-S relationship is linear. The α2/α1 ratio was used as an index of curvature of the T-S relationship. Another empirical curvature index (TC) was computed as equal to the torque corresponding to the half of the difference in stiffness at 0.4 and 0.8 TMVC. Perfectly linear relationships correspond to values of TC equal to 0.5 and curvilinear relationship corresponds to values lower than 0.5.Consider TMVC instructions were not exactly equal to the required torques. Therefore, the values of S which corresponded exactly to 20, 40, 60, and 80% TMVC  for each subject were computed by linear interpolation (or extrapolation) of the experimental individual data. The values of T and S used in these interpolations were the averages of the three contractions corresponding to a given instruction .In spite of the display of torque output on an oscilloscope, the actual torques corresponding to 20, 40, 60, and 80% S corresponding to a torque equal to 100 N·m (S100) was computed by linear interpolation of the experimental torque-stiffness data to compare MTS in the present study with the data in previous studies that used the quick release methods for the assessment of triceps surae stiffness.The value of −1) was computed as the difference in torque between times t (Tt) and t + 20 ms (Tt+20) [t = 0 to the end of the torque measurement for each value of Tt. MRTD corresponded to the highest value of RTD [The rate of torque development (RTD in N m s(Tt+20) :(4)RTD=e of RTD .0) as suggested by the results of an allometric study [1) as force and arm lever are proportional to BM2/3 and BM1/3, respectively. The dimensions of S0.2, S0.4, S0.6, and S0.8 are equal to torque·rad−1, that is, BM1·rad−1. With other things being equal, the values of S0.2, S0.4, S0.6, and S0.8 should depend on BM1. Therefore, the values of S0.2/BM, S0.4/BM, S0.6/BM, and S0.8/BM should be independent of body mass (BM1 rad−1·BM−1 = BM0·rad−1 = rad−1). Consequently, the value of S corresponding to the different torques  was normalized to body mass  when CMJ was correlated with stiffness.The value of CMJ is probably independent of body mass  is a dimensionless variable (N·m·rad−1·N−1·m−1 = N0·m0·rad−1 = rad−1). Therefore, S was expressed as S0.2/TMVC, S0.4/TMVC, S0.6/TMVC, and S0.8/TMVC for the comparisons of the torque-stiffness relationships in the different groups. As stiffness indices and for the same reasons, MRTD was related to body mass (N·m/s·BM) or TMVC (s−1) to study the relationship between CMJ and the rate of torque development.When normalized to n = 27). The comparisons of the results in groups H, M, and L for the anthropometric data, strength indices , and stiffness indices  were tested with a one-way ANOVA and a post hoc Bonferroni t-test. The differences between α1 and α2 or between β1 and β2 were tested with a two-way ANOVA with repeated measures and a post hoc Bonferroni t-test.The effect of MTS or MRTD upon CMJ was studied by means of the correlations between CMJ and the different indices of stiffness and rate of torque development in the whole group .All statistical analyses were conducted at r < 0.133; P > 0.05).There was no significant difference in BM and BH between the different groups . In addiT-S relationships are presented in n = 27) and in  S0.4/TMVC , groups H (P < 0.001) and M (P < 0.001) but not in group L (P = 0.216). Slope β2 was significantly lower in group L when compared to group H or M  from a linear relationship. The lack-of-fit tests indicated that the torque-stiffness relationships were significantly different from a linear relationship for groups H  and M  but not for group L .The TMVC, MRTD) and in values related to body mass  or to TMVC (MRTD/TMVC) are given in TMVC or TMVC/BM between groups H, M, and L. The value of CMJ was not significantly correlated  with strength indices (TMVC or TMVC/BM).The indices of torque and rate of torque development in absolute values :The differences in MRTD or MRTD/M, and L . The onlS0.4 but not with S0.2, S0.6, and S0.8:α2 (negative correlation) or β2 (positive correlation):CMJ was significantly correlated with rrelated  with α2α2/α1 was close to 1 in group L and was independent of maximal strength indices  and torque development . Interestingly, CMJ was significantly and negatively correlated with ratio α2/α1 or curvature index TC (Ratio ndex TC :(9)CMJ=P ≥ 0.184) although CMJ was significantly correlated with MRTD as well as stiffness indices. As a consequence, the prediction of CMJ was improved by including torque development indices in addition to stiffness indices in multiple linear regressions. For example,The rate of torque development was not significantly correlated with the different stiffness indices  and lowest  values of MRTD/BM in Figures These results are illustrated by separating the subjects with the highest (S0.4) was significantly higher in the best jumpers that presented a torque-stiffness relationship with a plateau.The present study was designed to relate vertical jump performance and ankle plantar flexor MTS or MRTD. The results showed that (i) CMJ was significantly correlated with the indices of torque development; (ii) CMJ was positively correlated with some indices of stiffness; (iii) the ankle plantar flexors MTS at low torque ( S100 (TMVC in the present study was within the range of the stiffness at 100 N·m reported by Hof [−1) and de Zee and Voigt [−1). The values of CMJ in groups H and M were high when compared with CMJ data in the literature measured with the same protocol [The values of stiffness in the present study were in agreement with the previous investigations on plantar flexor stiffness studied by means of fast controlled-release method , 25. For S100  that is d by Hof   and muscle fiber types. For example, MRFD is lower during voluntary contraction than during electrical stimulation [TMVC, MRTD/BM, and CMJ that was abnormally high in the best jumper when compared with the other subjects. The best values of CMJ could be partly explained not only by high and fast muscle activation but also by better timing of this activation. Indeed, according to Voigt et al. [The musculotendinous complex has to fulfill two contradictory requirements: to be compliant for elastic energy storage and stiff for the transmission of force. High compliance improves the possibility of elastic energy storage but lowers the rate of force development . The indmulation , 35, depmulation , and is mulation , 36. Themulation , 38. Thet et al. , the coot et al.  that is t et al. .The correlation coefficients between CMJ and MRTD indices explained that the differences in MRTD indices between groups H, M, and L were not significant with the exception of the difference between MRTD/BM in groups H and L. It is possible that the importance of MRTD was attenuated by the countermovement before the jump as prestretching of the muscles during the downward phase allowed the muscles to develop a higher level of active state and force before starting to shorten , 29, 42.α2; r = 0.690; P < 0.001) corresponded to a coefficient of determination equal to 0.476 only. After inclusion of indices of torque development in multiple linear regressions between CMJ and stiffness indices, the coefficient of determination was largely improved . Finally, as the rate of force development depends on muscle activation and muscle fiber type, it is likely that a multiple regression between CMJ, MRTD, and stiffness indices includes the main factors determining vertical jump performance.The correlation between CMJ and several stiffness indices of the plantar flexors agrees with the positive correlation between jump performance and the tendinous stiffness of the quadriceps studied by ultrasonography . HoweverTMVC (S0.4) were similar in the best jumper (subject BJ in S0.4/BM or S0.4/TMVC. The T-S relationship was linear in subject WJ in contrast to subject BJ (T-S relationship in agreement with the significant negative regression between CMJ and TC or ratio α2/α1. The force-length (or force-stretch) curve of isolated tendon presents a concave portion at low force (the “toe” region) followed by a “linear” segment [T-S curve. The stretch-torque curve in a fast controlled-release study of the plantar flexors and dorsi flexors in men [T-S relationship in group L could be described by a linear regression (TMVC in all the subjects (T-S relationship at high torque has been previously observed in a fast controlled-release study of the plantar flexors [TMVC in the best jumpers (The stiffness indices at 40% bject BJ . These r segment . An expos in men , 44 was s in men , 22 whengression  in agreesubjects , especia flexors : the tor jumpers  of the pThe results of the present study are not in favour of the hypothesis that a long compliant tendon is favorable to jump performance , 45, whiThe present study revealed that countermovement jump was significantly correlated with different indices of musculotendinous stiffness or maximal rate of torque development. Furthermore, it is suggested that differences in musculotendinous stiffness partly explain the better countermovement jump scores and that torque-stiffness relationship with a plateau at high torques is more frequent in the best jumpers.


The experimental results demonstrated that our design can measure soft and hard stiffness.During dental sinus lift surgery, it is important to monitor the thickness of the remaining maxilla to avoid perforating the sinus membrane. Therefore, a sensor should be integrated into ultrasonic dental tools to prevent undesirable damage. This paper presents a piezoelectric (PZT) sensor installed in an ultrasonic transducer to measure the stiffness of high and low materials. Four design types using three PZT ring materials and a split PZT for actuator and sensor ring materials were studied. Three sensor locations were also examined. The voltage signals of the sensor and the displacement of the actuator were analyzed to distinguish the low and high stiffness. Using sensor type T Recently, ultrasonic dental tools have been used extensively in scaling, micro-invasive implants, and other oral surgeries ,2,3. UltPast research  has examThis work presents a method of measuring the stiffness with high sensitivity, especially in the case of soft materials. The method employs PZT materials as the sensor to measure soft and hard stiffness. By analyzing the output voltage of the sensor, the stiffness of oral tissue can be detected. We designed several types of PZT sensor using different PZT materials and tested them at different locations. Even with light contact, the sensor maintained a high stiffness sensitivity value of about 2.47 Vm/kN. The combination of actuator and sensor can be used simultaneously for dental treatment and stiffness sensing.A conventional ultrasonic dental handpiece tool, shown in A PZT ring was placed inside the transducer as a sensor, as shown in According to clinical findings, the ultrasonic dental handpiece is usually operated at 30 kHz, which is outside the range of human hearing, 20 to 20,000 Hz. The location and type of a sensor strongly influence the sensitivity and the displacement. These two factors will be discussed below.1, T2, T3, were studied. For type T4, the PZT ring was divided into an actuator and a sensor. The parameters of the sensor are listed in As shown in i.e., A1, A2 and A3, to find the optimal location. In the study of sensor locations, we used only PZT-1 as the actuator. As shown in 2 set for the nearest node position. Therefore, the A1 set for the farthest node position was the opposite of A2. Finally, the A3 set was formed by considering independent adjustment of the preload of the sensor and the actuator. As shown in 1, the sensor was inserted between the ring actuator and the horn. In Position A2, the sensor was between the ring actuator and rear segment. In position A3, the sensor was glued at the tail end of the rear segment by using the instant adhesive of Loctite 403.Sensors at various locations generate different voltages due to the stress distribution in the transducer. The voltage of the sensor is in proportion to the force applied to the sensor. Hence, the location of a sensor will have a direct influence on its sensitivity. In this work, the sensors were placed at three different positions, This section is divided into two parts. First, the influences of the types and locations were investigated to determine the appropriate conditions for the sensor. Second, sensing capability was verified, and simply supported beams  with difA free vibration test, using the set-up shown in Human bone tissue is composed of several layers of different materials. According to Reference , the bonIn the experiment, simply-supported beams with different equivalent stiffness were used as test samples. The experimental apparatus of the stiffness measurement is illustrated in 3 was distorted at high input voltage; it was found that the glue become unstable under high temperature approximately 130 °C which exceeding the recommend temperature of operation. Moreover, set A1 produced the maximum longitudinal displacement and a lower sensor voltage than did set A2. According to 2 was much higher than that of A1. It can be inferred that the sensor voltage was higher because the sensor of set A2 was located close to the node of the transducer. In this work, a large displacement and sufficient voltage were needed for the device to work. Thus, the A1 type was used for the experimental sets T.2 was quite noticeable and indicated that the soft PVDF material obviously lowered the transducer displacement, even though the PVDF was very thin. In addition, the displacement of T1 was higher than that of T3. About the comparison of properties of T1 and T3, the value of each item was similar, except the Mechanical Quality Factor (QM). The value represents the magnitude of energy dissipation. This also indicated that a low QM corresponds to a high mechanical loss.As shown in 1 and T4. Both designs were able to estimate the stiffness of the sample under a low contact load of 3 N. The sensor design of T1 showed high stiffness sensitivity of 2.47 Vm/kN, and T4 had a stiffness sensitivity of 1.55 Vm/kN in the stiffness range of 0 to 25 kN/m. Noticed that there is a sudden jump at 2 kN/m for type T4. The phenomenon was believed in the cause of the assembly-gap. For T4 type, a 12.5% PZT ring was divided as a sensor by a manual cutting method with the diamond pen. The method might result in the measurement error during the measurement of the low equivalent stiffness due to the slight irregularities of the sensor edge.1 and T4 were capable of distinguishing materials of different stiffness. The difference in the design of type T4 should be noted. This design allows a sensor voltage to be obtained without the use of an independent PZT ring as a sensor. The signal produced by this design is also sufficient for analysis, with good sensitivity of 1.55 Vm/kN. This study also determined the optimal sensor location to be A1, where the PZT sensor can be placed for maximum displacement of the transducer.This investigation presents a new PZT sensor for integration into an ultrasonic dental tool. The sensor can distinguish hard and soft materials, even under a low contact load of 3 N. The stiffness of different test samples was detected by analyzing the voltage from the sensor. The experimental data showed that the location and the type of the sensor affected the sensitivity of the sensor and the displacement of the transducer. Measurements indicated that both type T


Diagnostic methods in medicine are currently rapidly evolving and constantly improving. This is true for areas such as molecular diagnostics, biomarkers, as well as medical imaging. As one example, positron emission tomography (PET) has been called the fastest growing medical technology ever. Also, molecular diagnostics, at both the gene and protein levels, are developing rapidly due to advances in technology and, thereby, creating new possibilities. Early and valid diagnosis is crucial for proper treatment of patients. Moreover, advanced diagnostic methods are crucial for the upcoming era of tailored therapy. From an economic viewpoint, the cost of advanced treatments are increasingly indicating the need for better stratification and therapy monitoring of treatment, in order that these advanced treatments are limited to patients able to respond favorably. Collectively, the exciting area of medical diagnostics seems never to have been more important for patients and society.Diagnostics, it is our ambition to give researchers the possibility to publish and read about these new improvements and use of diagnostic methods. With the pace of research within our field, it is essential to have a fast method for dissemination of data available to the research and clinical community. With an open access, peer-review journal, such as Diagnostics, we believe to have created exactly that kind of media and I find it a privilege to be founding Editor-in-Chief of this endeavor. There are no restrictions as to the length of papers allowing for great detail in the methodology, which is important if the methods are to be adopted by peers. In addition to regular full-length articles, we encourage authors to also submit reviews and short communications.With the launch of the new journal The scope of the journal is broad and, intentionally, multidisciplinary. This is based on the increasing use of diagnostic decision algorithms that combine several diagnostic approaches, in order to be more accurate and to be cost-effective. One example could be whether the use of a comparatively cheap biomarker in a blood sample may be used as a gate-keeper to select patients that need a more expensive medical imaging modality. Accordingly, we find it logical to cover all aspects of medical diagnostics in the same journal and thereby support a cross-disciplinary approach and viewpoint. Our editorial board naturally reflects this concept by covering all aspects of medical diagnosis. They have been selected among top-level researchers within various areas of diagnostics, considering both modalities as well as disease entities studied. We, the editorial board and team, are highly committed to the success of the journal and hope that it will grow and flourish. However, the key to being successful is the quality of manuscripts received. Therefore, we encourage all researchers to send in innovative contributions of high quality. We, on our side, can promise a fast handling and review procedure in order to ensure your research is published as quickly as possible.


We present a case of chronic acromioclavicular jointdislocation (Rockwood type 5) in which the choice ofacromioclavicular reconstruction using autogenoussemitendinosus tendon graft was made due to its superiorityin anatomical reconstruction of the coracoclavicularligaments, and the impact of postoperative rehabilitation onthe recovery of this patient. We also discuss the rationalebehind this.acromioclavicular joint dislocation, acromioclavicularreconstruction, autogenous semitendinosus tendon graft,rehabilitation approach Acromioclavicular joint (ACJ) dislocations have beenapproached differently in terms of surgical management. Inacute cases, reduction and stabilization of the ACJ, usuallyvia hardware fixation, allows for primary healing as theligaments are held in anatomical apposition. However, if it isa chronic injury, a reconstructive procedure is often required,one of the most commonly done being the modified Weaver-Dunn procedure. There is no gold standard in ACJreconstruction (ACJR) and many methods have beendescribed in literature, with variable outcomes. In recentyears, a technique using autogenous semitendinosus tendongraft has been advocated and proven to be superiorbiomechanically, clinically and radiologically compared tomore conventional methodsA 29-year old male presented to our outpatient departmentthree months after being involved in a motor vehicle accidentin which he fell off his motorcycle and landed on his leftshoulder. He complained of persistent left shoulder pain which did not go away despite rest and analgesics. Onexamination, the distal part of the left clavicle was noted tobe prominent and there was mild tenderness over theacromioclavicular joint (ACJ). He was unable to abduct hisleft shoulder beyond 90 degrees. Radiographic studies of theleft shoulder revealed a disrupted ACJ  using tendon grafts is not a newtechnique, but is less popular than more conventionalmethods such as the modified Weaver-Dunn procedurepossibly due to it being more technically demanding,requiring an extra procedure for tendon harvest, or ifcadaveric grafts are used, the high cost associated with it.Numerous complications have been reported with themodified Weaver-Dunn procedure and it has also beencriticized for placing the clavicle in a non-anatomicalposition. Therefore, anatomical ACJR was designed to placetendon grafts at the exact anatomic location of thecoracoclavicular (CC) ligaments and to reconstruct the ACJcapsule.Besides avoiding the need for implant removal andcomplications such as hardware migration, infection, andforeign body reaction, ACJR using tendon grafts isbiomechanically superior to coracoacromial ligamenttransfers. This was demonstrated by Lee et alTauber et al2 set out to confirm the clinical relevance of themore superior biomechanical properties of thesemitendinosus tendon graft and they found thatsemitendinosus tendon graft for CC ligament reconstruction(CCR) resulted in significantly superior clinical and radiologic outcomes compared to the modified Weaver-Dunnprocedure. In addition, CCR with an autogenous hamstringtendon graft was also shown to be satisfactory in treatingpainful non-united distal clavicle fractures with CCseparationPostoperative rehabilitation is another important aspect indetermining the outcome of surgery. Cote et alIn summary, ACJR using semitendinosus tendon graft hasbeen proven to be superior biochemically, clinically, andradiologically. However, the patient should be compliant tothe rehabilitation protocol prescribed and this involvescommunicating and working together with the sportsphysicians and physiotherapists to ensure an optimaloutcome of the reconstructive procedure. Failure of this, asshown in this case, resulted in failure of the surgery.


The Remembrance of the good done those we have loved is the only consolation when we have lost them. – DemoustierLike so many of those who had the chance to learn to know him, I was truly saddened by the all too soon and unexpected death of Laurentiu Mircea Popescu. This outstanding researcher, scientist and teacher influenced many, inspired his environment with his incredible energy, and never seized to follow his ideals to further our comprehension of molecular and cellular medicine.He was born on April 15th 1944, studied Medicine in Bucharest and then completed a PhD study at the world famous Carol Davila University of Bucharest, the same institution where Insulin had been described for the first time.It was an opportunity that he readily grasped when he was offered the chance to work as a postdoctoral fellow at the University of Leiden as well as later on as a Fogarty International Fellow at the NIH, Bethesda, Maryland, US. It was his remarkable decision - that was characteristic of him - to finally follow his election and nomination to go back to Bucharest instead of pursuing his undoubtedly promising further career abroad. Back in Bucharest he then chaired the prestigious Victor Babes Institute of Pathology and was a teacher to many young fellows and students.In retrospect it is of no wonder that during his professional life and his merits he became the Dean of the Medical Faculty and was then elected to preside the whole Carol Davila University, where he took full responsibility for his Alma Mater serving as the rector magnificus (President) from 1992 to 2004.Since 1995 he became a member and in 2003 the president of the Academy of Medical Sciences Section of the Romanian Academy of Sciences. He then from 2010 to 2011 acted as a vice president and became president of the European Federation of the European Academies of Sciences in 2012. In 2011 he became President-elect of the International Society for Adaptive Medicine.His scientific oeuvre is best characterized by the discovery of a hitherto undescribed ‘new’ cell type in a time, where, every cell type seemed to have been long since discovered. He realized the enormous potential of these cells for medical research, which has meanwhile also been acknowledged by the scientific community. This did not come by chance, as he himself humbly once reported in the title of one of his seminal papers , via Interstitial Cajal-Like Cells (ICLC) to TELOCYTES, J Cell Mol Med. 2010 Apr;14(4):729–740.). It was the ultimate consequence of tremendous efforts over many years to prove the concept of this new type of cells, from describing caveolar cells and Cajal-like cells until finally characterizing what he then termed ‘Telocytes’.www.telocytes.com) so that any researcher could (participate in/)benefit from his wisdom. By doing so he stimulated many young and senior researchers from all over the world to join his efforts and to find out more of what Telocytes could be capable of. Possible mechanisms and actions of TC could play a role in angiogenesis, tumorigenesis, Tissue Engineering Horch RE, Beier JP, Kneser U, Arkudas A, Successful human long-term application of in situ bone tissue engineering, J Cell Mol Med. 2014 Jul;18(7):1478–1485, Regenerative Medicine, just to name a few.Together with his fine team of coworkers he characterized Telocytes as an interstitial cell type with a small cell body and extremely long tentacle like extensions, named Telopodes (10–100 μm) and Podomers. These telopodes form a three dimensional network within the surrounding connective tissue. Because Podomers are smaller than 200 nm (and therefore cannot be detected by simple light microscopy) Telocytes had remained undetected for long. Only through the extremely labour intensive, precise multiplanar electron microscopical reconstruction of innumerable histological slices and sections Popescu and his group were able to reveal and decipher the hidden three dimensional cell structure. The fascination of Telocytes lies in many potential functional properties and possible modes of action as well as their relation to putative subepithelial and stromal stem cells. LM Popescu shared all his findings freely with the scientific community and tried to offer what he found with a specially designed website  which is another proof of his never ending enthusiasm and creativity. When he – some two decades back - started out to found a new journal in this highly competitive scientific field as the Editor in chief many of his friends could not believe that his endeavor could be successful at all. Despite such doubts LM Popescu showed better. It did not take too long for the incredible to become true and JCMM became one of the Top 10 rated journals in its field. He had seen the necessity to bring different areas of research together and his idea was to establish a platform focused on translational medicine, spanning disease-oriented basic research in molecular and cellular biology and pre-clinical investigations into molecular and cellular therapeutics. Even now when we look back it seems almost impossible what LM Popescu and his brilliant team in Romania achieved to manage the work load which a rapidly growing journal will naturally entail. We all thank him for his visionary thoughts and for establishing such an excellent journal that now in his sense truly does provide a unique platform for many highly gifted scientists from everywhere. Above his Telocyte works and other achievements the success story of this scientific ‘baby’ JCMM has shed so much light on the Carol Davila University in Bucharest that he will always be remembered not only in his country but worldwide.It also came naturally that he was honored with innumerous prizes and accolades, including multiple honorary doctor awards. Among them were highly esteemed awards, such as for instance the Gold medal of the International Academy of Cardiovascular Science. Five of the twenty-five well known scientists who had been honored with this decoration so far later on received the Nobel prize.My personal relationship with LM Popescu started long ago with his request for a contribution to JCMM in the area of Tissue Engineering and over time I was more than happy to learn to know him personally as an outstanding scientist and impressive personality over time. We eventually became friends and being his guest made one feel like visiting one’s family. Despite his multiple scientific and professional engagements he never forgot his loving family which he regarded as the resting pole and constant source of energy in his personal universe. He was the spiritus rector of many other researchers and I can truly say that he influenced my way of scientifically thinking. Whoever had the opportunity to learn to know LM Popescu can easily imagine what a splendid person we lost. The only consolation that remains is that he will never be forgotten by so many of us. A man’s worth is not measured by ‘how he died’, nor ‘what he gained’, but ‘how he lived’ and ‘what he gave’. Laurentiu Mircea Popescu gave us all so much, that his worth seems immeasurable.


This paper gives a brief overview on the impact of DSA development on graft outcome in organ transplantation with a focus on risk factors for  The employment of new immunosuppressive strategies in the late 1980s and 1990s and their efficacy to control T-cell alloimmunity led to a striking decrease in the occurrence of T-cell-mediated acute rejection episodes. Simultaneously, our shortcomings in controlling antibody-mediated rejection (AMR) were revealed and the importance of chronic AMR has become apparent. Mainly two developments contributed to a deeper understanding of antibody-mediated allograft injury: (1) the recognition that deposition of the complement split product C4d  may indicate antibody-mediated allograft injury and 2) the association of donor HLA-specific antibodies (DSA) detected by highly sensitive techniques with inferior outcome of kidney transplants  the asso–5. There de novo DSA against antigenic structures and result in failure of the transplanted organ due to antibody-mediated organ injury.Early after transplantation, acute AMR occurs in about 1 to 6% of patients; however, this frequency may increase up to 21 to 55% in patients who had detectable DSA already before transplantation and who received desensitization therapy . PersistAdditional antibodies that are discussed in the evolution of chronic AMR are MICA antibodies, angiotensin II type 1 receptor activating antibodies, and other antiendothelial cell antibodies –13. The  de novo HLA alloantibodies that are detected after kidney transplantation.In this overview, we focus on the impact of de novo DSA measured at the low positivity cut-off of 300 MFI is predictive of graft survival [Currently, features of AMR in the biopsy together with the detection of a circulating DSA are required for the histological diagnosis of antibody-mediated kidney graft rejection. In addition, evidence of antibody interaction with the vascular endothelium must be present, either by C4d positivity or microvascular inflammation (peritubular capillaries and/or glomerulitis) . Of notesurvival . Everly survival . de novo DSA, AMR, and graft loss are not uniformly described. In many patients with late antibody-mediated graft loss, even when HLA class I alloantibodies are detectable, circulating HLA class II de novo DSA are considered to be mainly responsible for rejection. Therefore, most authors believe that specifically HLA class II mismatches  confer an increased risk for late graft loss [ de novo development of DSA and subsequent occurrence of (chronic) AMR are younger age, deceased donor kidney transplantation, presence of HLA antibodies before transplantation, nonadherence to immunosuppressive medication (see below), and insufficient immunosuppression or drug minimization [Risk factors for the development ofaft loss –17. Due mization , 16, 17. de novo DSA development and AMR [Most importantly, early inflammatory events, such as infections, minor surgery, trauma, and particularly early (acute) T-cell-mediated rejection episodes, often precede and AMR –20. Even and AMR . de novo DSA development. de novo DSA, which made up 60% of all DSA and were directed against HLA class II antigen mismatches of the donor, were associated with strongly impaired graft survival: within 5 years from DSA detection, 50% of the patients in the study of Hidalgo lost their grafts. Wiebe et al. found a 10-fold increase in graft loss in patients who developed de novo DSA, with a 40% lower graft survival rate 10 years after DSA development compared to patients without de novo DSA [ de novo occurrence of DSA [ de novo DSA and non-DSA [Hidalgo et al. found DSA in 37% of patients who had an indication biopsy 7 days to 31 years after transplant . In partnovo DSA . Everly e of DSA . However non-DSA . PatientA recent development is the introduction of solid-phase assays that allow the distinction of complement-binding (C1q assay) or complement-activating (C4d assay) HLA antibodies from HLA antibodies that do not bind or activate complement. de novo DSA after transplantation found conflicting results [de novo and persistent/reemerging) was 54%, strikingly lower than the 93% rate in patients with DSA that were not complement-binding or the 94% rate in patients without any DSA. The higher graft loss rate in patients with complement-binding DSA was attributable to a higher rate of AMR, especially in the patients who developed complement-binding DSA de novo after kidney transplantation. Interestingly, pretransplant complement-binding DSA did not have the same predictive values since about half of the patients lost these antibodies after transplantation.While two early pediatric studies that investigated the use of the C1q assay for the detection of results , 26, a r results . The 5-yEinecke et al. reported in 2009 that antibody-mediated microcirculation injury is one of the leading causes of late graft loss, together with death with a functioning graft, recurrent renal disease, and interstitial fibrosis/tubular atrophy (of unknown origin) . Chronic de novo DSA were found to appear at a mean of 4.6 years after transplantation, and the prevalence of de novo DSA after 10 years was 20% in adherent as compared to a remarkable 60% in nonadherent graft recipients [ de novo DSA only when posttransplant DSA occurred after the current and all historic sera at the time of transplantation were negative at a 300 MFI cut-off and when patients showed no evidence of AMR in a 6-month protocol biopsy. With this definition, no de novo DSA were detectable at 6 months and only a 2% incidence of de novo DSA was recorded at 1 year.In a recent publication, 64% of graft losses in a selected patient cohort with indication biopsies were found attributable to (antibody-mediated) rejection [cipients . Of noteNot only nonadherence of the patient to immunosuppressive medication but also reduction of immunosuppression by the physician may lead to adverse outcomes after kidney transplantation. Opelz and Döhler hinted already in 2008 on the problem of “insufficient immunosuppression” as a major cause of graft loss. In an analysis of more than 25,000 kidney transplant recipients, they showed that, in patients with good graft function at year one, discontinuation or reduction after the first posttransplant year of cyclosporine, tacrolimus, or mycophenolate mofetil below certain threshold levels was associated with significantly reduced graft survival during the subsequent years . de novo DSA but has also significant impact when DSA already are present [ de novo DSA and acute graft dysfunction, whereas the rate was only 6% in patients with de novo DSA but stable graft function.Insufficient immunosuppression may also occur during immunosuppressive minimization (tapering) or calcineurin-inhibitor-avoidance trials. In a recent study, 14 of 61 patients (23%) that were converted from cyclosporine to everolimus at 3–4.5 months after transplantation developed DSA, compared to only 7 of 65 patients (11%) who continued on cyclosporine . Eight p present . Wiebe eSeveral important issues are covered by the consensus guidelines that have been published in early 2013 .(1) Posttransplant screening for DSA is recommended for all patient groups in the early postoperative period, however, at different time points dependent on the pretransplant risk of the patient for AMR. In “low risk” patients, who were not sensitized to HLA before transplantation and who received their first allograft, the possible presence of DSA should be examined at least once in the period from 3 to 12 months after transplantation. In “intermediate risk” patients, who were antibody-negative at the time of transplantation but had DSA in previous testing, DSA should be examined already during the first month. No further testing is recommended for both groups during the first year, unless (i) there is a change in immunosuppression, (ii) nonadherence is suspected, (iii) graft dysfunction occurs, or (iv) the patient is transferred to a remote outside center. (2) If DSA are present at any time, a biopsy should be performed, and if the biopsy result is positive, treatment of AMR is recommended. In DSA-positive “high risk” patients and in desensitized crossmatch-positive “very high risk” patients, in addition to DSA monitoring, a biopsy is recommended for all patients during the first 3 months after transplantation. Even if the biopsy result is negative in these two groups but there are rapidly increasing DSA or if the biopsy shows subclinical rejection, treatment of AMR should be initiated. In the absence of AMR, DSA should be monitored and immunosuppression maintained at higher levels. (3) Beyond year one, no routine DSA monitoring is recommended for the four risk groups, except when one of the abovementioned four conditions occurs. Of note, a minority of members within the guidelines group supported HLA antibody monitoring at least once a year in all patients to rule out antibody-mediated allograft injury at its earliest stage. (4) If DSA are detected beyond year 1, patients should be treated and monitored essentially as described above for the first year after transplantation.It needs to be mentioned that the consensus guidelines of TTS were published before Loupy and coworkers published their seminal paper on the impact of complement-binding HLA alloantibodies on kidney graft survival. de novo after transplantation and that are complement-binding/activating denote the highest risk for AMR and graft loss. However, also the recurrence of preexisting antibodies after transplantation or the development of de novo non-DSA may confer an increased risk for graft loss.In summary, despite its known technical limitations , the hig


JHPS, the Journal of Hip Preservation Surgery, our journal, your journal, something different, something new. Issue 1 is now out there and, if the welcoming comments we received at the recent International Society for Hip Arthroscopy meeting in Rio de Janeiro are anything to go by, JHPS is already filling a much-needed gap.I have had the privilege of editing for many years and for a variety of different journals. But then along comes JHPS you will know that an expert in the field will review it. At long last, someone will see your paper for the specialist beast it is and someone, admittedly anonymized, will give your labours a fair hearing. Reviewers, of course, are the unsung heroes of any peer-reviewed journal. They are the guardians of quality; without them a journal such as JHPS simply could not exist.To develop a new journal clearly takes time and when that baby takes its first steps, as an Editor-in-Chief you bite your nails to the quick. At least I do. I now have these stubby, fleshy things which might pass for fingers but having seen the quality of the first issue I realize I need not have worried. The quality is clear, the support has been tremendous, and the willingness of authors to submit and to write with such enthusiasm is something that I thought had escaped me in previous journals. And you should see the reviews. They are brilliant, fantastic, in a league of their own. Now, when you submit your paper to JHPS presently excels. The reviews are detailed, well constructed, in no way vindictive or biased and frequently immensely supportive. After all, a reviewer’s job is not just to decide whether a submission should be published but also to offer advice as to how it might be improved so that it can be accepted next time round. I call such submissions ‘almost-papers’. They are nearly there, not quite, but almost. A little jig here, a tiny jog there, a revamp of a discussion and a paper that might be rejected by journals that are not blessed with specialist reviewers, instantly becomes acceptable to JHPS. I simply had not realized how valuable specialist reviewers can be. They are, in my view, a breed apart and utter gold dust.Unsurprisingly, reviewers do not always agree. Indeed it is quite common that they take different, almost polarized views to the same paper. ‘Accept!’ clamours one, ‘Revise!’ yells another and ‘Reject!’ shouts the third, should we seek a further opinion. Yet although a reviewer’s conclusion is important, more critical is the analysis he (or she) chose to reach a decision. That seems to be where JHPS can hold its head up high, all readers and authors will be aware of potential flaws in the wider biomedical review system. What we have with our journal is not always available elsewhere. It can, for example, sometimes be dangerous to ask authors for their own recommendation of suitable reviewers, as it is not unknown for a recommendation to be falsified. Fabricated identities and contact details are proffered so that the peer review request goes straight back to the originating author. How simple it is for that author to give his own submission a perfect bill of health. Don’t believe me? Have a look at the New York Times [Journal of Vibration and Control was unfortunately affected by this. Sixty papers were retracted as a consequence.Yet although rk Times  or the srk Times  whose puMany journals have great difficulty in finding suitably qualified reviewers for specialist papers. This is a particular problem for the more general publications. One survey of peer review suggested that 56% of reviewers felt there was lack of guidance on how to review while 68% thought that formal training might be of value . That saJHPS reviewer team and our excellent Editorial Board. They are doing well and, as Editor-in-Chief, I trust them implicitly. They are most certainly our guardians of high standard. For those who have read our inaugural issue, I trust you agree that quality was up to par. I particularly enjoyed O’Donnell et al. [So thank Heavens for the l et al.  and theiJHPS is for you.And this, our second issue, the second in what feels such a very short time? Quality is once again within its core. Why not start by looking at Hogervorst and Vereecke’s review on the evolution of the osseous human hip ? I foundMy very best wishes to you all.


Thus far, validated whole blood assays used in in vitro fibrinolysis experiments using thromboelastometry (ROTEM) are lacking or have yet to be tested in humans.The objective was first, to establish a standardized modified ROTEM approach to detect both hypo- and hyperfibrinolysis. And second, to perform a technical and clinical validation of the assay.Blood was used of healthy volunteers, patients with sepsis, patients after cardiothoracic surgery, pregnant women, and cirrhotic liver disease patients. A whole blood tissue factor (TF) activated ROTEM assay with and without the addition of recombinant tissue plasminogen activator (rTPA) was developed. Plasma fibrinolysis determinants were measured in all volunteers and patients.Thirty five pM TF and additions of 125 and 175 ng/ml rTPA resulted in full lysis within 60 min in healthy volunteers. Coefficients of variation were below 10 % without and below 20 % with rTPA addition. In sepsis the hypofibrinolytic ROTEM profiles with 175 ng/ml rTPA were in line with the plasma determinants . After cardiothoracic surgery, reduced fibrinogen and platelet levels accounted for the reduced maximum clot firmness. The hypofibrinolytic profile is attributed to tranexamic acid use and elevated PAI-1 levels. The lowest rTPA concentration in cirrhosis resulted in hyperfibrinolysis in only few of the patients. In pregnancy normal profiles were found.Our high rTPA concentration demonstrates hypofibrinolytic profiles adequately in sepsis and after cardiothoracic surgery. Our low rTPA concentration of 125 ng/ml seems too high for demonstrating hyperfibrinolysis in cirrhotic liver disease.We were able to present a validated whole blood ROTEM approach to fibrinolysis testing using added rTPA, which can be of added value next to classical plasma based fibrinolysis assays. Fibrinolysis is the process of degradation of a fibrin clot into so-called fibrin degradation products (FDPs) of which the d-dimers are best known. Following coagulation, tissue-type plasminogen activator (tPA) induces fibrinolysis by activation of plasminogen into plasmin which enzymatically degrades fibrin into FDPs. To avoid excess clot lysis activity, the fibrinolytic system is under tight control of alpha 2-antiplasmin, plasminogen activator inhibitor-1 (PAI-1), and thrombin activated fibrinolysis inhibitor (TAFI). However, a disbalance in pro- and antifibrinolytic factors can result in either hyper- or hypofibrinolysis, which may contribute to the risk for bleeding or thrombosis, respectively. In trauma and cirrhosis the increased bleeding tendency is attributed to a hyperfibrinolytic state in combination with a rebalanced hemostatic system . In sepsOne of the therapeutic approaches to diminish overt fibrinolysis is treatment with tranexamic acid, which directly inhibits the action of plasmin. For instance, in cardiothoracic surgery this antifibrinolytic drug is being used to prevent and counteract extracorporeal circulation (ECC) induced hyperfibrinolysis , whereasBoth the diagnosis of the fibrinolytic state and the management of therapeutic interventions aimed at the fibrinolytic system could benefit from a sensitive but also robust laboratory assay. Although most proteins and enzymes involved in fibrinolysis can be quantified these do not properly reflect the dynamic status of the fibrinolytic system. Assays developed to detect hypo- or hyperfibrinolysis are not commonly used in daily practice because they are cumbersome, plasma-based and/or not suitable for bedside assessment . SeveralThe goal for our modified ROTEM test was to use whole blood, be tissue factor activated, have one application with and one without the addition of rTPA, and would have similar reproducibility in comparison to the commercial non-modified ROTEM tissue factor activated test (EXTEM). Ideally, it would have short(er) runtimes in comparison to plasma based fibrinolysis assays or markers, have good distinction between healthy volunteers and patient groups, be easy to interpret, and have results in line with plasma based markers for fibrinolysis. In this report we describe the development, the technical, and the clinical validation of a novel whole blood ROTEM based assay application including rTPA to induce fibrinolysis.rd trimester pregnancy, and cirrhotic liver disease Child-Pugh score B or C) was used for clinical validation. Any notion of anticoagulation use in a subject was reason to exclude this subject from the study. Septic patients were recruited within 1 h after the onset of sepsis as judged by the intensive care doctor in charge according to current guidelines [rd trimester of pregnancy were recruited at the policlinic during regular check-ups or at the ward before having elective caesarean section the next day. Child-Pugh score B and C cirrhosis patients were recruited via the policlinic or at the ward after which blood was withdrawn.The institutional Ethics Committee of the Maastricht UMC+ approved this study and of all subjects informed consent was obtained. No compensation was given for participation in this study. Blood of healthy volunteers was used to validate the assay and to define reference intervals, while the blood of 4 patient groups , 3idelines  after whidelines . Cardiot2 at 1 M and HN-Buffer  was prepared in advance and kept at 4–7 °C till further use.Human recombinant tissue factor  was reconstituted according to the manufacturer’s instructions obtaining a 1 IU/mL concentration. This TF solution together with CaClRecombinant tPA  was reconstituted according to the manufacturer’s instructions , immediately aliquoted, frozen, and kept at −80 °C till further use.The blood withdrawal was performed by venipuncture discarding the first 3 mL or, if a radial artery catheter was in situ, by flushing the first 5 mL before the blood was collected in vacuum tubes containing 3.2 % (w/v) citrate , 11 mM citrate with 50 μg/mL corn trypsin inhibitor  and 0.5 M citrate at pH 4.3 . Tubes were gently mixed directly after blood withdrawal.2, and rTPA (if applicable) were added to 300 μL whole blood to obtain final concentrations of 35 pM TF, 10 mM CaCl2, and 0, 125, and 175 ng/mL rTPA . Total volume of the reagents was maintained at 50 μL per cup by applying adequate volumes of HN-buffer.The ROTEM device and cups and pins were from TEM International GmbH . The device temperature was set to 37 °C and the maximum runtime to 120 min. TF, CaClmin-LOTmin)) and the FSc /(LTmin-LOTmin)).The following standard ROTEM parameters were analyzed per channel: CT (clotting time in seconds), MCF (maximum clot firmness in millimeters), LOT (lysis onset time in minutes), and LT (lysis time in minutes). The following derived parameters were calculated using the ROTEM data: the FS  using citrated whole blood. Final values were adjusted for the extra 1/9g for 5 min, followed by a second step at 10,000 g for 10 min. The PPP was directly aliquot, frozen, and kept at −80 °C till further use.Blood was spun twice to gather PPP: a first step at 2,500 A BCS® XP System  was used for determining PT (Dade Innovin), aPTT (Dade actin), alpha 2-antiplasmin activity (Berichrom α2-Antiplasmin), plasminogen activity (Berichrom Plasminogen), factor XIII activity (Berichrom Factor XIII), d-dimer levels (Innovance D-Dimer), and fibrinogen levels (Multifibrin U) in PPP according to the manufacturer’s instructions in batches.ELISA kits for measuring tPA activity (ZYMUPHEN tPA Activity), PAI-1 activity (ZYMUTEST PAI-1 Activity), and TAFI antigen (ZYMUTEST proTAFI Ag) were acquired from Hyphen Biomed  and measured in PPP according to the accompanied instructions in batches.Data were collected and analyzed with IBM SPSS Statistics v19.0.0 . Categorical data are presented as n (%), continuous data as median and inter quartile range (IQR).For reproducibility, coefficients of variation (CV’s) are expressed as the ratio of the standard deviation to the mean. Between run CV’s were calculated using 16 repeated measurements with blood of one withdrawal of one healthy volunteer. For 0 ng/mL rTPA CT and MCF values were analyzed and for 125 and 175 ng/mL rTPA LOT and LT values besides the CT and MCF. Furthermore within run CV’s were calculated from 11 different blood withdrawals in one person over a time span of six months. In this case CT, MCF, LOT, and LT were assessed at 175 ng/ml rTPA.2, TF, and rTPA was used.Optimal time from blood withdrawal to measurement was assessed by using blood of three healthy volunteers and keeping it at 37 °C till further use. CT, MCF, LOT, and LT were measured using the third condition (i.e. 175 ng/mL rTPA) at 30 min, 1 h, 2 h, 3 h, and 4 h after blood withdrawal and assessed for stability. For each time point a new vial of CaClp < 0.05 as statistically significant. Figures were constructed using Graphpad Prism v5.0a .Ninety five percent reference ranges were determined using MedCalc v12.0®  using data from healthy volunteers. Skewed data were normalized first and afterwards transformed back when calculating the 95 % reference ranges. Mann–Whitney-U was used for comparison testing. Determinants of the ROTEM parameters and their 95 % confidence interval (95 % CI) were calculated by multiple linear regression analysis assuming Before establishing the optimal concentrations for the rTPA induced fibrinolysis ROTEM assay, various configurations of TF and rTPA concentrations were investigated. This revealed that TF concentrations below 35 pM resulted in prolonged CT values, whereas the MCF was hardly influenced (data not shown). Therefore, the final TF concentration was set at 35 pM. In blood from healthy volunteers, full clot lysis was obtained at a final rTPA concentration of 125 ng/mL around 60 min, while at a final concentration of 175 ng/mL rTPA full lysis was observed around 45 min (data not shown). These concentrations were appropriate to maintain acceptable short runtimes. At both 125 and 175 ng/mL rTPA, ROTEM was characterized by a lower MCF compared to the assay without tPA (125 ng/mL rTPA: 2 mm (a 3.6 % decrease) and 175 ng/mL rTPA: 5 mm (a 8.4 % decrease)), while the CT prolonged by 5 s (a 11 % increase) and 7 s (a 17 % increase) respectively in comparison to the assay without rTPA.Assessment of reproducibility for the different ROTEM parameters showed between run CV’s of 9.5 % and 1.8 % for the CT and MCF at the 0 ng/mL rTPA concentration. Between run CV’s were 8.7 %, 4.1 %, 12.1 % and 18.8 % for CT, MCF, LOT, and LT at the 125 ng/mL rTPA concentration and for 175 ng/mL rTPA CV’s were 12.1 %, 4.9 %, 16.6 % and 17.1 % for each parameter, respectively.Within run CV’s showed 25 % for CT, 8.4 % for MCF, 16.0 % for LOT, and 27.2 % for LT at 175 ng/ml rTPA.To determine whole blood stability in the assay, ROTEM analysis was started at 30, 60, 120, 180, and 240 min after blood drawing. At 175 ng/mL rTPA, all ROTEM derived parameters remained stable up to 4 h after sample collection  while platelet count, white blood cell count, and fibrinogen levels were not different between the two sexes. Regarding the ROTEM parameters, CT values were significantly different between the two sexes with males having shorter CTs for all rTPA concentrations . Differences between males and females were not observed for the other ROTEM parameters: i.e. MCF, LOT, and LT for any of the three conditions.ROTEM analysis data from 40 healthy volunteers  was used to calculate the 95 % reference intervals  patients of which one patient did not receive tranexamic acid .In total we included 21 sepsis patients, 15 cirrhosis patients, 7 females in their 3Complete blood count  and measurement of PT and aPTT was performed revealing results that are compatible for these patient groups Table .Table 2CIn Fig. p = 0.0121), equal for pregnancy (p = 0.5289), and longer for sepsis (p < 0.0001) and CTS (p = 0.0013) in comparison to healthy volunteers. Although all statistically significant, none of the median clotting times of the groups was outside the normal range established in healthy volunteers. The MCF was lower for CTS (p = 0.0001) and cirrhosis (p = 0.0014), while it was higher in sepsis (p = 0.0003) and pregnancy (p = 0.0008). The MCF in sepsis and pregnancy were both statistically as well as clinically significant in comparison to the healthy volunteers. LOT was prolonged in sepsis (p = 0.0041) and CTS (p = 0.0206), but was equal in cirrhosis (p= 0.1624) and pregnancy (p = 0.1279). The LT could not be determined in any of the groups within the runtime of 120 min.In the absence of rTPA, the CT was shorter for cirrhosis (p < 0.001), whereas the LOT was equal in cirrhosis and pregnancy. The same was seen for the LT, FS, and FSc results, noting that LT could not be reached in any of the CTS patients as can be appreciated from Fig. At 125 ng/mL rTPA the LOT was prolonged in sepsis and CTS (c prolonged in sepsis and CTS (p < 0.001) and equal in cirrhosis and pregnancy.In Fig. Determinants of the cloth strength and fibrinolytic system were assessed for each patient group and the healthy volunteers and are presented in Fig. Median d-dimer levels were elevated (>500 ng/L) in all patient groups, while median FXIII activity levels were below the reference ranges in sepsis (68.1 %) and CTS (62.3 %) only. Median plasminogen activity levels were reduced in sepsis (81 %) and especially in CTS (54 %) and cirrhosis (68 %), while being elevated in a pregnant state (178 %) when compared to healthy volunteers (119 %). The alpha 2-antiplasmin levels were equal in pregnancy (117 %) and sepsis (121 %) compared to healthy volunteers (119 %), but reduced in CTS (56 %) and cirrhosis (77 %). PAI-1 activity levels were high in all patient groups. In those with sepsis the median PAI-1 level was 6.0 ng/mL (IQR 1.7–17.0) and in those with pregnancy the median level was 2.5 ng/mL (IQR 1.1–3.6). tPA activity was low in sepsis (0.01 IU/mL) and pregnancy (0.07 IU/mL) and normal in CTS (0.96 IU/mL) and cirrhosis (1.10 IU/mL) patients. Median TAFI antigen levels were within normal range (50–200 %) in all groups. Fibrinogen, as more a procoagulant marker, together with platelet levels both account for the MCF in the 0 ng/mL rTPA condition with a significant Pearson correlation R of 0.71 and 0.57, respectively.ECLT’s  a hypofibrinolytic state (long LOT and LT combined with reduced FS and FSc) in conjunction with a marked procoagulant state (high MCF) is evident, despite the fact that high D-dimer levels suggest a high fibrinolytic activity. ECLT testing showed a hypofibrinolytic state in sepsis, which is in agreement with our rTPA induced ROTEM assay. D-dimer levels are determinants of different processes , includiIn patients with CTS being administered tranexamic acid a hypofibrinolytic state is observed (reduced FS and FSc), although an overall reduced maximum clot firmness to start with is present in this group. The ECLT in this group did not show a hypofibrinolytic state, but rather a normal state when compared to healthy volunteers. The difference between the ECLT and our ROTEM assay appears to be due to the fact that tranexamic acid does not precipitate in the ECLT test . ReducedCirrhotic liver disease patients do not seem to differ from healthy volunteers regarding their global fibrinolytic rTPA-ROTEM profile with equal LOT, LT, FS, and FSc in both rTPA induced conditions together with a globally reduced procoagulant state. The ECLT was markedly reduced. Both findings are coherent with other studies as was researched and discussed previously by our group . This rePregnancy is associated with a gradual increase in PAI-1 over time , as confFibrinogen levels and also platelet levels seem to correlate well with MCF for any given group, an all-by-all no new finding .Thus far the test is able to pickup hypofibrinolysis accurately in groups of patients with the 175 ng/mL rTPA concentration and could guide therapy in CTS and sepsis. One could argue that the amount of tranexamic acid given to CTS patients is too much if even at the high concentration of rTPA no fibrinolysis is seen within 2 h. This assay could be used to titrate the drug following the ROTEM graphs and results in conjunction with clinical relevant outcomes. Trauma induced coagulopathy (TIC) is a very interesting syndrome in which overt hyperfbrinolysis is sometimes seen using ROTEM without the need for rTPA addition. As is shown by the Crash-2 trial  the use As a limitation, hyperfibrinolysis could not be shown in a group of patients with cirrhosis when averaging their results. However, some individual patients do show a hyperfibrinolytic potential, while others do not. Still, this assay might be useful for individual patients with cirrhotic liver disease to diagnose (and treat) hyperfibrinolysis, although the rTPA addition needs titrating to a lower concentration.Another limitation is the manual pipetting that is required up till now. Having ready to use solutions and implementing them together with the automatic pipetting function on the ROTEM device could greatly reduce the inter-observer variability, especially for the clotting times.Our rTPA induced fibrinolysis ROTEM assay showed different results in comparison to the ECLT test. This is because there are essential differences between both tests. The ECLT is plasma based and due to acidification of the plasma only few factors are precipitated, the euglobulin fraction. As such, the role of red blood cells and thrombocytes is excluded in the ECLT on fibrinolysis regulation. This makes our test a valuable addition to the arsenal of fibrinolysis testing.In conclusion, we developed a reproducible whole blood rTPA ROTEM assay for diagnosing hypofibrinolytic potential with short turnaround times, which in healthy volunteers seems to produce acceptable variations resulting in narrow reference intervals. The 175 ng/ml rTPA concentration appears to be sensitive for the medication effect of tranexamic acid on fibrinolysis, which is in contrast to the ECLT for tranexamic acid. This 175 ng/ml concentration may distinguish a hypo- from a normofibrinolytic potential. The implementation of this test needs to be evaluated in more prominent hyperfibrinolytic disease states, like trauma or thrombolysis therapy, in order to address the potential utility in the diagnostic workup of patients with fibrinolytic dysfunction, as well as in guiding anti-fibrinolytic management.


Winner: Dr. Jesse BloomRunner up: Dr. Alexander PlossViruses accepted nominations for a 2015 Young Investigator Prize in Virology. The target age was set at 40 and under. Over 50 nominations were received and were evaluated by a panel of judges comprised of Viruses editorial board members.With the goal of recognizing outstanding contributions to the field of virology by early-career investigators, last year Viruses Young Investigator Award.. Dr. Bloom received his Ph.D. with Dr. Frances Arnold and did postdoctoral training with Dr. David Baltimore, both at Caltech. Since 2011, he has been an Assistant Member in the Division of Basic Sciences at the Fred Hutchinson Cancer Research Center. Dr. Bloom’s research combines experimental and computational approaches to study influenza virus, with a focus on developing a better understanding of the biophysical and immunological constraints and selection pressures that shape influenza virus evolution. A major strength of his research is to seamlessly integrate molecular virology, next-generation sequencing, and computational biology to ask critical questions about influenza virus evolution. A highlight of Dr. Bloom’s postdoctoral research was an influential paper published in Science on the molecular basis for influenza virus resistance to oseltamivir (Tamiflu). More recently (ELife 2014), Dr. Bloom’s lab demonstrated that the “head” of the influenza hemagglutinin (HA) protein is highly tolerant of mutations. As the head of HA is the region of the protein that is targeted by antibodies, this finding sheds light on the remarkable ability of the influenza virus to escape the host immune response.I am pleased to announce Dr. Jesse Bloom of the Fred Hutchinson Cancer Research Center in Seattle, Washington, as the recipient of the 2015 Dr. Bloom has received a number of awards and honors, including a Searle Scholar Award and a Sloan Research Fellowship.When Dr. Bloom is not in the lab, he enjoys outdoor activities, such as running, hiking, and biking.Viruses conference, Viruses 2016—At the Forefront of Virus-Host Interactions, to be held 26–28 January 2016, in Basel, Switzerland, http://sciforum.net/conference/viruses-2016.In addition to the cash prize and plaque, Dr. Bloom will be an invited speaker at the 2016 Because of the outstanding quality of the nominations received for this award, we are also pleased to announce a runner-up: Dr. Alexander Ploss from Princeton University. Dr. Ploss conducted his Ph.D. research at the Memorial Sloan-Kettering Cancer Center in New York in the lab of Dr. Eric Palmer and did postdoctoral research with Dr. Charlie Rice at the Rockefeller University. In 2009, he was appointed Assistant Professor at the Rockefeller University and in 2013 he became an Assistant Professor at Princeton University. Dr. Ploss’s research is focused on addressing fundamental questions about hepatitis B and C virus infection using humanized mouse model systems. He is an author on over 60 scientific articles, many of which are published in high-impact journals. Dr. Ploss has received several honors and awards including the Astellas Young Investigator Award of the Infectious Disease Society of America and the Liver Scholar Award of the American Liver Foundation.When not in the lab, Dr. Ploss is playing his violin, or, together with his wife, caring for their four young children.Viruses sponsored a competition for travel awards for two graduate students or postdoctoral fellows to attend meetings of their choice. The 2015 travel award winners are Dr. Kirsty Short, a postdoctoral fellow in the lab of Dr. Thijs Kuiken, Department of Viroscience, Rotterdam, the Netherlands, and Dr. Redmond Smyth, a post-doctoral researcher in the lab of Dr. Roland Marquet, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.In addition to the Young Investigator Award, Viruses editorial staff and editorial board members, I wish to congratulate the four outstanding young virologists for their accomplishments.On behalf of the


From March 28 through April 2, 2015, the scientific community performing research on connexin-, pannexin- and innexin-based channels (gap junction channels and hemichannels) attended the International Gap Junction Conference in Valparaíso, Chile  for their invaluable support and assistance with the logistics of the meeting. In addition, we are indebted to the CINV, Pontificia Universidad Católica, GrupoBios, Nanion Technology and Loncotec for their financial support, which covered some of the activities associated with the Conference. Finally, we are thankful to the Chilean Millennium Initiative of the Chilean Government for the CINV (P09-022-F) grant directed by Dr. Ramón Latorre through which we financed several activities and allowed us granting of 43 international student fellowships.


Middle East respiratory syndrome coronavirus (MERS-CoV) with pandemic potential is a major worldwide threat to public health. However, vaccine development for this pathogen lags behind as immunity associated with protection is currently largely unknown. In this study, an immunoinformatics-driven genome-wide screening strategy of vaccine targets was performed to thoroughly screen the vital and effective dominant immunogens against MERS-CoV. Conservancy and population coverage analysis of the epitopes were done by the Immune Epitope Database. The results showed that the nucleocapsid (N) protein of MERS-CoV might be a better protective immunogen with high conservancy and potential eliciting both neutralizing antibodies and T-cell responses compared with spike (S) protein. Further, the B-cell, helper T-cell and cytotoxic T lymphocyte (CTL) epitopes were screened and mapped to the N protein. A total of 15 linear and 10 conformal B-cell epitopes that may induce protective neutralizing antibodies were obtained. Additionally, a total of 71 peptides with 9-mer core sequence were identified as helper T-cell epitopes, and 34 peptides were identified as CTL epitopes. Based on the maximum HLA binding alleles, top 10 helper T-cell epitopes and CTL epitopes that may elicit protective cellular immune responses against MERS-CoV were selected as MERS vaccine candidates. Population coverage analysis showed that the putative helper T-cell epitopes and CTL epitopes could cover the vast majority of the population in 15 geographic regions considered where vaccine would be employed. The B- and T-cell stimulation potentials of the screened epitopes is to be further validated for their efficient use as vaccines against MERS-CoV. Collectively, this study provides novel vaccine target candidates and may prompt further development of vaccines against MERS-CoV and other emerging infectious diseases. Betacoronavirus, and is a zoonotic virus that is transmitted from bats to camels, and then to humans [Middle East respiratory syndrome (MERS) is a newly emerging acute respiratory system infectious disease, which is characterised by acute pneumonia, respiratory failure, and renal failure and caused by MERS-coronavirus (MERS-CoV) ,2. MERS-o humans ,4,5. Theo humans . MERS-Coo humans . As of Jo humans . No liceet al. constructed a full-length infectious cDNA clone of the MERS-CoV genome that lacked of E gene by reverse genetics approach to develop attenuated viruses as vaccine candidates [As one of the most effective strategies to prevent virus infection, vaccination is considered to be indispensable especially in the absence of effective treatment drugs. The continuous increase of patients and a high mortality rate of MERS-CoV infection highlight the urgent need for safe and effective vaccines development. The majority of recent progresses focused on the viral S glycoprotein and receptor-binding domain (RBD) of S protein –19, and ndidates . TheoretEpitopes are also known as the antigenic determinant, which represents the minimal immunogenic region of a protein antigen and precisely elicit a specific immune responses . NumerouIn this study, based on newly available genome sequence data of MERS-CoV, numerous epitope vaccine candidates that could elicit protective humoral and cellular immune responses were obtained by immunoinformatics-driven vaccine target screening strategy. These results provided new vaccine epitope candidates for MERS vaccine development, and indicated that immunoinformatic-driven immunogen screening is a promising strategy to accelerate vaccine development of the emerging highly pathogenic pathogens.http://www.ncbi.nlm.nih.gov/) and used as an input for various bioinformatics tools for antigenicity assessment, secondary structure and 3D model prediction, and epitope prediction. These sequences come from different geographic regions such as Saudi Arabia, England, Qatar, Spain, Germany, Jordan, and Korea with time ranges from 2012 to 2015.The entire viral proteome sequences of all MERS-CoV isolates that include structural proteins spike protein (S), envelope protein (E), membrane protein (M), nucleocapsid protein (N), and non-structural proteins ORF3, ORF4a, ORF4b, ORF5 and ORF8b, and two replicase polyproteins ORF1ab and ORF1a, were retrieved from the National Center for Biotechnology Information database (http://www.ddg-pharmfac.net/vaxijen/VaxiJen/VaxiJen.html) was used for analyzing whole protein antigenicity and determined the most potent antigenic protein. The VaxiJen is a web server, that was developed by Dr. Doytchinova IA and Dr. Flower DR, from Faculty of Pharmacy, Medical University of Sofia, for prediction of protective antigens, tumor antigens and subunit vaccines, with prediction accuracy of 70% to 89% for the discrimination between antigens and non-antigens [http://web.expasy.org/protparam/) and a self-optimized prediction method for alignment (SOPMA) [https://npsa-prabi.ibcp.fr/cgi-bin/npsa_automat.pl?page=/NPSA/npsa_sopma.html) with default parameter. ProtParam is a tool which allows the computation of various parameters including the molecular weight, theoretical pI, amino acid composition, atomic composition, extinction coefficient, estimated half-life, instability index, aliphatic index and grand average of hydropathicity (GRAVY) for a given protein. The SOPMA method correctly predicts 69.5% of the secondary structure α-helix, β-sheet and coil [http://raptorx.uchicago.edu/) was used to predict the three-dimensional (3D) structure and binding residues of the chosen protein.Antigenicity refers to the ability of antigen that can be recognized by the immune system. Hence, to find the best potential candidate antigen, the VaxiJen v2.0 server  (http://antigens . In thisantigens  (http:// (SOPMA)  (https:/and coil . The Rapand coil  (http://http://tools.immuneepitope.org/bcell/) was applied to predict linear B-cell epitopes. The Kolaskar and Tongaonkar method has been applied to a large number of proteins to predict B-cell epitopes by the developers. Their results showed that the method can predict epitopes with about 75% accuracy; hence, it is better than most of the known methods [http://tools.immuneepitope.org/ellipro/) [The method of Kolaskar and Tongaonkar  at the I methods . Further methods  and Emin methods  with a tllipro/)  with thellipro/) .http://www.cbs.dtu.dk/services/NetMHCIIpan/) was used to predict helper T-cell epitopes. Threshold for strong binding peptides (IC50) was set at 50 nM to determine the binding and interaction potentials of helper T-cell epitope peptide and major histocompatibility complex (MHC) class II allele. The NetMHCIIpan-3.0 is the first pan-specific helper T-cell epitope prediction method that covers all human leucocyte antigen (HLA) class II molecules including HLA-DR, HLA-DP, and HLA-DQ. It can predict peptide binding to any HLA class II molecule in a specified protein sequence [The NetMHCIIpan 3.0 server   was used to predict the immunogenicity of the candidate epitopes [The cytotoxic T lymphocyte (CTL) epitope prediction was made using the IEDB analysis resource NetMHCpan (version 2.8) tool ,38 and tepitopes . This tohttp://tools.immuneepitope.org/tools/conservancy/iedb_input) at the IEDB was applied for the epitope conservancy analysis [The epitope conservancy analysis tool . AllerHunter is a SVM-pairwise system for assessment of allergenicity and allergic cross-reactivity in proteins. It aims to predict allergens and non-allergens with high sensitivity and specificity, without compromising efficiency at classification of proteins with similar sequences to known allergens [The allergenicity of the epitopes was analyzed by the AllerHunter server  (http://llergens .http://tools.immuneepitope.org/tools/population/iedb_input) [Due to the MHC restriction of T cell response, the peptides with more different HLA binding specificities mean more population coverage in defined geographical regions where the peptide-based vaccine might be employed. The population coverage rate of individual epitope was calculated using the IEDB population coverage tool (b_input) .Every epitope and its binding HLA alleles were added, and different geographic areas were also selected.1965H3102N594O611S7, 70 alpha helixes, 66 extended strands, 32 beta turns, and 245 random coils are obtained and shown in The selection of immunogen is the first step for vaccine design; hence, to obtain the most probable antigenic protein, the whole viral proteomes of all MERS-CoV isolates were retrieved and screened. A total of 99 MERS-CoV variants from different geographical regions with their entire proteomes were obtained . The antin silico identification of B-cell epitopes based on the IEDB database was performed. Based on the Kolaskar and Tongaonkar’s method of the IEDB, a total of 15 linear B-cell epitopes of the N protein of MERS-CoV were identified. The length of the epitopes ranged from 6 to 20 amino acids. These epitopes had 78–91% conservancy level among the specified N protein sequences. Notably, the epitopes 4PAAPRAVSF12 and 324NPVYFLRYSGAIKL337 were allergic to human; hence, they could not be vaccine candidates. Epitopes’ length, sequences, location, conservancy, and allergenicity are shown in 363KKEKKQ368, where 365E is the surface residue. The minimum value of surface probability is 0.074 for peptides 205GIGAVG210, where 207G is the surface residue  plays a crucial role in controlling virus infection. Hence, identification of CTL epitopes is vital for understanding the principles of T cell activation and epitope-driven vaccine design. Herein, a total of 34 immunogenic peptides with 9-mer sequences in the N protein of MERS-CoV were identified to be CTL epitopes using the MHC-I binding predictions of the IEDB with recommended methods , followed by 343NYNKWLELL351 . Yet, the epitopes 72AQNAGYWRR80  and 387RVQGSITQR395  had the minimum number of binding HLA-A alleles. Most CTL epitope candidates with a positive score of immunogenicity showed a high potential to elicit strong CTL response. Further, these CTL epitope candidates were highly conserved with 85–91% conservancy level among available N protein sequences of MERS-CoV isolates, and no epitope was found allergic to humans. Details of predicted putative CTL epitopes along with their respective binding HLA-A alleles are shown in As we all know, MHC-I restricted CD8 methods . They ca methods . Among tHLA distribution varies among different ethnic groups and geographic regions around the world. Thus, population coverage must be taken into account when designing an effective vaccine to cover as much as possible populations. In this study, all indicated alleles in supplementary data were identified as optimum binders with the predicted epitopes and were used to determine the population coverage for these epitopes. The high population coverage was found for all putative helper T-cell epitopes and CTL epitopes in 15 specified geographic regions of the world . For helEmerging infectious pathogens such as MERS-CoV, H5N1, and H7N9 are highly pathogenic for humans. For these pathogens, immunity associated with protection remain largely unknown. Gaps in understanding the protective immunity against these pathogens make developing vaccines for newly emerging infectious diseases more difficult and challenging . Thus, tet al. demonstrated that a SARS-CoV vaccine based on the N gene that was expressed by DNA plasmid and adenovirus vector could induce detectable antibody and IFN-γ [et al. [in vitro and in vivo tests for their antigenic and immunogenetic potentials.This study aim to screen and investigate the most antigenic protein of the MERS-CoV and to find out the B- and T-cell epitopes that were mapped on the most antigenic protein by using a strategy namely genome-wide screening of vaccine epitopes. Based on advances in bioinformatics, the immunoinformatics approach could be an effective and essential strategy for vaccine development of emerging highly pathogenic pathogens. In this study, an immunoinformatics-driven approach was used to screen vital dominant immunogens against MERS-CoV. The results showed that the N protein was a better antigenic protein with the highest antigenic scores compared with other viral proteins in entire viral proteome. However, nearly all current studies of MERS vaccine focused on the S protein of MERS-CoV –19, becand IFN-γ . Similarnd IFN-γ ,53. Morend IFN-γ –58. Addind IFN-γ ,60. And  [et al. . Based o108EAALPFRAVKDGIVWVHED126, showed a lower conservancy of 78% among different MERS-CoV isolates compared with other 14 epitopes, suggesting that it might be not an idea epitope candidate based on the fact that an epitope should be as conservative as possible to provide broader protection among different virus strains. In addition, various continuous and discontinuous B-cell epitopes were mapped on the N protein Click here for additional data file.S2 FigX-axis represents the amino acids, whereas Y-axis represents accessible propensity. Average antigenic score was 1.000. Area displayed by the threshold line is considered as potential B-cell accessible regions.(PDF)Click here for additional data file.S3 FigX-axis represents the amino acids, whereas Y-axis represents flexible propensity. Average antigenic score was 1.028. Area displayed by the threshold line is considered as potential B-cell flexible regions.(PDF)Click here for additional data file.S1 Table(XLS)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.


Allergy, Asthma & Clinical Immunology (AACI) was founded, and was published by BC Decker from that year until 2009. In 2009, a decision was made to change to an electronic format and the Journal joined BioMed Central.The Canadian Society of Allergy & Clinical Immunology, founded in 1945, published its first Journal in 1996, as the Canadian Journal of Allergy & Clinical Immunology, under the Editorship of Dr Gordon Sussman. It was a hard copy journal containing mostly solicited manuscripts and its circulation was limited primarily to Society members. In 2004, AACI never had more than a few hundred subscribers, compared to the 20,000 to 35,000 accesses to the articles when they transferred to an electronic format.It is interesting to note that a number of our most accessed papers were originally submitted to the hard copy version of the Journal produced by BC Decker  has increased progressively since 2009 from 0.1 to 0.5-0.6 in 2013 and the Source Normalized Impact per paper (SNIP) has increased from <0.1 to >0.8.Since joining BioMed Central, under the Editorships of Drs. Warrington, Kim & Watson, The number of manuscript publications has also increased progressively since 2010 from 33 in that year to 50 in 2013, the number in 2014 was at 40 as of July 2014.Clinical & Experimental Allergy. The UK is still third on the list of page visits.Regarding the Country of origin of the manuscripts published in the Journal Table , the majCitations have also increased since joining BioMed Central, from <10 in 2009 to 240 in 2013, an indication of the growing interest in articles published in the Journal.In terms of citations, it appears that guidelines are more frequently cited than other manuscripts, although we do not have information on the citation of our Primer on Allergy & Immunology which was published as a supplement. Articles in that supplement are among our most highly accessed.When we compare highly accessed articles all time with those accessed in the last month Table , there iAACI has also been successful in its publication of supplements. In addition to the yearly supplement containing abstracts from the Annual Meeting of the Canadian Society of Allergy & Clinical Immunology, we also publish abstracts from the Allergen NCE Inc. Annual Meeting, recently held in conjunction with the CSACI Meeting. This extremely valuable collaboration enhances and expands the basic science interest in the Annual Meeting and facilitates interactions between basic scientists, clinician scientists and clinicians.AACI has been in the form of an educational supplement providing review articles on Allergy & Clinical Immunology topics suitable for Medical School teaching and the education of non-specialist physicians. The articles in this supplement have also been among the most accessed publications in AACI. This emphasizes the strong educational value of the open access system particularly as the cost of textbooks in Allergy & Immunology increases progressively.A second successful contribution by AACI is in the form of guidelines for the treatment and management of allergic and immunologic disease. Some frequently accessed examples of these guidelines are provided in Table A third successful source of information in Reviewing data from Google Analytics, the number of page views per month has increased progressively to 34,660 in the month of July. Of these, 15,112 were unique visitors, while new visitors are typically about 20% of all visits. Of these, the majority are from the United States, followed by Canada, India and the United Kingdom. The number of new visitors is encouraging with regard to the increasing visibility of the Journal and interest in its content. Approximately 12,000 sessions originate from Google searches, compared to 189 from Bing and 143 from Yahoo. Two thousand one hundred and twenty visits were direct and 668 were from BioMed Central. The latter had the greatest number of page session, at 5.15, compared to 1.66 from Google and 1.59 from PubMed. Direct visits, most likely from return visitors, viewed 2.48 pages per session. These data are interesting in terms of the methods of access to the journal, with a greater number of visitors from search engines, who view only a limited number of pages, compared to visitors who come direct to the Journal or through BioMed Central.th year of publication, we would like to thank the Co-editors of AACI, the Editorial Board, who have worked hard to make the Journal a success, and the many reviewers who have contributed their time and expertise.In this, our 10In addition, we thank the Canadian Society of Allergy & Clinical Immunology, the Executive and Board and Management team without whose support, both financial and by their contributions to the Journal; we would not have achieved this success.Finally, we must thank the many staff at BioMed Central that have contributed to our success. A special thanks to Lisa Hussey and Holly Young, who have guided the Journal through the last several years successfully.AACI first began publishing in 2004, our goal was to publish high quality research and review manuscripts, with the aim of eventually achieving indexing in PubMed, Current Contents etc. Our manuscripts were then by invitation only. Since joining BioMed Central, we have achieved the aim of indexing, including now Science Citation Index Expanded, and are awaiting our first official Impact Factor from Thompson Reuters. What we wish to achieve in the next 10 years is a steady increase in the number and quality of submissions, so that we can enhance the international reputation of our journal and Society. This can be achieved by taking advantage of the tremendous advances in our understanding of allergic and immunologic diseases and the new treatments that have become available. This knowledge can be widely disseminated by the important medium of Open Access.When Richard Warrington, Editor-in-Chief, Allergy Asthma & Clinical ImmunologyPaul Keith, President, Canadian Society of Allergy & Clinical Immunology