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Radiologists assess the results of mammography, the key screening tool for the detection of breast cancer, to determine the presence of malignancy. They, routinely, compare recent and prior mammographic views to identify changes between the screenings. In case a new lesion appears in a mammogram, or a region is changing rapidly, it is more likely to be suspicious, compared to a lesion that remains unchanged and it is usually benign. However, visual evaluation of mammograms is challenging even for expert radiologists. For this reason, various Computer-Aided Diagnosis (CAD) algorithms are being developed to assist in the diagnosis of abnormal breast findings using mammograms. Most of the current CAD systems do so using only the most recent mammogram. This paper provides a review of the development of methods to emulate the radiological approach and perform automatic segmentation and/or classification of breast abnormalities using sequential mammogram pairs. It begins with demonstrating the importance of utilizing prior views in mammography, through the review of studies where the performance of expert and less-trained radiologists was compared. Following, image registration techniques and their application to mammography are presented. Subsequently, studies that implemented temporal analysis or subtraction of temporally sequential mammograms are summarized. Finally, a description of the open access mammography datasets is provided. This comprehensive review can serve as a thorough introduction to the use of prior information in breast cancer CAD systems but also provides indicative directions to guide future applications.

Breast cancer remains one of the leading cancers worldwide and is the main cause of death in women with cancer. Effective early-stage diagnosis can reduce the mortality rates of breast cancer. Currently, mammography is the most reliable screening method and has significantly decreased the mortality rates of these malignancies. However, accurate classification of breast abnormalities using mammograms is especially challenging, driving the development of Computer-Aided Diagnosis (CAD) systems. In this work, subtraction of temporally consecutive digital mammograms and machine learning were combined, to develop an algorithm for the automatic detection and classification of benign and malignant breast masses. A private dataset was collected specifically for this study. A total of 196 images were gathered, from 49 patients (two time points and two views of each breast), with precisely annotated mass locations and biopsy confirmed malignant cases. For the classification, ninety-six features were extracted and five feature selection techniques were combined. Ten classifiers were tested, using leave-one-patient-out and 7-fold cross-validation. The classification performance reached 91.7% sensitivity, 89.7% specificity and 90.8% accuracy, using Neural Networks, an improvement, compared to the state-of-the-art algorithms that utilized sequential mammograms for the classification of benign and malignant breast masses. This work demonstrates the effectiveness of combining subtraction of temporally sequential digital mammograms, along with machine learning, for the automatic classification of benign and malignant breast masses.

Merkel cell carcinoma (MCC) of the skin is a rare, aggressive and often fatal neuroendocrine skin cancer. The incidence of MCC has significantly increased in the last decades. Factors that have been associated with the development of MCC include infection with Merkel Cell polyomavirus (MCPyV), ultraviolet exposure, hematologic malignancies and immunosuppression.We present three cases of patients living with HIV who were diagnosed with MCC. HIV cases associated with MCC have been rarely reported and to our knowledge, not yet before in the UK.

Breast cancer remains the leading cause of cancer deaths and the second highest cause of death, in general, among women worldwide. Fortunately, over the last few decades, with the introduction of mammography, the mortality rate of breast cancer has significantly decreased. However, accurate classification of breast masses in mammograms is especially challenging. Various Computer-Aided Diagnosis (CAD) systems are being developed to assist radiologists with the accurate classification of breast abnormalities. In this study, classification of benign and malignant masses, based on the subtraction of temporally sequential digital mammograms and machine learning, is proposed. The performance of the algorithm was evaluated on a dataset created for the purposes of this study. In total, 196 images from 49 patients, with precisely annotated mass locations and biopsy confirmed malignant cases, were included. Ninety-six features were extracted and five feature selection algorithms were employed to identify the most important features. Ten classifiers were tested using leave-one-patient-out and 7-fold cross-validation. Neural Networks, achieved the highest classification performance with 90.85% accuracy and 0.91 AUC, an improvement compared to the state-of-the-art. These results demonstrate the effectiveness of the subtraction of temporally consecutive mammograms for the classification of breast masses as benign or malignant.

Objective: Cancer remains a major cause of morbidity and mortality globally, with 1 in 5 of all new cancers arising in the breast. The introduction of mammography for the radiological diagnosis of breast abnormalities, significantly decreased their mortality rates. Accurate detection and classification of breast masses in mammograms is especially challenging for various reasons, including low contrast and the normal variations of breast tissue density. Various Computer-Aided Diagnosis (CAD) systems are being developed to assist radiologists with the accurate classification of breast abnormalities. Methods: In this study, subtraction of temporally sequential digital mammograms and machine learning are proposed for the automatic segmentation and classification of masses. The performance of the algorithm was evaluated on a dataset created especially for the purposes of this study, with 320 images from 80 patients (two time points and two views of each breast) with precisely annotated mass locations by two radiologists. Results: Ninety-six features were extracted and ten classifiers were tested in a leave-one-patient-out and k-fold cross-validation process. Using Neural Networks, the detection of masses was 99.9% accurate. The classification accuracy of the masses as benign or suspicious increased from 92.6%, using the state-of-the-art temporal analysis, to 98%, using the proposed methodology. The improvement was statistically significant (p-value < 0.05). Conclusion: These results demonstrate the effectiveness of the subtraction of temporally consecutive mammograms for the diagnosis of breast masses. Clinical and Translational Impact Statement: The proposed algorithm has the potential to substantially contribute to the development of automated breast cancer Computer-Aided Diagnosis systems with significant impact on patient prognosis.

Detection of CTCs represents a poor prognostic factor in patients with early and metastatic breast cancer (mBC) and treatment with everolimus–exemestane (E/E) is an established effective treatment in hormone receptor-positive/HER2-negative mBC patients. The effect of E/E on CTCs in mBC patients was prospectively investigated. CTCs from 50 pre-treated patients with mBC receiving E/E were analyzed using the CellSearch (CS) platform and triple immunofluorescence (IF) staining for cytokeratin, M30 and Ki67 expression to assess their proliferative and apoptotic status. CTCs (by CS) were detected in 64% of patients before treatment and E/E administration resulted in their decreased prevalence [(n = 18; 36%, p = 0.004) and (n = 7; 19.4%, p = 0.019) post-1st and post-3rd treatment cycle, respectively] whereas it was significantly increased at disease progression (PD: 61%) compared to post-1st and post-3rd cycle (p = 0.049 and p = 0.021, respectively). Ki67-positive CTCs were detected in 60%, 60%, 17% and 50% of patients before treatment, post-1st, post-3rd cycle and at PD, respectively, while the opposite was observed for M30-positive CTCs (0% at baseline, 10% after the 1st cycle, 50% after the 3rd cycle and 0% at PD). The detection of even ≥ 1 CTC/5 ml after one cycle was associated with decreased PFS (3.3 vs 9.0 months, p = 0.025) whereas the detection of even ≥ 2 CTCs at PD was associated with decreased OS (32.4 vs 19.5 months; p = 0.009). The combination of E/E resulted in early elimination of proliferating CTCs in mBC patients and this effect was associated with a favorable clinical outcome.

Hidradenitis suppurativa (HS) is a chronic-inflammatory disease, characterized by painful inflamed nodules, abscesses, and pus-draining tunnels appearing in axillary, inguinal, and perianal skin areas. HS lesions contain various types of immigrated immune cells.Characterization of mediators supporting lesional B/plasma-cell persistence in HS.Skin samples from several cohorts of HS patients and control cohorts were assessed by RNA-sequencing, RT-qPCR, flow-cytometry, and immunohistofluorescence. Blood and cultured skin biopsies, keratinocytes, dermal fibroblasts, neutrophilic granulocytes (neutrophils), monocytes, and B-cells were analyzed. Complex systems biology approaches were used to evaluate bulk and single-cell RNA-sequencing data.The proportions of B/plasma cells, neutrophils, CD8Neutrophil-derived BAFF seems to support B/plasma-cell persistence and function in HS lesions CLINICAL IMPLICATION: Therapeutic targeting of BAFF pathway in HS is worth being explored in clinical trials.

Background Our aim was to demonstrate that automated detection and classification of breast microcalcifications, according to Breast Imaging Reporting and Data System (BI-RADS) categorisation, can be improved with the subtraction of sequential mammograms as opposed to using the most recent image only. Methods One hundred pairs of mammograms were retrospectively collected from two temporally sequential rounds. Fifty percent of the images included no (BI-RADS 1) or benign (BI-RADS 2) microcalcifications. The remaining exhibited suspicious findings (BI-RADS 4-5) in the recent image. Mammograms cannot be directly subtracted, due to tissue changes over time and breast deformation during mammography. To overcome this challenge, optimised preprocessing, image registration, and postprocessing procedures were developed. Machine learning techniques were employed to eliminate false positives (normal tissue misclassified as microcalcifications) and to classify the true microcalcifications as BI-RADS benign or suspicious. Ninety-six features were extracted and nine classifiers were evaluated with and without temporal subtraction. The performance was assessed by measuring sensitivity, specificity, accuracy, and area under the curve (AUC) at receiver operator characteristics analysis. Results Using temporal subtraction, the contrast ratio improved ~ 57 times compared to the most recent mammograms, enhancing the detection of the radiologic changes. Classifying as BI-RADS benign versus suspicious microcalcifications, resulted in 90.3% accuracy and 0.87 AUC, compared to 82.7% and 0.81 using just the most recent mammogram (p = 0.003). Conclusion Compared to using the most recent mammogram alone, temporal subtraction is more effective in the microcalcifications detection and classification and may play a role in automated diagnosis systems.

Detection of CTCs represents a poor prognostic factor in patients with early and metastatic breast cancer (mBC) and treatment with everolimus-exemestane (E/E) is an established effective treatment in hormone receptor-positive/HER2-negative mBC patients. The effect of E/E on CTCs in mBC patients was prospectively investigated.CTCs from 50 pre-treated patients with mBC receiving E/E were analyzed using the CellSearch (CS) platform and triple immunofluorescence (IF) staining for cytokeratin, M30 and Ki67 expression to assess their proliferative and apoptotic status.CTCs (by CS) were detected in 64% of patients before treatment and E/E administration resulted in their decreased prevalence [(n = 18; 36%, p = 0.004) and (n = 7; 19.4%, p = 0.019) post-1st and post-3rd treatment cycle, respectively] whereas it was significantly increased at disease progression (PD: 61%) compared to post-1st and post-3rd cycle (p = 0.049 and p = 0.021, respectively). Ki67-positive CTCs were detected in 60%, 60%, 17% and 50% of patients before treatment, post-1st, post-3rd cycle and at PD, respectively, while the opposite was observed for M30-positive CTCs (0% at baseline, 10% after the 1st cycle, 50% after the 3rd cycle and 0% at PD). The detection of even ≥ 1 CTC/5 ml after one cycle was associated with decreased PFS (3.3 vs 9.0 months, p = 0.025) whereas the detection of even ≥ 2 CTCs at PD was associated with decreased OS (32.4 vs 19.5 months; p = 0.009).The combination of E/E resulted in early elimination of proliferating CTCs in mBC patients and this effect was associated with a favorable clinical outcome.

The prevailing ‘division of labor’ concept in cellular immunity is that CD8+ T cells primarily utilize cytotoxic functions to kill target cells, while CD4+ T cells exert helper/inducer functions. Multiple subsets of CD4+ memory T cells have been characterized by distinct chemokine receptor expression. Here, we demonstrate that analogous CD8+ memory T-cell subsets exist, characterized by identical chemokine receptor expression signatures and controlled by similar generic programs. Among them, Tc2, Tc17 and Tc22 cells, in contrast to Tc1 and Tc17 + 1 cells, express IL-6R but not SLAMF7, completely lack cytotoxicity and instead display helper functions including CD40L expression. CD8+ helper T cells exhibit a unique TCR repertoire, express genes related to skin resident memory T cells (TRM) and are altered in the inflammatory skin disease psoriasis. Our findings reveal that the conventional view of CD4+ and CD8+ T cell capabilities and functions in human health and disease needs to be revised., We classically consider the T cell compartment divided into cytotoxic CD8+ T cells and multiple, different helper CD4+ T cell subsets. Here the authors demonstrate that distinct memory CD8+ T cell subsets phenotypically inhabit CD4+ T cell like populations including some with helper-like characteristics.

Breast cancer is one of the deadliest malignancies worldwide. In mammography, the most reliable screening tool for its diagnosis, expert radiologists review the mammograms to determine whether the patient has any signs of disease. Unfortunately, the evaluation of breast abnormalities is challenging, even for experienced radiologists. Computer-Aided Detection (CAD) systems can assist in the detection of breast cancer. In this work, an algorithm for the automatic detection and classification of masses, based on subtraction of sequential digital mammograms, image registration and machine learning, is presented. Previous studies assessed the use of sequential mammograms to perform temporal analysis by creating a new temporal feature vector. Temporal subtraction registers and subtracts the prior mammogram from the current one, prior to performing mass detection and classification. A new dataset, which includes sequential pairs from 40 patients (160 mammograms) with precisely annotated mass locations (benign and suspicious), was created to assess the performance of the algorithm. For the classification, various features were extracted and six classifiers were used in a leave-one-patient-out cross-validation. The accuracy of the classification of masses as benign or suspicious increased from 90.83% (with the previously described temporal analysis) to 96.51% (with temporal subtraction). The improvement was statistically significant with p < 0.05. These results demonstrate the effectiveness of the proposed technique of temporal subtraction of mammograms for the detection of masses.

Objectives The purpose of this study was to explore the trigonometric principles of the spherical osteotomy, establish guidelines for its application and test the guidelines on bone models using a new blade design. We propose a new rule of osteotomies incorporating the outlined geometric principles, and applicable to the use of spherical cuts in veterinary orthopaedic surgery. Materials and Methods The trigonometric principles for the execution of neutral, closing and opening spherical osteotomies were explored in silico. A modification of the existing commercially available dome blade was designed and manufactured such that it facilitated the performance of spherical osteotomy with a minimized blade radius. A pilot study was performed whereby the modified dome blade was used to create spherical osteotomy in canine radial bone models. The surfaces of the osteotomy models were laser-scanned using a three-dimensional (3D) scanner; the resultant scans were imported into and analysed using a commercial 3D analysis software. The accuracy of osteotomy execution was measured as the distance between the targeted centre of osteotomy and the actual centre of osteotomy as found on the 3D scans. Results By utilizing the geometric principles of spherical osteotomy, an accurate osteotomy position was achieved. The centre of the spherical cut performed on bone models was confirmed to be within 5% tolerance of the location as planned in silico demonstrating the accurate and relevant clinical application of geometric principles. Clinical Significance The trigonometric guidelines for the execution of spherical osteotomy can be applied in a pre-clinical environment with accuracy. The new guidelines combined with the proposed new rule for spherical osteotomy utilizing the new blade design are translatable into clinical application, permitting the surgeon to accurately plan osteotomy application while mitigating the significant loss of bone-to-bone contact during correction of torsional deformities inherent in the principles of dome osteotomy use.

A non-targeted metabolomic methodology using gas chromatography coupled to mass spectrometry in combination with headspace solid-phase microextraction was applied for the identification of pharmaceutical honey volatile metabolites. Common and rare honeys (citrus, fir, honeydew, pine, thyme, asfaka, arbutus, chestnut, and cotton), in a total of 32 samples, were collected from different regions in Greece. Seventy-three volatile organic compounds (VOCs) were identified and semi-quantified using the internal standard method. Among volatiles, the norisoprenoid 3,4,6,6-tetramethylbicyclo[3.2.1]oct-3-ene-2,8-dione, was identified for the first time to contribute to Greek honey aroma. Pharmaceutical VOCs of interest included: terpenes, norisoprenoids benzene derivatives/phenolic volatiles and other compounds. The content of such metabolites was affected by honey’s botanical origin (p

Pine honey represents the major type of honey produced in Greece. In that sense, the aim of the present study was to investigate if specific physicochemical and bioactive properties could serve as markers of its geographical origin. For this purpose, forty pine honey samples were collected during harvesting years 2011 and 2012 from Halkidiki and Thassos, the well-known pine honey producing areas in Greece. Physicochemical parameters taken into account, using conventional and literature cited methods, were: pH, CIE colour parameters L*,a*,b*, and browning index. Furthermore, colour intensity and the in vitro radical scavenging activity were estimated by the application of spectrometric assays. Results showed that, pine honeys exhibited statistically significant differences (p) in pH, colour intensity, and radical scavenging activity, depending on geographical origin. On the basis of radical scavenging activity results obtained, pine honeys proved to have a high in vitro antioxidant “character’’. Finally, perfect Pearson’s correlations (r=1) at the confidence level p

Collective adaptive systems provide secure and robust collaboration between heterogeneous entities such as humans and computer systems. Such entities have potentially conflicting goals that attempt to satisfy by interacting with each other. Understanding and analyzing their behavior and evolution requires technical, social and economic aspects of modeling. In this paper, we develop a new design principle to describe an integrated and multimodal urban mobility system and model the interactions of various entities by means of game theoretic techniques.

The prevailing 'division of labor' concept in cellular immunity is that CD8+ T cells primarily utilize cytotoxic functions to kill target cells, while CD4+ T cells exert helper/inducer functions. Multiple subsets of CD4+ memory T cells have been characterized by distinct chemokine receptor expression. Here, we demonstrate that analogous CD8+ memory T-cell subsets are present characterized by identical chemokine receptor expression signatures. Among them, Tc2, Tc17 and Tc22 cells, in contrast to Tc1 and Tc17+1 cells, expressed IL-6R but not SLAMF7, completely lacked cytotoxicity and instead displayed helper functions including CD40L expression. CD8+ helper T cells exhibited a unique TCR repertoire, expressed genes related to skin resident memory T cells (TRM) and were altered in the inflammatory skin disease psoriasis. Our findings provide evidence that the conventional view of CD4+ and CD8+ T cell capabilities and functions in human health and disease needs to be revised.

A great part of our knowledge on mammalian immunology has been established in laboratory settings. The use of inbred mouse strains enabled controlled studies of immune cell and molecule functions in defined settings. These studies were usually performed in specific-pathogen free (SPF) environments providing standardized conditions. In contrast, mammalians including humans living in their natural habitat are continuously facing pathogen encounters throughout their life. The influences of environmental conditions on the signatures of the immune system and on experimental outcomes are yet not well defined. Thus, the transferability of results obtained in current experimental systems to the physiological human situation has always been a matter of debate. Studies elucidating the diversity of "wild immunology" imprintings in detail and comparing it with those of "clean" lab mice are sparse. Here, we applied multidimensional mass cytometry to dissect phenotypic and functional differences between distinct groups of laboratory and pet shop mice as a source for "wild mice". For this purpose, we developed a 31-antibody panel for murine leukocyte subsets identification and a 35-antibody panel assessing various cytokines. Established murine leukocyte populations were easily identified and diverse immune signatures indicative of numerous pathogen encounters were classified particularly in pet shop mice and to a lesser extent in quarantine and non-SPF mice as compared to SPF mice. In addition, unsupervised analysis identified distinct clusters that associated strongly with the degree of pathogenic priming, including increased frequencies of activated NK cells and antigen-experienced B- and T-cell subsets. Our study unravels the complexity of immune signatures altered under physiological pathogen challenges and highlights the importance of carefully adapting laboratory settings for immunological studies in mice, including drug and therapy testing. © 2016 International Society for Advancement of Cytometry.

Greek unifloral honeys (pine, thyme, fir, orange blossom) were characterized and classified according to botanical origin based on phenolic compound content and conventional physicochemical parameters using MANOVA and Linear Discriminant Analysis. One hundred and nineteen honey samples were collected during the harvesting period 2011 from 14 different regions in Greece known to produce unifloral honey of good quality. The analysis of phenolic compounds quercetin (3,5,7,3′,4′-pentahydroxyflavone), myricetin (3,5,7,3′,4′,5′-hexahydroxyflavone), kaempferol (3,5,7,4′-tetrahydroxyflavone), chrysin (5,7-dihydroxyflavanone), and syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid), was performed by high pressure liquid chromatography. Conventional quality parameter analysis included the determination of: pH, free, lactonic and total acidity, electrical conductivity, moisture, ash, as well as lactonic/free acidity ratio and colour parameters L*, a*, and b*. Using 4 phenolic compounds and 10 conventional quality parameters honey samples were satisfactorily classified (96.6% correct prediction) according to botanical origin.

“Mutational signatures” are patterns of mutations that report DNA damage and subsequent repair processes that have occurred. Whole-genome sequencing (WGS) can provide additional information to standard diagnostic techniques and can identify therapeutic targets. A 32-yr-old male with xeroderma pigmentosum developed metastatic angiosarcoma that was unresponsive to three lines of conventional sarcoma therapies. WGS was performed on his primary cancer revealing a hypermutated tumor, including clonal ultraviolet radiation-induced mutational patterns (Signature 7) and subclonal signatures of mutated DNA polymerase epsilon (POLE) (Signature 10). These signatures are associated with response to immune checkpoint blockade. Immunohistochemistry confirmed high PD-L1 expression in metastatic deposits. The anti-PD-1 monoclonal antibody pembrolizumab was commenced off-label given the POLE mutation and high mutational load. After four cycles, there was a significant reduction in his disease with almost complete resolution of the metastatic deposits. This case highlights the importance of WGS in the analysis, interpretation, and treatment of cancers. We anticipate that as WGS becomes integral to the cancer diagnostic pathway, treatments will be stratified to the individual based on their unique genomic and/or transcriptomic profile, enhancing classical approaches of histologically driven treatment decisions.

A great part of our knowledge on mammalian immunology has been established in laboratory settings. The use of inbred mouse strains enabled controlled studies of immune cell and molecule functions in defined settings. These studies were usually performed in specific-pathogen free (SPF) environments providing standardized conditions. In contrast, mammalians including humans living in their natural habitat are continuously facing pathogen encounters throughout their life. The influences of environmental conditions on the signatures of the immune system and on experimental outcomes are yet not well defined. Thus, the transferability of results obtained in current experimental systems to the physiological human situation has always been a matter of debate. Studies elucidating the diversity of "wild immunology" imprintings in detail and comparing it with those of "clean" lab mice are sparse. Here, we applied multidimensional mass cytometry to dissect phenotypic and functional differences between distinct groups of laboratory and pet shop mice as a source for "wild mice". For this purpose, we developed a 31-antibody panel for murine leukocyte subsets identification and a 35-antibody panel assessing various cytokines. Established murine leukocyte populations were easily identified and diverse immune signatures indicative of numerous pathogen encounters were classified particularly in pet shop mice and to a lesser extent in quarantine and non-SPF mice as compared to SPF mice. In addition, unsupervised analysis identified distinct clusters that associated strongly with the degree of pathogenic priming, including increased frequencies of activated NK cells and antigen-experienced B- and T-cell subsets. Our study unravels the complexity of immune signatures altered under physiological pathogen challenges and highlights the importance of carefully adapting laboratory settings for immunological studies in mice, including drug and therapy testing. © 2016 International Society for Advancement of Cytometry.

The systemic adjuvant treatment of early breast cancer (EBC) has benefited from a multifaceted approach. Generic cytotoxic approaches, as well as a more targeted approach to the estrogen receptor or HER2 receptor are now established standards of care. Decades of innovative trials exploring bisphosphonates in breast cancer prevention and EBC for bone protection, as well as large prospective randomized trials have resulted in an overwhelming case for benefit in post menopausal women. Therapies such as everolimus and the PARP inhibitors, established in the secondary breast cancer setting, are being explored in the adjuvant setting for utility. Similarly, observational and retrospective studies have demonstrated a strong reduction in breast cancer risk with the use of metformin and aspirin, and hence large prospective randomized trials are underway.

Objective To report use of, and outcome after, string-of-pearls (SOP™) plate and multiple cerclage wire fixation for treatment of periprosthetic femoral fractures (PFF) associated with total hip replacement (THR) in dogs. Study Design Case series. Animals Dogs (n=6) with PFF after THR. Methods Clinical records (2005–2010) and radiographic evaluations of dogs that had PFF associated with THR, treated with a SOP™ plate and cerclage wires were retrospectively reviewed. Clinical and radiographic postoperative assessments were performed 4, 12, and 24 weeks postoperatively. Telephone follow-up was performed >12 months postoperatively. Results Three fractures occurred intraoperatively and 3 occurred postoperatively. One SOP™ failed at 2 weeks necessitating revision using 2 parallel SOP™ implants. One dog was euthanatized because of quadriceps muscle tie-down at 6 weeks. Other dogs were free of lameness with full range of motion of the stifle and hip joints at final clinical examination, and positive outcomes were maintained at >12 month telephone questionnaire. There was no evidence of implant failure and positive evidence of fracture healing at final radiographic follow-up. Conclusions Stabilization resulted in bone healing in 5 dogs; failure in 1 dog may be attributable to technical error. Optimal technical guidelines for use of the SOP™ in this circumstance are unknown, particularly where fracture configuration varies.

SummaryObjectives: To describe acute correction of antebrachial angular and rotational limb deformities (ARLD) using a new external skeletal fixator (ESF).Methods: Dogs that were presented with lameness caused by ARLD were treated by radial and ulnar osteotomies and acute realignment. A modified type-1b ESF incorporating double arches (DA-ESF) and a novel connecting configuration facilitated alignment with six degrees of freedom. Bilateral deformities were corrected surgically in the same session. Aseptic preparation of both antebrachii allowed comparison of limb alignment. Radiographic evaluation was performed using centre of rotation of angulation (CORA) methodology.Results: Thirty-five antebrachii (22 dogs) underwent surgery. Postoperative limb function was graded as good (n = 31), fair (n = 2), or poor (n = 2). Persistent medial carpal instability was associated with a suboptimal outcome. Postoperative radiographic images of the frontal and sagittal plane joint angles and elbow-to-carpus translation were compared with values that were reported in previous studies, and were within published reference ranges in most cases. Complications included delayed radial osteotomy union (n = 5), delayed ulnar osteotomy union (n = 2) and implant-associated morbidity (n = 3).Clinical relevance: A practical technique for acute correction of complex antebrachial ARLD is suggested, incorporating a new configuration of ESF. Putative limitations of radio-graphic planning using CORA may be compensated by careful attention to intra-operative visual and palpatory assessment.

The economic structure of service systems has steadily increased in complexity in recent years. This is due not only to specialization in direct material production and services offered, but also in the ownership and management of resources, the role of intangible assets such as process knowledge, and the context in which goods and services are consumed. This increase in complexity represents both a challenge and an opportunity in a service-oriented economy. In this paper, we offer a descriptive structure for the analysis of this complexity which combines graph theory and network flows with economic tools. Our analysis is based on publicly observable information and can be used to analyze service systems in terms of the value they deliver, how they deliver it, and how value can be discovered and increased. We show how this analysis can be applied (in the example of a car manufacturer and its service system for suppliers and dealerships) to improve customer satisfaction and provide options and analysis models for outsourcing decision makers.

Lack of time or economic difficulties prevent chronic obstructive pulmonary disease patients from communicating with their physicians, thus inducing exacerbation of their chronic condition and possible hospitalization. In this paper we propose a platform that integrates mobile application technologies and cloud computing to provide secure, robust, scalable and distributed backend for hosting health services that improve life quality in a cost effective way.

We consider a new workload allocation policy addressing fairness for user level performance measures. More specifically the criterion used for optimal workload allocation is the one which minimizes the maximum expected response time at computer systems to which jobs are routed. The policy to attain this criterion is therefore referred to as the min-max policy (MMP). It is shown that this optimization criterion is tantamount to routing to the fastest M processors, where M depends on system statistics and equalizing the expected response times on these processors. The algorithm to compute job routing probabilities is applicable to increasing continuous functions of system response time versus the job arrival rate. We next investigate some properties of the MMP and show that it results in minimizing the coefficient of variation of response time when the job processing times are exponentially distributed. We compare the MMP with the one that minimizes the mean overall response time. It is shown that the new policy attains fairness by equalizing the mean response times at different systems, at a tolerable increase in overall response time. Finally, we report on a sensitivity analysis with respect to changes in job arrival rate and errors in estimating this rate.

The aim of this paper is to briefly present the overall objectives and the expected outcome of an on-going effort concerning the design the implementation and the analysis of next generation intelligent energy systems based on Anticipatory control and a set of ICT emerging technologies and innovations.

Large-scale systems comprising of multiple heterogeneous entities are directly influenced by the interactions of their participating entities. Such entities, both physical and virtual, attempt to satisfy their objectives by dynamically collaborating with each other, and thus forming collective adaptive systems. These systems are subject to the dynamicity of the entities' objectives, and to changes to the environment. In this work we focus on the latter, i.e.\ on providing the means for entities in such systems to model, monitor and evaluate their perceived utility by participating in the system. This allows for them to make informed decisions about their interactions with other entities in the system. For this purpose we propose a utility-based approach for decision making, as well as an architecture that allows for the support of this approach.

Workloads in distributed database applications consist of queries and transactions. In order to address performance requirements, distributed transaction processing systems have to deal with two related issues: transaction routing and scheduling. Due to the distribution of data objects among nodes and the access cost incurred by remote accesses, efficient transaction routing is an important consideration for overall system performance. Another important consideration is workflow scheduling and routing. Workflows are complex units of work consisting of multiple, possibly interdependent, transactions. In this survey, we discuss a number of different transaction routing mechanisms and their performance.

To document outcome in 2 dogs and 2 cats after conversion of femoral head and neck excision (FHNE) to total hip replacement (THR).Case series.Dogs (n = 2) and 2 cats.For 1 dog and 2 cats, THR was performed using cemented acetabular and femoral components. Noncemented acetabular and cemented femoral components were used in 1 dog.All animals presented with severe hip pain and chronic lameness after unsuccessful FHNE. Potential causes of suboptimal outcome after FHNE were incomplete resection of the femoral neck (n = 3) and fibrous adhesions involving the sciatic nerve (n = 2). Post-FHNE remodeling of the proximal femur and acetabulum necessitated unconventional modifications of surgical technique. In all 4 cases, final clinical outcome and radiographic reassessment were satisfactory. Aseptic loosening of the acetabular bone-cement interface necessitating surgical revision was the only complication noted in 1 cat.Despite severe preoperative pain and chronic functional impairment in all cases, conversion of FHNE to THR produced marked clinical improvement including return to unrestricted exercise within 12 weeks of surgery.

To report use of, and outcome after, string-of-pearls (SOP™) plate and multiple cerclage wire fixation for treatment of periprosthetic femoral fractures (PFF) associated with total hip replacement (THR) in dogs.Case series.Dogs (n=6) with PFF after THR.Clinical records (2005-2010) and radiographic evaluations of dogs that had PFF associated with THR, treated with a SOP™ plate and cerclage wires were retrospectively reviewed. Clinical and radiographic postoperative assessments were performed 4, 12, and 24 weeks postoperatively. Telephone follow-up was performed12 months postoperatively.Three fractures occurred intraoperatively and 3 occurred postoperatively. One SOP™ failed at 2 weeks necessitating revision using 2 parallel SOP™ implants. One dog was euthanatized because of quadriceps muscle tie-down at 6 weeks. Other dogs were free of lameness with full range of motion of the stifle and hip joints at final clinical examination, and positive outcomes were maintained at12 month telephone questionnaire. There was no evidence of implant failure and positive evidence of fracture healing at final radiographic follow-up.Stabilization resulted in bone healing in 5 dogs; failure in 1 dog may be attributable to technical error. Optimal technical guidelines for use of the SOP™ in this circumstance are unknown, particularly where fracture configuration varies.

Interdependency is a constant of business. Businesses form complex networks for the exchanging of goods and services. Service networks models represent the interconnections among companies, their parts and individuals in terms of services that are provided and consumed. Due to the size of nowadays service networks, their models tend to grow very large. The effective management of service network models requires methods for limiting the amount of data presented on the basis of what is needed through views. We identify a hierarchy of views on service network models, namely offering-centric views, participant views and multilateral views. The offering-centric views focus on one service that is offered by one participant. Participant views present the entirety of the data related to one participant. Multilateral views represent the data about a set of participants. Additionally, we investigate the correlations between these views and the mechanisms for aggregating and projecting them from each other and from service network models.

The authors propose and evaluate an efficient hierarchical clustering and allocation algorithm that drastically reduces the interprocess communications cost while observing lower and upper bounds of utilization for the individual processors. They compare the algorithm with branch-and-bound-type algorithms that can produce allocations with minimal communication cost, and show a very encouraging time complexity/suboptimality tradeoff in favor of the algorithm, at least for a class of process clusters and their random combinations which it is believed occur naturally in distributed applications. The heuristic allocation is well suited for a changing environment, where processors may fail or be added to the system and where the workload patterns may change unpredictably and/or periodically. >

Consumers increasingly use online services in their everyday life: when they drive a car, at home and at work. We address the problem of selecting for the consumer, the most valuable online service, according to the consumer value preferences. We combine our work for value analysis of service networks with our work on selecting services based on quality of service requirements. We show with examples (car manufacturer and its service system), how service delivery monitoring and service brokers can be used to improve consumer satisfaction, and discuss how this work can be extended in the future, to achieve viable and adaptive, dynamically evolving service ecosystems.

The Internet has catered for the transformation of traditional "stovepiped" service companies into global service networks fostering co-production of value to more effectively and efficiently satisfy the ever-growing demands of mundane customers. The catalyst of this change is the happenstance of Service Oriented Computing, which provides a natural distributed computing technology paradigm for implementing and evolving such highly distributed networks of autonomous trading partners with coordinate and cooperative actions. However, how to faithfully (re-)map service networks to business processes and service realizations and vice-versa is still partly terra incognita. In this paper, we introduce a semi-automatic model transformation approach for creating the abstract business processes that take place between trading partners from models of service networks, assuming limited human-involvement focused on selecting reusable transformation patterns. This approach is explored and validated using a realistic case study reflecting best practices in the telecommunications industry.

Networks of interdependent organizations cooperate to produce goods or, nowadays, services that are of value to their markets as well as to the participating organizations. Such co-operations can be supported by corresponding business processes which are based on SOA technology. Developing and managing SOA-based business processes in such service networks necessitates a comprehensive architecture which is on the one hand grounded on solid design principles, and on the other hand capturing best-practices and experiences. Such an architecture is currently lacking. This paper outlines a first attempt to develop and validate an architecture for developing, monitoring, measuring and optimizing SOA-enabled business processes in service networks. A case study from the telecommunications industry is analyzed, and different aspects of service networks are addressed.

e19044 Background: Platinum-based chemotherapy is the standard front-line treatment for patients with advanced Non Small Cell Lung Cancer (NSCLC). However, third generation non-platinum combination...

Background: The utility of CTC enumeration in predicting patient (pt) outcome has been demonstrated in metastatic breast cancer (MBC) treated with chemotherapy or endocrine therapy. In this study we evaluated the clinical impact of CTC assessment in terms of both enumeration and characterization in breast cancer pts treated with exemestane plus everolimus. Patients and methods: Thirty-nine pts with hormone receptor (HR)-positive, HER2-negative MBC, received exemestane plus everolimus. CTC enumeration in peripheral blood (7.5 ml) was performed before treatment (n=39), post cycles 1 (n=39) and 3 (n=29), on disease re-evaluation and on relapse, whichever occurred first, using the CellSearch System. CTC characteristics were determined at the same time points by immunofluorescence (IF) analysis of PBMC cytospins (106 cells), triple stained with pancytokeratin (CK) antibody along with Ki67 and M30 as proliferation and apoptosis markers, respectively, using the Ariol System. Patients were assessed by CT scans and bone scan, every 3 months or as clinically indicated. Results: At the cut-off of ≥ 1 CTC, 25 of 39 (64%) pts had detectable CTCs at baseline, 12 (31%) of 39 post-1st and 10 (34.5%) of 29 post-3rd cycle. Ten (25.6%) pts remained CTC(+) and 12 (30.8%) CTC(-) both at baseline and post-1st cycle; 15 (38.5%) CTC(+) pts turned to CTC(-) and 2 (5%) CTC(-) turned to (+). CTC positivity after the first cycle was associated with shorter median progression-free survival (PFS) compared to CTC(-) status (3.9 vs 8 mo, p=0.031). Shorter PFS was also recorded for pts that remained CTC(+) at both time points compared to all other (p=0.02). At the cut-offs of ≥ 2 and ≥ 5 CTCs, 16 (41%) and 9 (23%) pts were CTC(+) at baseline, respectively; post-1st cycle, 7 (18%) and 4 (10%) pts were CTC(+) (at ≥ 2 and ≥ 5 CTCs, respectively). Post-3rd cycle the positivity rate was 17% for both cut-offs and these pts had significantly shorter PFS compared to CTC(-) pts (3.7 vs 8.7 months, p=0.048). Efficacy assessment revealed partial response in 3 (7.7%) pts, stable disease in 27 (69.23%) and progressive disease (PD) in 8 (20.5%); 1 pt was non-evaluable for response. Among pts determined CTC(+) post-1st cycle (cut-off ≥ 2 CTCs), 57% progressed compared to 13% of CTC(-) pts (p=0.02). In addition, at the post-3rd cycle evaluation, pts with PD had significantly higher CTC counts compared to non-progressors (mean ± SEM; 10 ± 5.78/pt vs 1.62±0.83/pt, p=0.027). By the use of IF 43%, 44% and 40% of CTC(+) pts had proliferative [Ki67(+)/M30(-)] CTCs at baseline, post -1st and -3rd cycles, respectively (cut-off ≥ 1 CTC); 67%, 50% and 50% of those pts, respectively, experienced PD. Apoptotic [Ki67(-)/M30(+)] CTCs were detected in 14%, 22% and 60% of CTC(+) pts at baseline, post -1st and -3rd cycles, respectively; none of the pts with apoptotic CTCs experienced PD. Conclusions: CTC enumeration and characterization in terms of proliferation and apoptosis during the course of treatment has significant predictive and prognostic implications in patients with MBC receiving the combination of exemestane plus everolimus. Citation Format: Sofia Agelaki, Dimitris Mavroudis, Maria Spiliotaki, Eleni Politaki, Maria A Papadaki, Stella Apostolaki, Christos Nikolaou, Vassilis Georgoulias. CTC enumeration and characterization has predictive and prognostic implications in patients with metastatic breast cancer treated with exemestane plus the mTOR inhibitor everolimus [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-13.

In today’s Information Systems, users present credentials with local significance, to be authenticated and gain access to internal functionality. Users have different login-password combinations for each online service, or even different credentials for different roles within a service. As a result they tend to make poor password choices that are easy to remember, or even repeat the same login-password information on different services. This poses security threats to service providers and a privacy risk for end-users. The solution is to shift to identity management systems. Such a system will issue a digital identity for every user and will be able to control the full life-cycle of these identities, from creation to termination. Another aspect of such a system is the single sign-on mechanism, whereby a single action of user authentication and authorization can permit the user to access multiple services. The benefits are improved security, accountability and privacy protection.

Now that the first wave of excitement on e-commerce has subsided, and after the sobering experience of the dot-com bubble burst, there is a growing understanding that e-commerce is not about a different way of doing commerce, and e-business is not about a different way of doing business. E-Business is about doing business – in a better, more competitive and productive way. To improve business, one has to transform business and the processes that it uses.

A novel approach to allocating and sharing communication and computational resources in a distributed system is described. The approach, which is based on concepts drawn from microeconomics, uses algorithms that are competitive rather than cooperative. The effectiveness of these concepts is demonstrated by describing an economy that improves the performance of a distributed system by implementing load balancing. In this economy, competition sets prices for the resources in the system. Jobs complete for the resources by issuing bids, and the resource allocation decisions are made through auctions held by the processors. The benefits of the method include limited complexity and algorithms that are intrinsically decentralized and modular. Simulation studies show that these economies achieve substantial performance benefits. >

Workload management algorithms for satisfying administration defined response time goals in transaction processing systems are presented. Each arriving transaction belongs to a predefined transaction class, and the system administrator defines an average response time goal for each transaction class. A dynamic transaction priority algorithm and a set of transaction routing algorithms for multiple processor transaction systems are given. These algorithms set priorities and route transactions based on the data objects accessed by the transactions, the current load of each system, and the goal satisfaction of the transaction classes. The algorithms have low overhead, and a detailed simulation study shows that they substantially improve goal satisfaction compared to previous work. >

A new approach to performing resource allocation in autonomous distributed computer systems is explored. As opposed to previous work which is based on interprocessor cooperation, the distributed system is modeled as a competitive society of microeconomic agents. The model is applied to the problem of managing distributed, replicated data objects. In this economy, jobs and transactions submitting read/write operations on data objects pay the processors to perform the operations. The processors use the revenue they earn to lease copies of data objects on which they can make a profit. The data objects themselves are active agents and set the prices for leasing copies. The economy is evaluated by a simulation study. The experiments show that the economy can substantially improve performance by varying the placement and number of copies of each data object. >

The paper presents the HERMES specification language, which is introduced to express scripts for complex activities involving coordination and collaboration. The language is part of a framework for network-centric applications, providing a two-level framework for expressing metadata. Service flow rules define communication channels between software components and actions triggered by run time events. The semantics of HERMES supports a model for dynamic and adaptive work sessions in open environments.

Workflow management systems are developed to support and automate the execution of business processes, by assigning tasks to agents according to the workflow specification. Current state-of-the-art workflow systems are mainly concerned with the routing and assignment of tasks, providing little support for tasks related to administration and management. This deficiency is exacerbated in dynamic open environments, where services provided and managed by multiple autonomous authorities need to be integrated. Such environments significantly stretch the assumptions underlying current state-of-the-art workflow system designs, especially as network-centric applications become widespread. We propose a framework, service level management, for addressing all system administration in an integrated manner in the context of a workflow execution model that allows for dynamic adaptation (reconfiguration) of work sessions in a dynamic and heterogeneous run-time environment. Service level management requires a comprehensive monitoring infrastructure. We present our design for such an infrastructure, which is part of our current work towards developing the Aurora architecture for supporting work sessions.