Calcification of the medial collateral ligament (MCL) of the knee is a very rare disease. We report on a case of a patient with a calcifying lesion within the MCL and simultaneous calcifying tendinitis of the rotator cuff in both shoulders.Calcification of the MCL was diagnosed both via x-ray and magnetic resonance imaging (MRI) and was successfully treated surgically. Calcifying tendinitis of the rotator cuff was successfully treated applying conservative methods.This is the first case report of a patient suffering from both a calcifying lesion within the medial collateral ligament and calcifying tendinitis of the rotator cuff in both shoulders. Clinical symptoms, radio-morphological characteristics and macroscopic features were very similar and therefore it can be postulated that the underlying pathophysiology is the same in both diseases. Our experience suggests that magnetic resonance imaging and x-ray are invaluable tools for the diagnosis of this inflammatory calcifying disease of the ligament, and that surgical repair provides a good outcome if conservative treatment fails. It seems that calcification of the MCL is more likely to require surgery than calcifying tendinitis of the rotator cuff. However, the exact reason for this remains unclear to date. The medial collateral ligament is a very complex apparatus, connecting the medial surface of the femoral condyle to the tibia. Its function is to resist forces applied from the outside of the knee preventing the medial or inner part of the joint from widening. Moreover the MCL is considered a static stabilizer. Its structure is triangular and little expansible. Its origin is located proximally of the medial epicondyle of the femur next to the adductor tubercle, whereas its attachment lies below the medial condyle of the tibia on its medial surface .Calcifying tendinitis is referred to as a pathological condition that is characterized by deposition of calcium-phospate particles - in their crystalline form hydroxyapatite - within a tendon. The aetiology and the factors that predispose to the development of symptoms are still not entirely clear. Different hypotheses have been proposed in the literature but most of them are still not proven or under investigation , 3 Some The pathophysiological cascade involves a locally decreased oxygen tension within the affected tissue that leads to fibrocartilaginous metaplasia and eventually to calcification of the fibrocartilaginous matrix . This coThe typical first clinical manifestation is subacute low-grade pain that commonly increases during nighttime. Later, during the resorptive stage which involves vascular invasion and migration of phagocytic cells and the development of an edema leading to increased intratendinous pressure, the disease is characterized by sharp acute pain limiting the range of motion of the affected joint .As calcifying tendinitis is usually a self-limiting condition, conservative treatment should be the first line therapy –8.Calcification of the MCL is a very rare disease. In the recent literature only three reports on single symptomatic calcifications of the medial collateral ligament of the knee joint can be found. None of these reports describes the involvement of other parts of the body. To our knowledge, we are the first to demonstrate a case of a patient suffering from both a calcification of the medial collateral ligament of the knee and calcifying tendinitis of the rotator cuff –11.A 50-year-old caucasian woman was referred to our clinic with a 12 months history of severe, recurrent pain episodes in her right knee. She was a non-smoker, with no other notable family or medical history for any pathological condition. Systemic diseases such as gout, systemic sclerosis, dermatomyositis, and sarcoidosis or any metabolic or endocrine disorders such as hyperparathyroidism and renal failure were excluded. There were no past trauma incidents. Her orthopedic surgeon had diagnosed a calcifying lesion of the MCL 9 months prior to admission to our hospital and had treated her conservatively under the assumption of a calcifying tendinitis-like pathological condition. After some temporary pain relief she still suffered from pain at the medial side of the knee and limited range of motion. The conservative management included analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), electro-therapy and shock wave therapy.Physical examination of the right knee revealed local pain and swelling over the medial femoral condyle with intact soft tissues and no joint effusion. The patient was able to fully extend her knee but flexion was limited to 120° with increasing pain at the MCL beginning with 90° flexion. Patellar mobility was not limited. There was no ligament laxity and clinical tests for detection of meniscus lesions were all negative. There was no sensorimotor deficit. Blood tests showed no evidence of haematological or metabolic abnormality. Knee x-rays revealed linear soft tissue opacity medial to the femoral condyle, suggesting a lobate calcifying lesion within the proximal and middle section of the MCL and surrounding tissue. Antero-posterior, lateral and merchant’s views verified the presence of the calcified lesion. MRI without contrast agent of the knee confirmed the presence of this lobate structure, which was characterized by an hypointense signal on the T2 weighted images, located in direct vicinity of the intact MCL in the coronal and sagittal plane, with direct contact to the ligament structure, which was seen in the sagittal and axial plane images of the knee. There were no signs for a mature bony lesion , followed by the infraspinatus (15 % of cases) and subscapularis (5 % of cases) tendon, is most commonly affected . Women sAfter the shoulder, the hip is the second frequent location for the development of calcification deposits, most commonly found in the gluteus medius tendon at the greater trochanter. Furthermore the posterolateral femoral attachment of the gluteus maximus can be involved. Other areas of involvement include the iliopsoas tendon insertion at the lesser trochanter, and the ischial origins of the common hamstring tendons .Another joint which can be affected is the elbow, including the bursa and the flexor and extensor tendon complexes at the epicondylar origins, the triceps, brachialis, and biceps tendons. It can also occur in the medial and lateral collateral ligamentous complexes , 14.Other parts of the upper extremity that can be involved are the wrist and the hand. The wrist is more frequently affected than the hand. The pisiform insertion site of the flexor carpi ulnaris tendon is reportedly the main site of involvement in the wrist. In the hand, deposits in the metacarpophalangeal and interphalangeal regions are not uncommon .In the ankle and foot, calcifications can involve a plethora of structures, among them the flexor hallucis longus and brevis and the peroneus tendons .In the knee, calcification deposits can occur in the joint, on the extrasynovial anterior or posterior cruciate ligament , 18. UsuCalcification deposits typically present on MR imaging as rounded areas of low signal intensity on all imaging sequences. The deposits are particularly conspicuous on gradient echo imaging. In the acute symptomatic phase the process has an aggressive appearance with marrow and soft tissue edema that may mimic infection, trauma, or neoplasm .An association between acute pain attacks and histological evidence of calcium resorption has been described previously . Most syPosttraumatic calcification can appear in different locations, including the medial collateral ligament. The term ‘Pellegrini-Stieda lesion’ is used for the latter finding, and is named after both doctors Pellegrini and Stieda, who described this phenomenon for the first time in 1905 and 1907, respectively. However, it was suggested by Koenig, Koehler and Pfister in 1909, that there are Pellegrini-Stieda shades, who aren’t necessarily caused by trauma and may have other etiologies –25.The Pellegrini-Stieda disease is a relatively rare phenomenon and is commonly associated with sports injuries. It is thought that Pellegrini-Stieda lesions are post-traumatic ossifications following an avulsion injury to the attachment of the medial collateral ligament, at the medial femoral condyle. Tearing fibres of the ligament at its superior femoral attachment can cause hematoma or inflammatory edema. The soft tissue can be also affected and absorbs calcium salts during the later stages of the disease. This mechanism takes place approximately 2–6 weeks after the trauma. In the next stage of the disease, the calcium salts can be resorbed which results in a degradation of the lesion or an ossified mesh can develop, which usually gets connected to the femoral condyle by a pedicle within the next 6 months. The calcification of the superior femoral attachment is in most cases characteristic, confirmed by x-ray and often associated with ruptures of the anterior cruciate ligament , 27.Calcification deposits typically present on MRI imaging as rounded areas of low signal intensity on all imaging sequences. The deposits are particularly conspicuous on gradient echo imaging. In the acute symptomatic phase the process has an aggressive appearance with marrow and soft tissue edema that may mimic infection, trauma, or neoplasm .Most of the patients with this post-traumatic calcification of the MCL are asymptomatic. The term Pellegrini-Stieda syndrome is only used if the symptoms can be directly associated with the appearance of the Pellegrini-Stieda shadow . They caThe kind of calcification of the MCL presented in our case seems to be similar to the Pellegrini-Stieda syndrome at the first glance, but has to be distinguished from this entity in terms of its pathophysiology and -morphology. The calcification body in our case was not localized at the insertion of the ligament and also differed in its radiological morphology and appearance. Ossification of Pellegrini-Stieda type lesions are of concave and flattened, whereas the calcification seen in our case was rounded and lobate, clearly circumscribed and dense, corresponding to type 1 of the radiological classification of calcifying tendinitis by Gaertner and Heyer . The intThis is the first reported case of a patient suffering from both a calcifying lesion of the medial collateral ligament of the knee and calcifying tendinitis of the rotator cuff in both shoulders.In the literature three reports with seven cases describing single symptomatic calcifications of the medial collateral ligament of the knee can be found. Five patients were successfully treated by surgical resection, two patients were treated conservatively with a positive result. There were no reports that one of them had other parts of the body involved in a calcification process –11.In the precedent medical history of our patient, she had suffered from calcifying tendinitis in both shoulders, and had successfully been treated conservatively. Because of a rupture of the tendon of the musculus supraspinatus the patient required surgery 17 years later, which revealed no remaining or recurrent calcification bodies.Our experience suggests that magnetic resonance imaging and x-ray evaluation are invaluable tools in the diagnosis of this condition and that surgical repair provides a good outcome, if conservative treatment fails.In contrast to calcifying tendinitis of the rotator cuff, calcification of the MCL is a very rare disease. Because the patient in our report suffered from both of these diseases, one can come to the conclusion that there is probably the same kind of etiology, however, the exact mechanism of the calcium deposition involved in these two conditions is not entirely clear. Analogous to the rotator cuff, conservative treatment regimes can be used, although it seems that the calcification of the MCL is a condition that is more resistant to conservative therapy than common calcifying tendinitis of the rotator cuff. A possible reason could be the difference in the pathomechanism of the two lesions. It is well known that the integrity of the rotator cuff can be affected due to pathological mechanisms such as inner and outer impingement leading to structural changes. On the other hand the pathological mechanisms leading to an impairment of the MCL are different. In general, the MCL is damaged by extrinsic indirect stresses which might result in different structural changes as seen in the tendon , 34.MCL, medial collateral ligament; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-inflammatory drugs


Practice-based population health (PBPH) management is the proactive management of patients by their primary care clinical team. The ability of clinics to engage in PBPH and the means by which they incorporate it in a clinical setting remain unknown.We conducted the Canadian Population Health Management Challenge to determine the capacity and preparedness of primary care settings to engage in PBPH using their existing medical record systems and to understand the complexities that may exist in PBPH implementation.We recruited a sample of electronic medical record (EMR) -enabled and paper-based clinics from across Canada to participate in the challenge. The challenge required clinic staff and physicians to complete time-controlled, evidence-based practice reviews of their patients who may benefit from evidence-informed care, treatment, or interventions across five different areas . We formulated a preparedness index to measure the capacity of clinics to engage in PBPH management. Finally, we conducted follow-up qualitative interviews to provide richer understanding of PBPH implementation and related issues .A total of 11 primary care clinics participated, representing 21 clinician practices. EMR-enabled clinics completed a full review of charts in an average of 1.37 hours. On the contrary, paper-based clinics reviewed nearly 10% of their charts in an average of 3.9 hours, hinting that they would have required an estimated 40 hours to complete a review of charts in their practice. Furthermore, the index revealed a major gap in preparedness between the EMR and paper-based clinics (0.86–3.78 vs 0.05–0.12), as well as a broad range among the EMR clinics. Finally, building on the results of the qualitative analysis, we identified factors facilitating the integration of PBPH.Our results suggest that EMR usage is pivotal in setting the foundation to support PBPH. The wide range of performance variation among EMR-enabled clinics suggests that EMR functionality and optimization, its support of clinical practice workflow, and policy issues to ensure adoption of standards are critical issues to facilitate PBPH. In Canada, the federal government spends 50% of its total budget on the Canada Health Transfer to the provinces and territories . One comTo do this, scholars and practitioners have increasingly recognized the importance of actively managing population health at the primary care level as an essential factor in improving quality of care outcomes ,9. It isOne major effort has been to establish practice-based population health (PBPH) methodologies and procedures for primary care practice ,14. PBPHOne of the key elements that can improve practice engagement with PBPH is the integration of information technology, data quality of electronic patient records, and integrated administrative and clinical workflow ,20. ThisThe benefits of electronic systems have been well recognized in the extant literature. For instance, research shows that the use of EMRs in hospital and ambulatory care settings can improve patient safety and reduce adverse events, by using alerts and reminders . In addiIn the context of population health management and PBPH, clinicians’ use of and consultation with patient data and the provision of alert and reminder functionalities has been shown to support chronic disease management . Use of Despite the potential benefits, optimizing use of EMR functionalities in primary care has been particularly complex and challenging . In factWe report the design and results of the Canadian Population Health Management Challenge, in which we assessed paper-based and EMR-enabled primary care clinics located in Canada on their capacity and preparedness to engage in PBPH management. More specifically, we aimed to answer these questions: How prepared are clinics to adopt PBPH? What are the factors that facilitate PBPH management?We invited a sample of primary care clinics from across Canada to participate in the Population Health Management Challenge. The challenge required clinic staff or a lead physician to complete time-controlled, evidence-based practice reviews of their patients who may benefit from evidence-informed care, treatment, or interventions across five clinical areas . We sought practices with EMR systems and practices with paper-based patient records. Requests for participation were disseminated broadly via Canada Health Infoway’s provincial peer network programs and across provincial EMR funding programs. Programs were encouraged to share the invitation broadly across their networks; therefore, we do not know the total number of invitations disseminated. Community-based primary care clinics or clinician practices were eligible to participate. Clinics interested in participating contacted the study coordinator by email and were later interviewed to determine eligibility and review participation requirements. Clinics that volunteered to participate were required to appoint a lead physician or a staff member for a 6-hour period to complete the challenge at a specified date and time. Real-time monitoring and support was provided while participants completed the time-controlled, evidence-based practice reviews that made up the 6 challenge modules using a Web-based tool. The Web-based tool systematically captured the time to complete each evidence-based review module. All participants completed a Web-based orientation and registration session before the date and time they initiated the challenge. Participants completed 2 rounds of the challenge (round 1 in August 2011 and round 2 in October–November 2011).Clinic and clinician practice demographic data were collected during the orientation and training session: (1) the descriptive characteristics of the clinic and participating clinician practices , (2) the type and use of chart recording systems , and (3) the challenge participant’s function within the clinic. The challenge consisted of 6 evidence-based review modules requiring participants to review active patient charts or records and enter the results of their review—all within a specified time limit , each completed sequentially . We chosParticipants were allowed 45 to 60 minutes to complete each module. The time taken by each participant was systematically recorded by the Web-based data entry tool with automated time-out features for each module. In the event of a participant time-out, the module was halted (data entry no longer possible) and the data collected to that point were recorded to the database.To support and enhance our understanding of user experience with the tool and ensure quality of the data collected, we conducted on-site observations at 2 clinics. Each challenge participant completed a follow-up semistructured phone interview. We developed the interview guide based on a review of the extant literature and the observational site visits that we conducted with the first paper-based and EMR-enabled sites while they completed the challenge. The guide was refined jointly with the research team and validated through 2 pilot interviews. All interviews were recorded and transcribed verbatim. As a quality improvement study, this study was not reviewed by a research ethics board. The research team did not consult patients’ records and challenge modules did not require the capture of personal health information.We formulated a preparedness score as a relative measure of a clinic’s capacity to engage in PBPH management. We based clinic preparedness on two key principles: timeliness and completeness. A clinic that requires less time to specify a defined patient population with complete clinical criteria across its full panel of patients is deemed to be more prepared for PBPH management than a clinic that takes longer to complete a full panel review or has incomplete clinical criteria.We used 2 sets of values to compute the PBPH preparedness score: (1) the total time required to complete the challenge modules, and (2) the percentage of data fields that were completed within challenge modules (degradation factor). We computed the score for each clinic that undertook the challenge on behalf of one or more clinician practices and that was supported by the time data recorded automatically by the Web-based tool and the self-reported proportion of charts actually reviewed to the overall number of patients in the physician’s practice.For each practice, we computed the mean percentage of modules completed, inclusive of all the data fields in each of the 6 modules. We then defined the mean percentage complete for clinics with multiple participating practices as the average of the mean percentage complete across all the physician practices of the clinic on a module-by-module basis. Then we combined the mean percentage complete for the clinic with the time allocated for the completion of each module and the actual time taken by the clinic to complete the modules for all practices, according to the following formula: score =  / time taken by all practices to complete section.The PBPH preparedness score can be interpreted as the percentage of the challenge that the clinic was able to complete in the allotted time. The inverse of the score, multiplied by the overall time allowed to complete the challenge, provides an estimation of the time the clinic would require to complete all tasks across modules that composed the challenge.More precisely, we defined the percentage complete as the ratio of the number of charts that had all criteria identified (either met the criteria or did not) over the total number of charts in the clinic. This is estimated and self-reported by challenge participants for each module before advancing to the next module whether they reached the time limit or not. For the first participating clinics, we assigned an average percentage complete based on notes taken by the on-site observers. Missing values for the percentage complete of a task were imputed using the following two rules. First, if the practice had complete clinical criteria data fields within the module, we assigned full percentage (100%) complete, as all data elements were present for the required analysis. Second, if such information was not provided, we assigned zero percentage to the associated percentage completed.We ranked clinics based on their fastest time and completeness of clinical criteria, ordering them from the highest to lowest capacity to conduct PBPH management based on the preparedness score.We analyzed qualitative data in 2 stages. We first performed a within-case analysis of the resulting transcripts. Within-case analysis allowed us to focus on the particularities of each case. We used documentation and observational data to corroborate and validate the insight provided by the interviews . We thenA total of 55 clinics responded to the national communications strategy inviting participation in the study. The study coordinator contacted and interviewed interested practices to determine eligibility and review participation requirements. Of these, 11  clinics volunteered to participate in the challenge. The remaining 44 declined to participate due to lack of time and available staff, or because of personal, business, or operational conflicts with the timing of the data collection periods. Among EMR-enabled clinics, the lack of knowledge about data retrieval and getting queries from an EMR was consistently mentioned as the key reason for nonparticipation. For clinics with paper-based record systems, the task of data retrieval through manual chart reviews was the key barrier to participation. During the orientation session conducted preceding the challenge, 1 paper-based clinic withdrew because the tasks were deemed beyond the capacity of the designated staff member assigned to the challenge.Among volunteering clinics, the main motivation to participate in the challenge was, first, to assess their performance vis-à-vis other clinics and, second, to evaluate the efficiency of their current practices. Additionally, clinic managers hoped that the challenge could advance adoption and optimized use of EMRs in Canada more generally by highlighting the potential benefits of advanced use to colleagues, regional partners, and government agencies.Challenge modules were completed either by a primary care physician (4 clinics) or by medical record or information technology staff (7). Overall, EMR-enabled clinics completed a full review (100% of active patient records) in an average of 1.37 hours. Paper-based clinics reviewed approximately 10% of charts in 3.9 hours, thus requiring an estimated 40 hours (or 1 work week) to complete a full practice review . On a scTo better understand the discrepancies between the clinics’ preparedness and performance on conducting the challenge, we relied on our qualitative data. The analysis helped clarify the main challenges and critical issues that facilitate PBPH in primary care settings.Overall, our analysis showed that participants saw data retrieval as a critical activity in their current practice, but many mentioned that they do not perform it frequently enough or on a regular basis. Yet some indicated that data retrieval may not be equally important for every staff member or clinician depending on their role in patient and population health management.Clinical teams tend to collect a lot of information in an EMR; all interviewees were concerned that this rich source of data was not always exploited adequately. The most common challenge found to inhibit proper use of data was the logistics of data retrieval. Most participants believed that data retrieval is a difficult, time-consuming task that was not comprehensive enough in their clinic, and has technical problems and limitations that influence database updates and integration. Exploiting the data  was also regarded as a complex process that necessitates both a good understanding of the system’s functionalities and good access to the raw data. Almost all participants mentioned that they were not satisfied with their current data retrieval process in their practice, mostly because of the technical limitations of their systems and lack of resources required to keep track of and manage the quality of the data stored in their system.In the participants’ opinion, the most important action to be taken to improve the data retrieval process was to standardize the data items, tools, and data entry forms. Most clinics emphasized the need for an easier-to-use and more consistent data entry method and codification, so that it would reduce the complexity for physicians. They also highlighted the need for making systems more user-friendly and easier to navigate for the average staff member or clinician, particularly for those without advanced computer or statistical programming knowledge or skills.Overall, participants assessed their participation in the challenge as a positive experience, which helped them validate their views about EMRs. It also reinforced their ideas about the effectiveness and efficiency of their current work practices and systems used in the clinic, and that it highlighted limitations. For paper-based clinics, our results supported the importance of investing in EMRs, and displayed the significant differences in terms of processing efficiencies of PBPH. For EMR-enabled clinics, the study highlighted to management and staff the ways in which they can improve their use of the system , as well as where they can enhance existing tools to improve work habits, quality of care, and performance.Our study aimed to assess the capacity and preparedness of primary care settings for PBPH. First, we developed a preparedness score to reflect upon the relative performance of the participating clinics. The sampling approach allowed the performance of paper-based manual record systems to be compared to that of EMR-enabled or automated patient record systems.While the preparedness score shows that EMR-enabled clinics have a higher capacity and confidence in PBPH reviews, our results also highlight a gap in the ranges of preparedness scores observed. We found a 7-fold (7.2 times) difference between the best-performing paper-based clinic and the worst-performing EMR clinic. Although a performance gap was to be expected based on existing research , the cliIn the cases of the best-performing EMR clinics, the challenge participant was a physician, as opposed to an archivist, medical office assistant, or information technology professional, who was reporting on behalf of a single practice. These clinics achieved a performance level that was, at least, 1.5 times better than the subsequent clinic among the ranked scores. Our qualitative data suggest that familiarity with the record layout and its content could explain the enhanced performance. Therefore, performance across all EMRs could be improved by incorporating data entry standards as well as coding standards. In this regard, data entry standards  and coding standards  would allow medical personnel to “know where to look” and to effectively use the search capabilities of EMRs in support of PBPH. As discussed by participants, searching text fields for misspelled or aliased terms presents added complexity to the review and is also time consuming, which can further negatively affect the implementation of PBPH into practice workflow. Overall, these results are consistent with previous findings that emphasize the important role of EMRs  as the necessary factor in transforming the quality of primary care services ,40.Regarding paper-based clinics, the best-performing clinic achieved a performance level that was 1.7 times better than the next paper-based clinic and 2.4 times better than the lowest-level paper-based clinic. The observational data suggest that this enhanced performance was due to the mixed search strategy used by the best-performing clinic. In each module of the challenge, the initial population was determined using data held in the clinic’s electronic scheduling and electronic billing systems. Once these sources had provided a narrowly defined population list, the paper charts were reviewed. The repurposing of these electronic systems allowed this clinic to effectively cross-reference their patient records and establish initial subpopulations. From this, it can be seen that PBPH could possibly be undertaken by a paper-based clinic using a series of cross-reference tables or registries. This approach could prove effective in small practices where the administrative burden of maintaining the registries could be minimized. However, in a large practice, the strategy would be extremely labor intensive and subject to completeness concerns.Most clinics chose to report on a single clinician’s practice. However, in a few cases, multiple practices were included. In line with the general findings, our data imply that, in these cases, EMR-enabled clinics have a clear advantage over paper-based clinics. In a paper-based clinic, the formulation of the query, which is the actual act of pulling a filed chart and looking at composite clinical notes and information, must be undertaken anew for each practice. In an EMR-enabled clinic, the formulation of the query is done for the first practice but is simply reused for the subsequent practice(s).Finally, the analysis of follow-up interviews revealed the key challenges clinicians face in PBPH management. The most important issue in pursuing PBPH is the lack of systematic data storage retrieval practices in clinics. Despite advances in using information systems in health care contexts (whether for PBPH or not), many clinicians still perceive EMR use as an encounter-based electronic patient chart, instead of a tool to support prospective care and panel management . DespiteWe must acknowledge some limitations to this study. Neither the instrument of measure  nor the measure derived from the instrument (the preparedness score) was rigorously validated. Validation of the preparedness score could prove advantageous, as it could be a tool for government agencies and clinic managers to evaluate the degree of preparedness and to assess the required effort and cost in undertaking PBPH. Nevertheless, to date, the preparedness score has exhibited important interpretation properties that would support the evaluation of the cost-benefit of different medical record keeping processes.The results of this study suggest that the PBPH preparedness score reflects the preparedness of the clinics participating in the challenge. The use of an EMR seems pivotal in setting the foundation to support PBPH management in primary care and subsequently to drive the associated beneficial outcomes for patients and clinicians. The range of capacity in EMR-enabled clinics suggests that for PBPH management to be effectively undertaken, key determinants of EMR optimization need to be addressed.Despite the limitations, the study provides important contributions. The insights proposed by our findings can be used to show the criticality of EMR adoption for pursuing PBPH management. Although the results of previous studies looking at the advantages of EMR adoption have been mixed ,25,26, o


This device enables rapid circumferential scanning of topologically complex luminal surfaces of hollow organs  and produces quantitative images of the relative concentrations of SERS NPs that are present. Human and swine studies have demonstrated the speed and simplicity of this technique. This approach also offers unparalleled multiplexing capabilities by simultaneously detecting the unique spectral fingerprints of multiple SERS NPs. Therefore, this new screening strategy has the potential to improve diagnosis and to guide therapy by enabling sensitive quantitative molecular detection of small and otherwise hard-to-detect lesions in the context of white-light endoscopy.The detection of biomarker-targeting surface-enhanced Raman scattering (SERS) nanoparticles (NPs) in the human gastrointestinal tract has the potential to improve early cancer detection; however, a clinically relevant device with rapid Raman-imaging capability has not been described. Here we report the design and  Endoscopy is currently the gold standard for cancer screening in the gastrointestinal (GI) tract. This white-light imaging modality enables clinicians to inspect the esophagus, stomach, and colon to detect lesions such as adenomas and carcinomas. GI endoscopy relies upon an examiner’s ability to detect gross anomalies on an otherwise healthy luminal surface. In the colon, many precancerous lesions present as polyps that protrude from the surface by more than 2 mm and are reliably detected by visual inspection. However, the detection of precancerous lesions in the esophagus and stomach is considerably more challenging because most of these lesions do not elevate into a polypoid shape. There exists an increasing recognition of the importance of detecting non-polypoid precancerous lesions in the colon and the contribution of missed lesions to the failure of colonoscopy-based cancer prevention programs –4.Endoscopic detection of small polyps and flat lesions in the colon could be improved by adding an imaging modality that is capable of providing functional  information in addition to the structural macroscopic information provided by white-light imaging. Incorporating a molecular imaging modality could help clinicians to locate, diagnose, and stage small and otherwise hard-to-detect lesions, as well as to improve the characterization of these lesions.in vitro or in living tissues [14) is possible due to the multilayer  structure of SERS particles [Raman spectroscopy can be used as a label-free modality providing information about basic chemical bonds  through the analysis of the nominally weak inelastic scattering of photons by such molecular motifs  tissues . Unfortuarticles –8. An ouarticles ,8. Sincearticles . These tOur group, as well as others, have demonstrated the tumor targeting capabilities of several types of conjugated Raman nanoparticles in preclinical animal models and with preclinical systems ,8,10–17.in-vivo imaging of large, complex surfaces. In order to comprehensively scan a portion of the GI tract, such as within the colon or esophagus, within a clinically relevant period of time, a new scanning imaging system needed to be developed.We previously described a point-detection device that demonstrated its potential use with SERS NPs as a screening tool for cancers of the esophagus, colon, cervix, or skin in circumstances where small areas of tissue need to be examined. However as a point-detection device, images could only be created on-the-bench by physically moving the sample ,18, whicHere, we describe the design, development and testing of a new opto-electro-mechanical device that has the capability to rapidly and systematically scan large tissue surfaces and produce images of structural and multiplexed functional data within the context of the traditional endoscopic-imaging procedure. In addition, we developed software to display the images in a manner that is readily interpretable by the clinician. The data can be displayed as flat 2-D images, or rendered onto a cylindrical surface to depict organs like the colon and esophagus, where the user can rotate the volume renderings and view the data from any direction to further improve interpretation.The form factor of our imaging device was designed to allow it to be inserted through the accessory channel of a clinical endoscope and to be used in parallel with white-light endoscopy screening. Circumferential scanning could then rapidly assess the binding of functionalized SERS NPs to tumor targets, thus providing multiplexed molecular information from the entire tissue surface. Here we demonstrate that signals from a panel of SERS flavors can be simultaneously collected and processed into quantitative multiplexed images to inform and guide the endoscopist.A unique feature of this device is that it is a non-contact system, which has been designed and optimized for efficient use over a wide range of clinically relevant working distances. The human colon has an average radius of 25 mm when insufflated . AssuminThe approving committee for the human study is the Stanford University IRB; the IRB protocol ID is 15766. Written informed consent for the study was obtained from all patients. The IRB approved written informed consent as the consent procedure.We have created a small, flexible, fiber-optic-based Raman imaging device, designed for human use, that utilizes circumferential scanning to comprehensively image the lumen of a hollow organ Figs  and 2. B2 of tissue (the approximate footprint of the exposed cell surface). If 100 μm2 is equivalent to the cross-sectional area of approximately 9,000 SERS nanoparticles, then only 2.7% (or ~240 NPs) of the tissue area would need to be covered by NPs. In other words, a minimum of 783,000 nanoparticles would need to lie within the effective area of the collimated laser  limits for incident light, the smallest sample of NPs that produces a signal of at least one standard deviation above the mean background is 783,000 NPs  at the proximal entrance of their accessory channels that limits the rigid length of any inserted device. By minimizing the overall length of the rigid distal end of our imaging device to no more than 25.5 mm  and tranWhile the SERS NPs require USA FDA approval in order to be used in humans, the imaging device alone was used in a patient to analyze the variability of the background signal and the usability of the device. A male patient undergoing routine colonoscopy screening consented to participate in the study and the device was tested in this patient by an experienced endoscopist . Signal in vivo human study, the three-dimensional topography of the colon could be recreated by utilizing the weighting factor for the first principal component of the acquired background signal . However, practical guidelines for endoscopy require that the clinician not move the endoscope without having a clear view of the investigated organ to prevent injury or perforation. Thus, turning off the light of the endoscope increases the risk of complications as well as the procedural time and the duration in which patient is sedated. Also, fluorescence endomicroscopes like the Cellvizio (Mauna Kea Technologies) provide cellular-resolution images, but at the expense of a large field-of-view (since the space bandwidth product must remain constant). This limits their use to localized, and often predetermined, areas of interest rather than for screening purposes; thus, the ability to survey large areas in a short time frame is not possible.There is always a general tradeoff between resolution and field-of-view when designing optical systems. Although the resolution and image quality are lower in our approach than others, such as fluorescence microendoscopy, the advantage is that the user is able to scan clinically relevant surface areas quickly and conveniently making it suitable as a screening tool. The use of SERS NPs compensates, in part, for this lower resolution by providing intense signals that enable detection of relatively small lesions as well as enabling multiplexed molecular imaging.The SERS imaging strategy we propose has additional unique advantages. The complex narrow-band Raman spectra of the SERS NPs allows for simultaneous multiplexed detection using a single excitation wavelength. Although multiplexing can be achieved using fluorophores, their broad emission spectra limit the number of fluorophores that can be unmixed reliably, especially when a single excitation wavelength is used. Also, by measuring the entire spectrum with each acquisition and unmixing with our least-squares and PCA algorithm , our sys-1 Stokes shift from the laser wavelength); this means that the absorption and scattering properties of the tissue affect the detection of all SERS flavors equally. This serves to increase the robustness of ratiometric imaging using SERS NPs as compared to fluorophores. In comparison, the efficient excitation of multiple fluorophores would require more complex illumination, consisting of multiple wavelengths, and multiple filters; thus precluding the sole utilization of the near-infrared transparency window.The enhanced Raman effect can occur at any frequency of incident light within the broad plasmon resonance of the NP (unlike fluorophores which have specific and comparably narrow absorption peaks that vary with each fluorophore). Thus, we were free to choose the illumination wavelength of our system to be 785 nm, in the near-infrared window where absorption from tissue, water, and blood is minimal , allowinAn additional advantage of SERS NPs is that they do not photobleach, which is a limitation of quantum dots and fluorophore-based endoscopy. SERS NPs also have the potential to exhibit higher avidity than dyes and labeled reagents since a single NP can bind to multiple receptors. Lastly, in contrast to fluorophores, these SERS NPs emit a uniformly bright signal across the different SERS NP flavors ; plottedThe non-contact feature of the endoscopic imaging device developed in this study allows the user to scan large, topologically complex surfaces much faster than devices requiring tissue contact. With a rotational speed of 1 rev/s and an axial retraction speed of 1 mm/s, approximately 10 min will be required to scan the entire proximal 2 ft of the colon, which can be performed in parallel with the conventional endoscopy screening. In addition, because the illumination laser is collimated, a constant optical power density can be reliably kept below MPE limits, and resolution is independent of working distance. Topical application of the SERS NPs within the colon lumen, as opposed to intravenous injection, can be performed to potentially minimize toxicity to the patient, as demonstrated in mice .Luminal imaging of multiplexed SERS NPs is a platform technology for rapid functional imaging, which has the potential to distinguish various stages of malignancy and different cancer types in areas of the body accessible to endoscopy, such as the colon, esophagus and stomach, and adapted for use in the oral cavity, cervix, and bladder.S1 Video3D rendered animation illustrating the illumination beam (red) and collected light (yellow) as well as all the assembly of all inner components. Also shown is the scanning of the beam as the device is deployed through the accessory channel of an endoscope scanning the luminal wall of the colon. Bends and folds of the colon are also depicted in the animation.(MOV)Click here for additional data file.S2 VideoThe left frame shows the device scanning the paper phantom as it is being axially retracted. The center and right frames show two real-time displayed representations of the SERS signals as they are being acquired. The signals from all the SERS flavors are being acquired simultaneously and displayed in real-time both as a 2D image (center) and cylindrical three-dimensional model (right). Each of the SERS flavors was assigned a specific color. The right frame of the video, you will see that the image is being periodically rotated about the z-axis. The user is able to rotate the cylindrical three-dimensional rendering at any point during the scan in order to view the results from any direction.(MOV)Click here for additional data file.S3 VideoThe white light video on the left shows the phantom and the axial retraction of the device. The beam can be seen sweeping along the lumen surface and the video on the right is being generated in real-time. The signals from all the SERS flavors as well as the topography information are being acquired simultaneously and displayed in real-time. The data is initially displayed from an intraluminal view which is a similar view obtained from white the white light endoscope, but is easily rotated by the user.(MOV)Click here for additional data file.S4 Video(MOV)Click here for additional data file.S5 VideoThe illumination beam can be seen scanning the colon wall in a human patient as the endoscope is being retracted.(MOV)Click here for additional data file.S6 Video(MOV)Click here for additional data file.S1 FileFurther details regarding the device fabrication as well as the methods used for the experimental setup and statistical analysis can be found here.(DOCX)Click here for additional data file.


Methanopyrus, which in turn points to archaeal tRNA introns as the most primitive introns and the anticodon usage of Methanopyrus as an ancient mode of wobble. The prediction of the coevolution theory of the genetic code that the code should be a mutable code has led to the isolation of optional and mandatory synthetic life forms with altered protein alphabets.The origins of the components of genetic coding are examined in the present study. Genetic information arose from replicator induction by metabolite in accordance with the metabolic expansion law. Messenger RNA and transfer RNA stemmed from a template for binding the aminoacyl-RNA synthetase ribozymes employed to synthesize peptide prosthetic groups on RNAs in the Peptidated RNA World. Coevolution of the genetic code with amino acid biosynthesis generated tRNA paralogs that identify a last universal common ancestor (LUCA) of extant life close to  The chain of information transfers from DNA to messenger RNA, and through genetic coding to proteins requires the assembly of multiple essential components. The pathway was a long one, winding through the ages to recruit all the components. Earlier we have enquired into the development of the gene, Peptidated RNA World, genetic code, last universal common ancestor (LUCA) and synthetic life. In the present study, enquiry is expanded to include the origins of messenger RNA, transfer RNA, intron, triplet codon, wobble base pairing and biological domains.Primitive Earth as a planet within a habitable zone was formed with chemical constituents including carbon compounds. Prebiotic chemical reactions on the planet together with an influx of matter from space produced building blocks including nucleotides and amino acids (aa). Accordingly, prebiotic chemistry was compatible with the rise of a living world based on nucleic acids and proteins as informational macromolecules. In this regard, the capability of RNA to serve both information storage and catalysis supports the formation of an RNA World prior to the present-day Protein World ,2,3,4. Areplicator induction by metabolite, whereby dead-end duplexes containing fRNAs capable of binding metabolite ligands are selectively split apart by the ligands to restart template-directed polymerization. In contrast, dead-end duplexes containing non-functional RNAs that do not bind any metabolite ligand will remain unsplit and degrade, releasing their nucleotides for incorporation into the fRNAs -tRNA compound to [product aa]-tRNA, handing to the product amino acid a tRNA and its anticodon that belonged to the precursor amino acid. In so doing, there is a significant probability that the tRNAs of the product and the precursor will turn out to be paralogous. CET thus suggests that tRNAs and eARSs are particularly promising sources of paralogs that can be employed for rooting phylogenetic trees in search of a LUCA. Analysis of eARS sequences shows that the %-identity between same-species TrpRS and TyrRS is highest in Archaea, intermediate in Eukarya and lowest in Bacteria, and the  Archaea . However Archaea . In cont Stage 6 , which wviz. when the encoded amino acid ensemble was so proficient that a translation error of << 1.5% was achieved [Once the genetic code added the Phase 2 amino acids to the Phase 1 amino acids, there was no further expansion even though in principle the eight 1aa codon boxes in the present-day code could accommodate eight more amino acids by turning into 2aa boxes. The reason is that each entry of a new amino acid, replacing a preexisting amino acid as the assignee of one or more codons, generated replacement noise. As the performance of the proteome including the translation machinery improved with code expansion, the background translation noise was reduced, rendering the replacement noise less acceptable. Accordingly, code expansion would shut down when translation noise was sufficiently low, achieved . It follachieved ,160. Thiachieved .In conclusion, the coevolution theory, proposed to explain the structure of the code, has been verified by wide ranging evidence. In addition, it has revealed the importance of amino acid–RNA cooperation, side chain imperative, tRNA paralogs from code expansion, and feedback to ensure near perfection as factors that prove fundamental as well to the delineation of other stages of life’s emergence. As a result, the eight stages of the emergence process are beginning to be definable as a continuous chain of events uninterrupted by abysmal discontinuities. Identification of an Mka-proximal LUCA clarifies the origins of intron and wobble, and recognition of the Peptidated RNA World as the starting point of peptide coding facilitates analysis of the origins of messenger RNA and transfer RNA. Furthermore, based on the extensive changes undergone by the code to provide codons to biosynthetically derived amino acids, the code is predicted by CET to be an intrinsically mutable, not frozen, code. Experimental proof of this prediction through the isolation of optional and mandatory synthetic life forms has opened up a nascent synthetic life biosphere parallel to the canonical biosphere. The synthetic life forms enable the recruitment of a fast growing variety of unnatural NCAAs into proteins comparable to the NCAAs generated by post-translational modifications. In contrast to post-translational modifications which allow only site-specific NCAA insertions, the altered protein alphabets of synthetic life forms allow both proteome-wide and site-specific NCAA insertions, thereby amplifying the scope of new approaches to a deeper understanding of protein chemistry and evolution. That the DNA alphabet is likewise mutable further expands the potential of synthetic life. The possibility thus arises of designing proteins using altered alphabets with novel amino acids to achieve enhanced performance, and implanting the altered alphabets into transgenic organisms for the production of proteins and vaccines with increased efficacy. Consequently, synthetic life forms can be expected to bring with them a harvest of unimagined insights into how life came about in the past, and how it might develop in the future.


A neural network model of biophysical neurons in the midbrain is presented to drive a muscle fiber oculomotor plant during horizontal monkey saccades. Neural circuitry, including omnipause neuron, premotor excitatory and inhibitory burst neurons, long lead burst neuron, tonic neuron, interneuron, abducens nucleus, and oculomotor nucleus, is developed to examine saccade dynamics. The time-optimal control strategy by realization of agonist and antagonist controller models is investigated. In consequence, each agonist muscle fiber is stimulated by an agonist neuron, while an antagonist muscle fiber is unstimulated by a pause and step from the antagonist neuron. It is concluded that the neural network is constrained by a minimum duration of the agonist pulse and that the most dominant factor in determining the saccade magnitude is the number of active neurons for the small saccades. For the large saccades, however, the duration of agonist burst firing significantly affects the control of saccades. The proposed saccadic circuitry establishes a complete model of saccade generation since it not only includes the neural circuits at both the premotor and motor stages of the saccade generator, but also uses a time-optimal controller to yield the desired saccade magnitude. Saccades are described as fast eye movements in which a target is tracked by registering the image of that target on the fovea. The saccade neural network requires involvement of a series of neurons designed to imitate the behavior of actual neuronal populations in the horizontal saccade controller. A generic neuron model is therefore desired to quantify the neural stimulations meticulously, thus reflecting the physiology linked to the dendrite, cell body, axon, and presynaptic terminal of each neuron. The continuing research effort in demonstrating such a model has been driven by the need to provide the means to develop a network of neurons, tailored to the complexity involved with inherent physiological evidence. To encompass all of the desired neural behaviors for the other neurons, several modifications to the generic neuron model seem necessary that directly impact its firing rate trajectory –3.The widespread use of spiking neural networks (SNNs) lies in leveraging efficient learning algorithms to the spike response models . A spikeTime-optimal control theory of the horizontal saccades establishes the fact that there is a minimum time required for the eyes to reach their destination by involving thousands of neurons. Conjugate goal-directed horizontal saccades were well characterized by a first-order time-optimal neural controller . The anaThe muscle fiber model (MFM) improves the oculomotor plant model by using several configurations of muscle fibers in series or parallel to drive the eyes to their destination . In otheIn this paper, we focus on neural control of horizontal monkey saccades. A neural network model of saccade-related neural sites in the midbrain is first presented. We next characterize the underlying dynamics of each neural site in the network, which needs to be treated in the case of spiking neurons. In consequence, to match the dynamics of the neurons and the synapses, saccadic circuitry, including omnipause neuron (OPN), premotor excitatory burst neuron (EBN), inhibitory burst neuron (IBN), long lead burst neuron (LLBN), tonic neuron (TN), interneuron (IN), and motoneurons of abducens nucleus (AN) and oculomotor nucleus (ON), is developed. Finally, the motoneuronal control signals drive a time-optimal controller that stimulates a MFM model of the oculomotor plant. We abbreviate the “conjugate goal-directed horizontal monkey saccade” with the term “saccade” throughout the paper. The terms “motoneurons” and “agonist (antagonist) neurons” are also substitutable in this paper.Neurophysiological evidence and developmental studies indicate that important neural populations, consisting of the cerebellum, superior colliculus (SC), thalamus, cortex, and other nuclei in the brainstem, are involved in the initiation and control of saccades –3, 13–15In the context of the neuroanatomical connectivity structure in The PPRF encompasses neurons that show dominantly increasing burst frequencies of up to 1,000 Hz during the saccade and remain inactive during the periods of fixation. The LLBN and the medium lead burst neuron (MLBN) are the two types of burst neurons in the PPRF. The LLBN forms an excitatory synapse to the IBN and an inhibitory synapse to the OPN.There are two types of neurons in the MLBN: the EBN and the IBN. The EBN serves as one of the vital excitatory inputs for the saccade controller. The primary inputs to this neuron are the excitatory input of the SC and the inhibitory input from the contralateral IBN and OPN. This neuron forms excitatory synapses to the TN and the AN. The IBN, though, controls the firing of the EBN as well as the TN, both of which are on the opposite side of the network to the corresponding IBN. It also inhibits the ON and the IN on the same side as itself. This neuron receives excitatory inputs from the FN of the cerebellum on the opposite side and the LLBN on the same side and an inhibitory input from the OPN.Many excitatory and inhibitory INs in the central nervous system stimulate and control motoneurons. The cerebellum aggregates most of these INs whose functionality depends on the anatomical aspects and properties of their membranes. The IN receives the excitatory and inhibitory inputs from the corresponding TN and IBN, respectively. It consecutively provides the step component to the agonist and antagonist neural controllers. As with the TN, the utility of the modified FHN model under the tonic bursting mode exhibits this particular neural spiking activity . The folThe saccade generator investigated in this work is built upon the extant research , 16, 17.The structure of the saccade neural network leverages neural coding so that burst duration is transformed into saccade amplitude under the time-optimal condition. Such coding manifests activities, including the onset of burst firing before saccade, peak firing rate, and end of firing with respect to the saccade termination, for each neuron on the basis of the physiological evidence. These characteristics are provided for the neural sites  as a fraThe firing rate trajectories of a medium lead burst neuron of monkey data for saccades of 4°, 8°, 12°, 16°, and 20° are provided , 20. ThiAs motoneurons receive excitatory input from the ipsilateral EBN, the burst discharge in them during a saccade is adequately similar to the EBN bursting. Such burst discharge in the motoneurons is responsible for the movement of the rectus muscles during a saccade. The firing rate trajectory of the EBN is of prime importance in control of such a saccade. The presented EBN model  showed aT represents the saccade termination. The negative time for each neural site refers to the onset of the burst before saccade  is released from inhibition.The ipsilateral IBN is stimulated by the ipsilateral LLBN and the contralateral FN of the cerebellum. When released from inhibition, the ipsilateral EBN responds with a postinhibitory rebound burst for a brief period of time. The EBN, when stimulated by the contralateral FN (and perhaps the SC), enables a special membrane property that causes a high-frequency burst that decays slowly until being inhibited by the contralateral IBN. The burst firing activity of EBN is integrated through the connection with the TN. The IN follows closely the same integration mechanism as that of the TN.The burst firing in the ipsilateral IBN inhibits the contralateral EBN, IN, and AN, as well as the ipsilateral ON.The burst firing in the ipsilateral EBN causes the burst in the ipsilateral AN, which then stimulates the ipsilateral lateral rectus muscle and the contralateral ON. With the stimulation of the lateral rectus muscle by the ipsilateral AN and the inhibition of the ipsilateral medial rectus muscle via the ON, a saccade occurs in the right eye. Simultaneously, the contralateral medial rectus muscle is stimulated by the contralateral ON, and, with the inhibition of the contralateral lateral rectus muscle via the AN, a saccade occurs in the left eye. Hence, the eyes move conjugately under the control of a single drive center. During the fixation periods, the INs provide the steady-state tensions required to keep the eyes at the desired destination.At the termination time, the cerebellar vermis, operating through the Purkinje cells, inhibits the contralateral FN and stimulates the ipsilateral FN. Some of the stimulation of the ipsilateral LLBN and IBN is lost because of the inhibition of the contralateral FN. The ipsilateral FN stimulates the contralateral LLBN, EBN, and IBN. The contralateral EBN then stimulates the contralateral AN. The contralateral IBN then inhibits the ipsilateral EBN, TN, and AN and contralateral ON. This inhibition removes the stimulus to the agonist muscle.The ipsilateral FN stimulation of the contralateral EBN allows for modest bursting in the contralateral EBN. This activity then stimulates the contralateral AN and ipsilateral ON. Once the SC ceases firing, the stimulus to the LLBN stops, allowing the resumption of OPN firing that inhibits the ipsilateral and contralateral MLBN, hence terminating the saccade.The following description outlines eight steps required to implement the saccade control strategy in the context of The advances in computational neural modeling have supplied us with abundant information at different structural scales, such as the biophysical , 5, the A typical neuron embodies four major components: cell body, dendrites, axon, and presynaptic terminals, as shown in long lead burst neuron (LLBN),omnipause neuron (OPN),excitatory burst neuron (EBN),inhibitory burst neuron (IBN),tonic neuron (TN),interneuron (IN),abducens nucleus (AN),oculomotor nucleus (ON).A complete understanding of the properties of a membrane by means of standard biophysics, biochemistry, and electronic models of the neuron will lead to a better analysis of membrane potential response. This response is dependent on how much neurotransmitter is received from the presynaptic terminal of the adjacent neurons; thereby, the neuron becomes hyperbolized or depolarized. A generic neuron circuit model is introduced in this section, together with the description of the modifications required to populate a neural network for control of saccades. The saccade neural network includes eight neuron populations at premotor and motor levels as seen in The saccade circuitry underlies the dynamics of the above eight distinct neurons, each of which contributes to the control mechanism of the saccade. Except for the OPN, the proposed parallel-distributed neural network proposed parallel-distributed neural network accommodates two of each of the other neurons in the network. The dendrite model delineated below is adjustable to the stimulation mechanism of all eight neurons. The axon model for all spiking neurons, except the EBN and OPN, adheres to the Hodgkin-Huxley (HH) model. The EBN and OPN are neurons that fire automatically when released from inhibition—these neurons are modeled using a modified HH model . The TN The dendrite is partitioned into a number of membrane compartments, each of which has predetermined length and diameter. Each compartment in the dendrite has three passive electrical characteristics: electromotive force (emf), resistance, and capacitance, as shown in is). The node equation for the first dendrite compartment isvm1 is the membrane potential of the first compartment and vm2 is the membrane potential of the second compartment. The membrane resistance REQ, capacitance Cm, and the emf VTH characterize each compartment. Ra is the axial resistance.The presynaptic input to the dendrite is modeled as a pulse train current source ) through the axial resistance Ra.The last dendrite compartment receives just one input from its preceding compartment. The corresponding node equation isThe neurons' dendrite model is realized by experimental tuning of the parametric capacitance and resistance properties of the basic dendrite model. This parametric adaptation allows for the accommodation of the synaptic transmission in the neural network as required to stimulate each postsynaptic neuron. Each neuron's dendrite rise time constant determines the delay to emulate the postsynaptic potential propagation along the dendrite, consistent with the initiation of firing with respect to the saccade onset provided in VTH at steady state. Computational efficiency accrues when the minimum number of compartments in the dendrite model is required. We chose to include 14 compartments in the dendrite to achieve the desired membrane properties in each type of neuron. For example, the EBN dendritic membrane potential across the first, second, third, and last compartments is illustrated in Initial condition of the capacitor is set to Vm as a function of stimulus current Im from the dendrite and voltage-dependent conductance of the sodium and potassium channels is [The Hodgkin-Huxley (HH) model of the axon serves as the basis for the neurons modeled here—only the EBN and OPN are based on a modified HH model . This nonnels is (4)g−KN4Vm; that is,Vrp is −60 mV.The coefficients in the above first-order system of differential equations are related exponentially to the membrane potential N, M, and H differential expressions in . In what follows, the active-state tensions are defined as the low-pass filtered neural innervation signals.Nag represents the agonist neural innervation input from which the agonist active-state tension, Fag, is generated. The agonist time constant τag is expressed by two step functions dependent on the agonist activation time constant, τgac, and the deactivation time constant τgde. t1 indicates that the saccade has the latent period, and t2 is the start of the transition slide interval for the agonist controller. It is noteworthy that the activation (deactivation) time constant in the model accounts for the different dynamic characteristics of muscle upon increasing (decreasing) stimulation.The agonist controller is a first-order pulse-slide-step neuronal controller that describes the agonist active-state tension as the low-pass filtered neural stimulation signal . The neuNant denotes the antagonist neural innervation input and the Fant is the antagonist active-state tension generated. The antagonist time constant is describable by two step functions, introducing the antagonist deactivation time constant, τtde, and the activation time constant τtac. t1 takes into account the latent period, and t3 is the onset of the change to the step component necessary to keep the eyeball steady at its destination.The antagonist muscle is unstimulated by a pause during the saccade and remains fixed by a step input to keep the eyeball at its destination. To serve this purpose, a first-order pause-step neuronal controller is defined . The neuThe time-optimal controller has been found to be reasonably consistent with the characteristics of the main-sequence diagrams . In whatA linear homeomorphic MFM that captures the nonlinear properties of the muscle, namely, force-velocity and length-tension relationships, is investigated . The musThe rigorous analysis of the MFM including both the length-tension and the force-velocity characteristics indicates that this model agrees with the previous results from the whole muscle model , 12. Theθ is the angle of displacement of the eyeball from the primary position, and x denotes the respective change in length of arc. The changes in the length of the agonist muscle on the left and the antagonist muscle on the right are shown by xag and xant, respectively. There are 2n columns of muscle fibers, each of which has m muscle fibers in series. Each column of muscle fibers also includes two tendon elements, whose viscous and elastic elements are B2 and Kse, at the top and bottom of it. Each structural unit of muscle fiber is modeled by a viscous element, B1, an elastic element, Klt, and an active state generator, Fji, where 1 ≤ i ≤ 2n and 2 ≤ j ≤ m + 1. The change from the primary position at node j in the muscle fiber column i is denoted by xji. Note that Nji exhibits the input to the agonist and antagonist controller models stated formerly. Motoneurons provide the saccadic neural innervation signals to each muscle fiber in our time-optimal controller. The advantage of the state-variables approach facilitated the mathematical descriptions of the oculomotor plant and its implementation in the MATLAB/Simulink [y1i = xag − x2i, the net torque developed by the agonist MFM isj = 1 and m + 2), the state equation isj ≤ m + 1) isTi is the tension generated by each muscle fiber column.The focus of our attention herein is the description of an oculomotor plant in which the MFMs of the agonist and antagonist rectus eye muscles are incorporated . The MFMSimulink . With den + 1 ≤ i ≤ 2n), after definition of y1i = xant − x2i, the net torque developed by the antagonist MFM isj = 1 and m + 2) isj ≤ m + 1) are represented byTi denotes the tension developed by each muscle fiber column. Consequently, the third-order linear differential equation to solve for the optimal solution for a saccade is [Jp denotes the moment of inertia of the eyeball, Bp denotes the viscous element of the eyeball, and the passive elasticity of the eyeball is represented by Kp. r is the radius of eyeball (10 mm for monkey). It is assumed that the muscles are primarily stretched by 3.705 mm [In a similar approach for the antagonist MFM n +  ≤ i ≤ 2nNote that the above expressions show that the inputs to the MFM are the agonist and antagonist active-state tensions. These tensions are obtained by low-pass filtering of the motoneurons' innervation signals as previously described for both the pulse-slide-step and pause-step controllers.Fji were yielded in the previous work [The analytical solutions for all ous work , and it ous work  involvedous work ).Two small saccades (4° and 8°) and three large saccades  have been the focal point of our simulations of horizontal monkey saccades under the first-order time-optimal control strategy. All neural populations consisted of 14 dendrite compartments with membrane properties included in n = 1 and m = 100), since this coordination provided sufficient resolution in matching the experimental data [We arranged 100 identical muscle fibers , axonal membrane potential (second column), and synaptic current pulse train (third column) of the ipsilateral burst neurons and IN in generation of the 16° saccade are shown in It is obvious that the synapse propagation raises different excitatory and inhibitory postsynaptic potentials in the dendritic compartments of each postsynaptic neuron . The trAs evident by different firing rate trajectories for the EBN, this neuron has tightly coupled characteristics to the saccade . For theImplementing the OPN dendrite and synapse models in order that this neuron stops inhibiting the EBN about 10 ms before the saccade and resumes its inhibition almost when the saccade ends was subject to numerous experimental tunings see . WithoutWhile the midbrain coordination mechanism in generating saccades is qualitatively studied , 15, comA time-optimal neuronal control strategy for human saccadic eye movements was first proposed based on experimental data analysis . We usedThe set of agonist-antagonist control inputs to the muscle fiber oculomotor plant supports the time-optimal controller in which the motoneurons' firing rate does not determine the saccade magnitude. The application of the MFM in the oculomotor plant proves important in accommodating the constraint on the number of active neurons firing maximally in controlling the saccade magnitude. The number of the active neurons is a key parameter whose adjustment in the MFM is vital in providing the desired saccade control simulation results. It follows from our observations that the duration of the agonist burst firing and the number of active agonist neurons are integral to determining the saccade size see .It is noteworthy that the duration of agonist burst discharge is of prime significance in determining the saccade magnitude as seen in The final eye position results establish evidence for the acceptable performance of the proposed neural circuitry and the exploited time-optimal controller in modeling the horizontal monkey saccades. The dependence of these different saccades on the agonist pulse duration has been found to be well presented by our time-optimal controller. The simulation results substantiate the time-optimal controller by the close agreement obtained with the analytical solutions of saccade characteristics , 12. ThiWe simulated five different conjugate goal-directed horizontal monkey saccades: 4°, 8°, 12°, 16°, and 20°, under the first-order time-optimal control strategy. A parallel-distributed neural network model of the midbrain was first presented. To develop the quantitative computational models that establish the basis of this functional neural network model, we next described the saccade burst generator dynamics. A neural circuit model was then demonstrated and parameterized to match the firing characteristics of eight neuron populations at both the premotor and motor stages. In this context, we elevated the neural modeling from a single neuron to a network of neurons. Our control strategy was to define two controllers, namely, agonist and antagonist controller models, characterized by the pulse-slide-step and pause-step waveforms, respectively. The horizontal monkey saccades were well characterized by integrating the neural controllers into a third-order linear muscle fiber oculomotor plant. 100 identical muscle fibers were connected in series in both the agonist and antagonist muscles in the oculomotor plant. Under the time-optimal strategy, the number of neurons that actively fire and the duration of the agonist pulse determined the saccade magnitude. The choice of the number of active neurons proved accurate in adapting the muscle fiber model to provide the desired control simulation results. The proposed saccadic circuitry is thus a complete model of saccade generation since it not only includes the neural circuits at both the premotor and motor stages of the saccade generator, but also uses a time-optimal controller to yield the desired saccade magnitude for both the small and large saccades. The saccade characteristics were found to be well correlated with those found by analytical descriptions and experimental data.


To introduce a new method for generating the clinical target volume (CTV) from gross tumor volume (GTV) using the geodesic distance calculation for glioma.One glioblastoma patient was enrolled. The GTV and natural barriers were contoured on each slice of the computer tomography (CT) simulation images. Then, a graphic processing unit based on a parallel Euclidean distance transform was used to generate the CTV considering natural barriers. Three-dimensional (3D) visualization technique was applied to show the delineation results. Speed of operation and precision were compared between this new delineation method and the traditional method.In considering spatial barriers, the shortest distance from the point sheltered from these barriers equals the sum of the distance along the shortest path between the two points; this consists of several segments and evades the spatial barriers, rather than being the direct Euclidean distance between two points. The CTV was generated irregularly rather than as a spherical shape. The time required to generate the CTV was greatly reduced. Moreover, this new method improved inter- and intra-observer variability in defining the CTV.Compared with the traditional CTV delineation, this new method using geodesic distance calculation not only greatly shortens the time to modify the CTV, but also has better reproducibility. Postoperative adjuvant radiotherapy has become the standard of care in the management of gliomas Definition of the target volume of gliomas is governed by rules There are two basic methods used for defining distance: the Euclidean distance and the geodesic distance Herein, we introduce a new method for the calculation of geodesic distance using a combination of medical imaging, three-dimensional (3D) geometric calculation and medical visualization analysis with the objective of improving the accuracy and consistency of CTV delineation.™: Varian, Palo Alto, CA, USA), and the GTV and natural barriers such as the skull and cerebral falx were contoured on each CT slice.The study was approved by the Ethics Committee of the First Affiliated Hospital of College of Medicine at Zhejiang University and written informed consent was obtained from the single GBM patient enrolled. Prior to radiotherapy, a CT simulation was performed using a dedicated CT scanner . Images were transferred to the TPS  based on the GTV. In the first growth iteration, the system calculated the shortest distance in space from the GTV for each point based on the 3D Voronoi diagram to attain the corresponding segment L. If the distance was longer than d, the corresponding point was removed from the growth target volume. If the distance was shorter than d, it was necessary to judge if the segment L intersected with the barriers. If the segment L intersected with the barriers, the point was similarly removed from the target volume. The green area in ds was denoted as the cumulative shortest distance between the point and the GTV, then ds for each point in the target volume was the shortest Euclidean distance away from the GTV in the first growth iteration.After the 3D Voronoi diagram had been obtained and the spatial octree for the barriers constructed, we obtained the final target volume by calculation of the multiple iterative growths. First, the CTV was generated using the default external diffusion value  of ds for point b and the distance between point c and point b. Otherwise, the point c was removed from the target volume. As for the calculated value of dc, if it was smaller than the present value of ds for point c, it should be updated and added to the target volume. After multiple follow-up growth iterations, the cumulated Euclidean distance ds from each boundary point to GTV was equal to d.Based on the previous growth iterations, the distance field for the area sheltered by the barriers was recalculated for the following growth iterations. As for point To test the usefulness of this new method, five radiation oncologists with at least 5 years’ experience were asked to delineate the CTV based on the same GTV using the TPS (EclipseTM: Varian). The CTV was defined as the GTV plus a 2.5 cm margin. Using the traditional method, after automatic and isotropic expansion as a regular spherical shape, the CTV was manually modified to account for the skull and cerebral falx. Then one single physician was also asked to delineate the CTV on 5 different days. Using the current new method, the five physicians and one single physician on 5 different days were asked to delineate the skull and cerebral falx; then the CTV was automatically generated from the GTV. The inter- and intra-observer variability in the delineated volume and the conformity index (CI) were compared. The delineated volume and the CI were calculated using TPS software. The CI of the five delineated structures was defined as the ratio of the overlapping volume and the encompassing total delineated volume. A CI of 1 indicated perfectly overlapping volumes. A CI of 0.5 indicated that the observers agreed regarding 50% of the total delineated volume  (A) and (B) shows the models that were used to compare the CTV results obtained using direct Euclidean distance expansion and geodesic distance calculation; a regular spherical-shaped CTV could be seen in the former approach, and considerable manual effort was required at a later stage to modify the CTV. In contrast, using the geodesic distance calculation that takes the corpus callosum and cerebral flax into consideration, the CTV was generated much more reliably.  (C–E) shows the 3D visualization results from the CT simulation when the CTV was generated automatically using the geodesic distance calculation, when taking into consideration nothing, the cerebral falx, the skull.  (F) shows the CTV that was obtained using the current geodesic distance calculation method to automatically cross the cerebral falx and the deselected area beyond the skull.In the current study involving GBM, the GTV was tracked as feature points when the 3D Voronoi diagram was computed, and the skull and cerebral falx were tracked as barriers when the final CTV was calculated automatically.  (A) demonstrates the disagreement (inter-observer variability) regarding the CTV volume and shape among the five physicians using the traditional CTV delineation. Furthermore, inconsistency (intra-observer variability) involving one single physician on 5 different days could also be found, as shown in As shown in If we take a bird's-eye view of postoperative radiotherapy for glioma over the past decades, great progress has been achieved, ranging from target volume and radiation dose delivery to physical technology. With regard to physical technology, IMRT has been shown to improve radiation dose distribution in the target volume, as well as to reduce the dose exposure of normal tissues compared with conventional radiotherapy In recent years, greater attention has been focused on target volume delineation. The use of CT and MR registered imaging has been reported to reduce inter-observer variability in target volume delineation regarding postoperative irradiation of high-grade gliomas The Euclidean distance transform method is widely applied in many fields, such as image processing, computer vision, graphics, and computation geometry The new method we have developed to generate the CTV from the GTV using the geodesic distance calculation automatically crosses natural barriers. It is feasible for use in glioma radiotherapy and has demonstrated not only a considerable reduction in the time required to generate the CTV, but also an improvement in the accuracy of delineation. It should be admitted that only there was one patient included in this preliminary study since our objective was to find a proof of the principle method. We are now doing our further study applying this new method in much more complicated circumstances involving more anatomical barriers and different tumor sites. We also plan to evaluate if there is a dosimetric advantage regarding the target volume and critical target organs when this new approach is integrated into TPS software.Apart from anatomical barriers, white matter fiber orientation and tumor growth kinetics should also be taken into account when performing CTV expansion. Therefore, in our future study we will also evaluate DTI combined with visualization technology, formulate a corresponding mathematical model, and calculate the 3D geometric fields using iso-surface extraction techniques. The current study provides a theoretical base regarding new criteria for target definition in postoperative radiotherapy of gliomas.


In this study, a novel grey self-memory coupling model was developed to forecast the incidence rates of two notifiable infectious diseases (dysentery and gonorrhea); the effectiveness and applicability of this model was assessed based on its ability to predict the epidemiological trend of infectious diseases in China.The linear model, the conventional GM model and the GM model with self-memory principle  model) were used to predict the incidence rates of the two notifiable infectious diseases based on statistical incidence data. Both simulation accuracy and prediction accuracy were assessed to compare the predictive performances of the three models. The best-fit model was applied to predict future incidence rates.Simulation results show that the SMGM model can take full advantage of the systematic multi-time historical data and possesses superior predictive performance compared with the linear model and the conventional GM model. By applying the novel SMGM model, we obtained the possible incidence rates of the two representative notifiable infectious diseases in China.The disadvantages of the conventional grey prediction model, such as sensitivity to initial value, can be overcome by the self-memory principle. The novel grey self-memory coupling model can predict the incidence rates of infectious diseases more accurately than the conventional model, and may provide useful references for making decisions involving infectious disease prevention and control. Prevention and control of infectious diseases is an increasingly important public health issue. After World War II, developments in preventive medicine, clinical medicine, and preclinical medicine have served major roles in preventing and controlling infectious diseases. Many acute or chronic infectious diseases have been effectively controlled by the use of antibiotics and vaccines A statistical analytical method that combines mathematics and infectious disease epidemiology is used to predict the emergence of infectious diseases. This method has been widely applied for early warning and forecast of all types of infectious diseases. Model-based prediction methods for epidemics have been a major research focus in public health. Studies commonly combine statistical analysis  show limitations On the basis of retrieved modeling methods, the self-memory principle of dynamic system was first proposed by Cao in 1993 Neisseria gonorrhoeae, is a highly communicable sexually transmitted infection and, due to its short incubation period, may serve as an indicator of recent risky sexual behavior in symptomatic cases In the fields of epidemiology and public hygiene, the occurrence and prevalence of an infectious disease are commonly accompanied by irregular individual fluctuations due to many internal and external unstable factors. Hence, the spread and prevalence of an infectious disease can be regarded as a dynamical variable grey system with stochastic fluctuation. The grey prediction models have been effectively utilized for forecast and analysis of the morbidity and mortality of epidemics, such as parasitosis and phymatosis In this study, prediction performances of the SMGM model, the conventional GM model and the linear model were compared. The model with the best fit was then utilized to deduce emerging epidemic tendencies. We propose that the grey self-memory coupling prediction model is appropriate for forecasting the incidence rates of infectious diseases in China. Results of our analyses may provide effective guidance in the decision-making process for the prevention and control of epidemics.In this study, the incidence rates of two types of notifiable infectious diseases (dysentery and gonorrhea) were investigated. The incidence rates of the two infectious diseases were obtained from public governmental statistical data, published by the China Health Statistical Yearbook of 2013 The linear model was formulated as y = mx+b. Detailed principles of modeling analysis and accuracy assessment of the grey self-memory coupling prediction method have been described previously by Wu et al. After the accumulated original statistical data are generated and the moving average is calculated, the grey system GM model can weaken the randomness of the original data and generate regular cumulative data. Consequently, the prediction model can be approximated by the solution of a linear first-order differential equation. Nevertheless, the self-memory principle not only emphasizes the overall exponential development tendency of the dynamical system, but also its individual stochastic fluctuations. After introducing the memory function, which contains historical information, into the system's dynamic differential equation, the equation can be transformed into a difference-integral equation, called self-memorization equation, by defining the inner product in Hilbert space. Because the systematic self-memorization equation contains multiple time-point initial fields instead of only single time-point initial field, the weakness of being sensitive to the initial value of the original dynamic differential equation can be overcome. By studying systematic inner memorability, the systematic overall exponential development tendency with individual stochastic fluctuations can be modeled and predicted. The superiority of the self-memory principle lies in the fact that the systematic predictive ability can be improved by not only combining dynamics calculations and estimating parameters of historical data, but also extracting systematic information from historical data in statistics.For our modeling analysis, the incidence data of the two infectious diseases from 2004 to 2011 were taken as the modeling samples  model was derived as follows:Step 1. Assume that the sequence Step 2. The basic form of the GM model is defined as Eq. 1 accordingly. Consider the inverse accumulated generationStep 3. The whitenization equation of the GM model is given by Thus, the simulative value of sequence The procedure followed to develop a novel SMGM  model is as follows:Step 1. Determining the self-memory dynamic equation.Let Eq. 2, is considered systematic self-memory dynamic equation of the grey self-memory coupling model:The differential equation Eq. 3 and supposing that variables Eq. 3 is obtained as Let one time set Eq. 5, after applying calculus and performing integration by parts, applying the median theorem, and performing algebraic operations, a difference-integral equation is deduced as:For every integral term in the left-hand side of Step 3. Discretizing the self-memory prediction equation.Eq. 6 can be converted intoEq. 7, denotes the relative contributions of historical data at Eq. 7 emphasizes serial correlation of the system by itself, i.e., the self-memory characteristic of the system. Therefore, Eq. 7 is the self-memory prediction equation of the system. If integral operation is substituted by summation and differential is transformed into difference in Eq. 7, then the mid-value Let Step 4. Solving the self-memory prediction model.Assuming that there are Eq. 8 can be expressed in matrix form as follows:Then, Eq. 9 turns into Let Simulation and prediction accuracy is an important criterion for evaluating prediction models. Accuracy test must be performed to evaluate the rationality and reliability of prediction models before extrapolation and application. Consequently, two popular test criteria such as variance ratio and small error probability In the same way, given The absolute percentage error at time The calculation was performed, as mentioned above, with the help of MATLAB software for computational efficiency. The programming procedure for the SMGM model is shown in The incidence rates of two representative infectious diseases (dysentery and gonorrhea) from 2004 to 2012 in China were adopted to demonstrate the practicability and effectiveness of the proposed SMGM model and its superiority to the linear model and the conventional GM model. On the whole, the time series of incidence rates of dysentery and gonorrhea all showed an obvious exponential decreasing tendency. They were accompanied by some irregular individual fluctuations due to unstable changes imposed by social and economic factors. Therefore, two SMGM models were established to model and predict the incidence rates, and were compared with their corresponding linear models and conventional GM models. When performing the modeling analysis, the incidence rates of the first eight time-points were taken as modeling samples, and the data of the ninth time-point was selected as the test sample for the prediction test. In accordance with the principles and the steps mentioned above, two SMGM models were established to forecast incidence rates. The value of retrospective order was uniformly determined as Based on the incidence data of dysentery from 2004 to 2011, the differential equation of conventional GM model can be formulated as follows:Eq. 10 be the dynamic kernel (4) into Let the right-side term of The simulated values and errors of the linear model, the conventional GM model and the SMGM model are presented in Based on the incidence data of gonorrhea from 2004 to 2011, the differential equation of the conventional GM model is formulated as follows:Then, the prediction equation of gonorrhea incidence can be similarly obtained by using the same formula above, where the memory coefficients matrix isThe simulated values and errors of the linear model, the conventional GM model and the SMGM model are presented in Furthermore, The GM model, as a basic and typical grey system prediction model, mainly reflects the statistical laws of diseases by processing the corresponding statistical data. Through conversion of the original sequence, the model establishes a regression equation based on the regular generated sequence. Consequently, prediction of the dynamic development trend of diseases can be conducted using the regression equation. The GM model is gradually developing into a common analytical method for both medicine and public health In this paper, the conventional GM model and the SMGM model were utilized to predict the incidence rates of three representative infectious diseases in China. Analysis of simulation results indicated that the SMGM model possesses more superior predictive performance than the conventional GM model. Therefore, the SMGM model was selected to predict the future incidence rates of three infectious diseases in China. The incidence rate is the most straightforward and objective index, which evaluates the effect of prevention and control measures, because the numerator of the incidence rate is the new morbidity number within a time of resignation. The model significantly reduces prediction error of future incidence rates of infectious diseases. The combination of self-memory component and the grey system model can obtain encouraging prediction performances. This coupling model is a practical forecasting tool for infectious diseases with characteristics of stable epidemic factors, because its requirements of the original data are not as strict as those of other common statistical models. Therefore, the novel coupling prediction model can be used to predict the regularity of occurrence and development of infectious diseases and to identify their dynamic tendencies, thus providing a scientific basis for the prevention and control of infectious diseases.Results of our simulations show that the novel grey self-memory coupling prediction model has improved the prediction accuracy of incidence rates, especially for short-term prediction. However, the model has certain limitations. First, when the grey self-memory coupling model is applied to long-term prediction, the prediction accuracy may decline. For this reason, the model needs to be further amended