An ontology for cell types that covers the prokaryotic, fungal, animal and plant worlds is described. It includes over 680 cell types. These cell types are classified under several generic categories and are organized as a directed acyclic graph.   and can be viewed using standard ontology visualization tools such as OBO-Edit and COBrA.We describe an ontology for cell types that covers the prokaryotic, fungal, animal and plant worlds. It includes over 680 cell types. These cell types are classified under several generic categories and are organized as a directed acyclic graph. The ontology is available in the formats adopted by the Open Biological Ontologies umbrella and is designed to be used in the context of model organism genome and other biological databases. The ontology is freely available at  Mus musculus) [Zea mays) [Drosophila melanogaster) [One of the most challenging problems now facing the model organism databases is the formal description of phenotypic data. While some databases, for example those for mouse (usculus) , corn (Zea mays)  and fruiogaster) , includeogaster) -5, the aNotch gene and all of the cell types in Drosophila and Caenorhabditis elegans that express the closest homolog of this gene; list all of the genes in mouse, rat, human and zebrafish that are expressed in the cell type Schwann_cell; CL:0000218; list all of the genes in D. melanogaster and C. elegans that have a mutant phenotype in the cell types that develop from the cell type myoblast; CL:0000056. The use of the cell ontology will thereby promote the de facto integration of data from diverse databases.To address these needs, we have developed an ontology that describes the cell types of the major model organisms, both animal and plant. Its use will allow a biologist to query a single database with such questions as: list all of the cell types in mouse that express the Drosophila, Arabidopsis thaliana and C. elegans), and ontologies for mouse pathology and human disease.Since the development of the Gene Ontology (GO) for the annotation of attributes of gene products , many onThere are several other ontologies that include cell types such as Systematized Nomenclature of Medicine (SNOMED) , the Foude facto integration of data from diverse databases, as described above. This approach does, however, pose conceptual problems: for example, are a mammalian 'muscle_cell' and a nematode 'muscle_cell' homologous? In this particular example we have little doubt that the answer is 'yes'; both of these cell types are evolutionary descendants of the first metazoan's 'muscle_cell'. In other cases, however, matters are not quite as straightforward, a plant 'hair_cell', a 'hair_cell' of the mammalian cochlea and an insect 'hair_cell' are probably not homologous, despite some similarities in their functions and genes expressed within them [The first design decision was whether we should attempt to integrate cell types from all phyla within a single ontology or build independent ontologies for different taxonomic groups. The former has the great advantage of facilitating hin them . Despiteis_a and develops_from relationships. The former is a subsumption relationship, in which the child term is a more restrictive concept than its parent (thus chondrocyte is_a mesenchyme_cell). The latter is used to code developmental lineage relationships between concepts, for example that a hepatocyte develops_from a mesenchymal_cell. The is_a relationship implies inheritance, so that any properties of the parent concept are inherited by its children; the develops_from concept carries no inheritance implications.The ontology consists of concepts or terms (nodes) that are linked by two types of relationships (edges). This means that the ontology appears as a complex hierarchy  where a given term (or concept) may not only have several children, but also several parents. The parent and child terms are connected to each other by Arabidopsis [The rules for building the ontology are the same as those defined by the GO Consortium. That is, each concept in the Cell Ontology has an identifier with the syntax CL:nnnnnnn, where nnnnnnn is a unique integer, and CL identifies the Cell Ontology, . In addition, if there are precisely equivalent terms in other databases, for example in the Fungal Anatomy , Arabidobidopsis , Plant Obidopsis  or FlyBabidopsis , then thbidopsis . Thus, iThe two top-level nodes of the Cell Ontology are cell_in_vivo and experimentally_modified_cell. The former includes cell types that occur in nature, the latter those that are experimentally derived, including cell lines and such constructs as protoplasts. Experimentally derived cells are under-represented in the current version of the ontology. Naturally occurring cells are classified both by organism-independent categories and by organism . The organism-independent classification of cells follows several different criteria that include: 'function' , histology , lineage  and ploidy . The present version of the Cell Ontology has an average 'depth' of about 10 nodes.The richness of the ontology can be illustrated by example Figure . KupfferOntologies in bioinformatics are intended to capture and formalize a domain of knowledge, and the ontology reported here attempts to do this within the domain of cell types. It is designed to be useful in the sense that a researcher should be able to find, in a rapid and intuitive way, any cell type in any of the major model organisms and, having found it, learn a considerable amount about that cell type and its relationships to other biological objects.Drosophila and Arabidopsis ontologies [A core feature of the ontology, and one that differentiates it from other resources that contain cell types such as SNOMED and the FMA ,9, and ttologies ,17, is tThe expected short-term use of the ontology will thus be in cataloguing phenotypes and gene expression patterns. Indeed, it is quite surprising that those who work with model organisms still lack the bioinformatics resources needed to catalogue, archive and access the details of the phenotypes emerging from mutant screens and natural variations. A robust representation of normal and mutant phenotypes in all of the model organisms will require ontologies for a wide range of macroscopic properties  and we view the cell ontology as a component of this programme that should be useful in cataloguing phenotypes (and other attributes) associated with cell types.In the long term we expect that molecular biology and biological databases will move beyond being gene-centric and that biological mechanisms will be studied at a more integrated level. Cells are the biological units with which tissues and organs and organ systems are built. A rich and explicit description of cell types across phyla that are adapted by biological databases will help facilitate this transition.ashburner@ebi.ac.uk.Finally, it should be pointed out that, like many such resources, this ontology is not complete: although it contains all the common cell types, there will certainly be some that have been omitted. Most importantly, although many of the cell types are fully described by function, morphology, organism, and so on, others are inadequately described and more relationships need to be made. A particular weakness is the fact that the category identified as experimentally_modified_cell has yet to be populated, and doing this will involve consideration of the various cell lines held in the major collections. As with other community resources, community input is essential for the development and maintenance of the Cell Ontology; biologists with comments and additions are therefore welcome to contribute to the ontology and should contact the curator Drosophila, Caenorhabditis, zebrafish, Dictyostelium discoideum, Arabidopsis, fungi and prokaryotes). These cell types have been collated from our own knowledge, from major textbooks , fro example , and froThe ontology was constructed using the open source Java tool OBO-Edit (previously known as DAG-Edit) , which iThe Cell Ontology is available from the OBO site . Followi


These tumors include angiomyolipoma (AML), clear cell "sugar" tumors of the lung (CCST), lymphangioleiomyomatosis (LAM), clear cell myomelanocytic tumors of the falciform ligament and distinctive clear cell tumors at various other anatomic sites.The World Health Organization recently recognized a family of neoplasms showing at least partial morphological or immunohistochemical evidence of a putative A 41-year old gravida-1 para-1 with tuberous sclerosis presented with an incidentally identified 2.2 cm mass. The morphology and immunohistochemical profile was consistent with PEComa. Distinct aggregates of HMB-45 epithelioid cells were present in an occasionally distinctive perivascular distribution in the myometrium, small bowel lamina propria and ovarian hila. These distinctive aggregates, for which we propose the designation "PEComatosis" based on their intraabdominal distribution, did not display cytological atypia, mitotic activity or necrosis. CGH and DNA ploidy analysis showed a balanced chromosomal profile and diploid nuclei, respectively. There was no recurrence or metastases at 35 months' follow-up. Fifty-one previously reported cases of non-AML, LAM and CCST PEComas [perivascular epithelioid cell tumors- not otherwise specified (PEComa-NOS)] are reviewed.The lesions may be a reflection of tumor multicentricity, in which each may be a potential nidus for the development of future more well-developed tumors. Alternatively, they may be a manifestation of a poorly understood "field effect", in which there is an increased propensity to develop tumors of this type throughout the abdomen. Finally, and least likely in our opinion, they may represent tumor spread from its primary site. The non-benign cases (mean diameter of 11 cases: 7.5 cm) tended to be larger than the benign cases (mean diameter of 24 cases: 4.54 cm); the statistical significance of the difference (p = 0.022) is maintained even when the outlier effect of the 1 case with a 20 cm diameter tumor reported by Folpe et al  in the nWe have presented herein the first documented case of a PEComa NOS of the uterine cervix. In addition to the primary tumor, aggregates of HMB-45+ clear cells were present at several other intraabdominal sites, including the small bowel lamina propria, ovarian hila and myometrium. Based on this pattern of distribution of tumor cells, we propose the designation "PEComatosis" to describe such aggregates. The morphogenetic basis for the intraabdominal lesions remains unclear. The similarity in morphologic features and immunophenotype between the cervical and extracervical lesions suggests that either a) both lesions arise from the same site or progenitor, or b) they both represent tissue responses of different degrees to the same stimulus. Several possibilities were considered, all of which are necessarily speculative. The lesions may be a reflection of tumor multicentricity, in which each may be a potential nidus for the development of future more well-developed tumors. Alternatively, they may be a manifestation of a poorly understood "field effect", in which there is an increased propensity to develop tumors of this type throughout the abdomen. Finally, and least likely in our opinion, they represented the tumor spread   from its primary site.leiomyomatosis peritonealis disseminata (LPD), gliomatosis peritonei and the recently described diffuse cartilaginous metaplasia of the peritoneum [gliomatosis peritonei is believed to represent an overgrowth of glial implants from ovarian teratomas [de novo proliferation of PEC at those sites. However, whether these are foci that would have undergone involution or continued proliferating into tumor masses remains unclear. Do these lesions represent a manifestation of a poorly understood "field effect", in which there is an increased propensity to develop tumors of this type throughout abdomen? The most obvious underlying condition in this particular patient is tuberous sclerosis. A potentially comparable condition may exist in the lungs. In a few patients with and without tuberous sclerosis, a distinctive diffuse pulmonary interstitial proliferation has been described [The diffuse occurrence of apparently heterologous tissue is a well-known phenomenon in the peritoneal cavity. These include ritoneum ,52. In Lescribed -56. Thesescribed -53. Whetescribed .any tumor, it is unclear what significance there is of the presence or absence of individual features or small combinations thereof.The issues raised by this case highlight the absence of well-established morphologic criteria predicting aggressiveness or malignancy in PEComas. Based on an analysis of 31 of the 51 reported cases detailed in Additional file Since the relevance of any set of pathologic criteria is ultimately dependent on their correlation to clinical behavior based on published experience, we analyzed in greater detail the clinicopathologic features of those 12 cases in which aggressive behavior was already manifest and compared them to those of the 25 cases with benign outcomes. It is well recognized by the authors that this separation is artificial, the definitional threshold for 'aggressiveness" is low, and that for example the recurrence of a tumor is by no means necessarily indicative of its malignancy. Nonetheless, this separation allows comparative analysis of groups of cases whose clinical behaviors have been shown to be different.With regard to morphologic appearance, some features appeared to distinguish the two groups. Nuclear atypia  was more likely to be present in the non-benign group, with this feature described in 8 of the 10 cases in which a comment was rendered. However, some degree of nuclear atypia was also described in 9 of the 25 cases in the benign group; the atypia in all of the latter cases were described as "minimal" or mild to moderate. Two cases that, in our opinion, showed the highest degree of nuclear atypia (in addition to high mitotic activity and necrosis) were unfortunately reported without follow-up information .Mitotic activity was uniformly low in the benign group, with no mitotic figures identified in 13/25 (52%) cases and rare (<1/20HPF) mitotic figures found in the remainder with information. However, for the purposes of answering the more clinically relevant question, i.e. segregation of the non-benign group, mitotic activity was not useful. Only 3 of the 10 non-benign cases (in which mitotic activity information was given) showed significant mitotic activity (≥ 6/10HPF). In the remaining 7 cases, mitotic figures were described as "rare" (n = 3), "low" (n = 2) and <1/20hpF (n = 2).th case described as showing "gelatinous-appearing material" macroscopically [et al [Necrosis was a common feature of cases in the non-benign group, being present in 7 of 11 cases 64%), with an 8opically . However4%, with et al [encapsulated 9 cm mass involving the terminal ileum and cecum [th and 8th cases showed only local infiltration [et al [We also analyzed the degree and types of tumor infiltration as another potential discriminator between the benign and non-benign groups. In what remains the largest series of PEComa NOS reported to date, Vang and Kempson  divided et al  "appearend cecum  which meltration ,14. Anotn [et al , which wOverall, the experience with PEComas NOS is currently too limited to make a definitive assessment of prognostic features. In addition, the above analysis presumes a biologic homogeneity to tumors arising from various anatomic sites table . Nonetheet al [et al [An important differential consideration for PEComas arising in the uterus is epithelioid smooth muscle tumors. Vang and Kempson  expresseet al  who demoet al  found iml [et al , twelve l [et al ,61. Thesl [et al  that HMBAlthough the association between some members of the PEComa family (AML and LAM) and the tuberous sclerosis complex is well-known, this case represents only the third case of a PEComa NOS reported to occur in a patient with stigmata of this complex. Both of the previous cases were primary in the uterus ,40. Evenet al [The validity of segregating a tumor group based almost entirely on the clear appearance of constituent cells and immunoreactivity for melanogenesis markers may be proven if recurrent molecular or cytogenetic abnormalities are identified in this group. However, remarkably sparse information exists on the cytogenetic or molecular pathogenesis of PEComa NOS. Using conventional cytogenetics, Folpe et al  identifiet al . No otheet al . Our casIn summary, we have documented herein the first case of a PEComa NOS of the uterine cervix occurring in a tuberous sclerosis patient. With the description of additional cases, more insight into their behavior and predictive morphologic parameters may be achieved.The authors declare that they have no competing interests.OF wrote the original version of the manuscript.PH and VP diagnosed the case and supervised the entire project.DH and MRM collected clinical and pathologic data and participated in manuscript preparation.DH also contributed statistical analysis.LM, YY, PH and MBQ performed and/or analyzed and interpreted the CGH. All authors have read and approved the final manuscript.Additional file 1: PEComa additional file 1. doc : All reported cases of PEComa NOSAdditional file 2: PEComa additional file 2. doc: Morphologic analysis of the 37 cases of PEComa NOS with adequate follow-up information, classified by outcomeClick here for fileClick here for file


Abdominal surgical site infections are among the most common complications of inpatient admissions and have serious consequences for outcomes and costs. Different risk factors may be involved, including age, sex, nutrition and immunity, prophylactic antibiotics, operation type and duration, type of shaving, and secondary infections. This study aimed to determine the risk factors affecting abdominal surgical site infections and their incidence at Imam Khomeini, a major referral teaching hospital in Iran.Patients (n = 802) who had undergone abdominal surgery were studied and the relationships among variables were analyzed by Student's t and Chi-square tests. The subjects were followed for 30 days and by a 20-item questionnaire. Data were collected through pre- and post-operative examinations and telephone follow-ups.Of the 802 patients, 139 suffered from SSI (17.4%). In 40.8% of the cases, the wound was dirty infected. The average age for the patients was 46.7 years. The operations were elective in 75.7% of the cases and 24.7% were urgent. The average duration of the operation was 2.24 hours, the average duration of pre-operative hospital stay 4.31 days and the average length of (pre- and post-operation) hospital stay 11.2 days. Three quarters of the cases were shaved 12 hours before the operation. The increased operation time, increased bed stay, electivity of the operation, septicity of the wound, type of incision, the administration of prophylactic antibiotic, type of operation, background disease, and the increased time lapse between shaving and operation all significantly associated with SSI with a p-value less than 0.001.In view of the high rate of SSI reported here (17.4% compared with the 14% quoted in literature), this study suggests that by reducing the average operation time to less than 2 hours, the average preoperative stay to 4 days and the overall stay to less than 11 days, and approximating the timing of shaving to the operation and substituting cefazolin for cefaluthin when prophylactic antibiotic is to be administered, the SSI may be reduced to a more acceptable level. SSIs are among the most common hospital acquired infections comprising 14–16 percent of inpatient infections. Such inClean wounds (1.5–3.7%); clean-contaminated wounds 3–4%); contaminated wounds (8.5%); dirty-infected wounds (28–40%); in laparoscopy (10%) umbilical hernia (2–5%); in the cancer of the colon without taking antimicrobial drugs (30–60%); or with antibiotic and proper intestine wash (10%); in colostomy (above 50%); in colon perforation (20%); in stomach cancer and surgery (20%); in hernionite (50%); in adult appendectomy (10–20%); in children's appendicitis (2–5%); in aged appendicitis and in pregnant women (10–50%); and in AIDS victims (above 50%); in liver abscess (20%); in hydatid cyst (2–5%); in acute and chronic cholecystectomy without stones (10%); in acute septic cholangitis (10–20%); in laparoscopic cholecystectomy (2–5%); and in splenectomy (2–5%) [%; contamSSI is identified with redness, inflammation, heat, pain, a temperature of 38°C, and septic drainage from the surgical site during the 30 days following operation. SeveralWhile we could not find any significant correlation between sex and SSI rate, age proved to be an important factor; the rate of wound infection for 15 to 24-year-old patients was only10% but increased significantly for those over 65 years of age. The extent of SSI was doubled for obese patients. The duration of surgical operation also proved to be a significant factor: only 3% of operations lasting 30 minutes or less led to infection, while for operations lasting more than 6 hours this rate leapt to 18%. SSI rate increased with longer durations of preoperative bed stay, but preoperative showers with a disinfecting soap such as chlorhexidine or Betadine decreased the cutaneous bacterial load. According to Kruise, the rate of infection was reduced to 1.3% among patients who showered with disinfecting soap containing hexachlorophene. In those who showered with ordinary soap the corresponding figure was 2.1%, and for patients who did not shower at all it increased to 2.3%. However, another study on 5536 subjects showed no decrease in SSI in patients who showered with chlorhexidine preoperatively; the rate was 4% [In this study, 802 patients in a teaching hospital during the 15 months from April 2002 to July 2003 underwent abdominal surgery and were studied for SSI and the factors affecting it. Initially, 884 patients were recruited for the study but 82 were excluded on the basis of the following criteria: deficient medical records; patients operated at a different hospital and subsequently transferred to Imam's Hospital: or patients deceased during the operation or within the following 30 days.The dependent variable in this study was abdominal surgical site infection, defined as redness, swelling, pain, temperature above 38°C, during the 30 days after operation. The independent variables were: age, sex, site operated, body mass index, time of shaving the site of incision, administration of prophylactic antibiotics, type of surgical operation, duration of operation, duration of preoperative bed stay; preoperative shower, type of shaving, and accompanying conditions.The data were collected through a 20-item questionnaire. The stages for data collection and information completion were as follows: identification of patients; preoperative interview; postoperative interview; record completion; weekly examinations and telephone follow-ups for 30 days following operation; and pre-discharge examinations. The collected data were analyzed by the SPSS 10 package, using Student's t-test for continuous variables and chi-square test.for categorical variables.To the best of our ability, this study was conducted with due attention to research ethics.however, problems met in the follow-ups the patient's discharge imposed limitations on the studyOf the 802 patients studied who had undergone abdominal surgery 139 (17.4%) suffered from SSI as defined in Table The body mass index for 73 patients (9.1%) was above 30, indicating obesity. Over half the patients (403 cases) suffered from accompanying conditions such as diabetes, high arterial blood pressure, kidney or liver failure, malignancy, febrile condition, cardiac disorders, thyroid disorders, blood disease, chronic obstructive pulmonary disease, convulsion, hyperlipidemia, or immunological disorders; or had previously undergone surgical operations. The rest were free of accompanying conditions Table .We found no significant correlations between SSI incidence and sex or preoperative shower. However, correlations with duration of operation, duration of preoperative bed stay, electivity of surgery, lengthening of preoperative shaving time, increasing age, wound infection, site of surgery, type of incision, accompanying disorders, and type of prophylactic antibiotic administered before operation were all significant at p < 0.001. Although differences in SSI rates were not significantly related to BMI, a trend was apparent: SSI rate was higher with low and high BMI.The following prophylactic antibiotics were used: ampicillin, gentamicine, cephalothin, metronidazole, ceftriaxone and cefazoline table .For the 802 participants in this study, the SSI reported was 17.4%, which is well above the 14–16% reported in other studies [SSI is not correlated with sex , in agreThe findings supported the literature by showing that administration of prophylactic antibiotic half an hour before the operation would bring about the best results and the lowest SSI . This waThe literature shows that with the duration of above 2 hours, the risk of SSI increases . The aveThe time of shaving when it approaches the operation and if done by clippers, reduces the SSI risk. In this study the two times: one hour before surgical operations and 12 hours before that were contrasted which supported previous findings with p = 0.001. This is one area where we can lower the risk by approximating the time of shaving as much as possible to that of operation.Other such factors quoted in the literature as the conditions of the operating theatre, personal hygiene, acompanying diseases, immunological disorders, smoking, techniques of surgery, the surgeon's expertise, duration of surgical scrub, preoperative skin preparation, poor hemostasis, failure to obliterate dead space, tissue trauma, and inadequate sterilization of instruments, which were not included in this study might be considered as confounding factors.Considering the relatively higher rate of SSI in this study (17.4% compared with the 14% quoted in the literature), especially in such cases as stomach cancers and umbilical hernia, where the rate is considerablly higher, we should carefully reconsider the whole operation procedure. In general, we should do our best to reduce the average operation duration to less than 2 hours and the average preoperative bed stay to less than 4 days. Thus, the present average of 11.2 days for the total bed stay would be reduced to less than 11 days. The time of shaving should approximate the operation time as much as possible. Finally, when the administration of prophylactic antibiotics is required, cefazoline is recommended to substitute cephalothin.Razavy: main researcher Ibrahimpour: Sabouri Kashani: Jafarian: (counsult)The author(s) declare that they have no competing interests.The pre-publication history for this paper can be accessed here:


Engaging practicing physicians in educational strategies that reinforce guideline adoption and improve the quality of healthcare may be difficult. Push technologies such as email offer new opportunities to engage physicians in online educational reinforcing strategies. The objectives are to investigate 1) the effectiveness of email announcements in engaging recruited community-based primary care physicians in an online guideline reinforcement strategy designed to promote Chlamydia screening, 2) the characteristics of physicians who respond to email announcements, as well as 3) how quickly and when they respond to email announcements.Over a 45-week period, 445 recruited physicians received up to 33 email contacts announcing and reminding them of an online women's health guideline reinforcing CME activity. Participation was defined as physician log-on at least once to the website. Data were analyzed to determine participation, to compare characteristics of participants with recruited physicians who did not participate, and to determine at what point and when participants logged on.Of 445 recruited physicians with accurate email addresses, 47.2% logged on and completed at least one module. There were no significant differences by age, race, or specialty between participants and non-participants. Female physicians, US medical graduates and MDs had higher participation rates than male physicians, international medical graduates and DOs. Physicians with higher baseline screening rates were significantly more likely to log on to the course. The first 10 emails were the most effective in engaging community-based physicians to complete the intervention. Physicians were more likely to log on in the afternoon and evening and on Monday or Thursday.Email course reminders may enhance recruitment of physicians to interventions designed to reinforce guideline adoption; physicians' response to email reminders may vary by gender, degree, and country of medical training. Repetition of email communications contributes to physician online participation. Many clinical practice guidelines have been disseminated through print publications and the Internet to improve the quality of healthcare. Complex physician behavior-change interventions have been created and applied to clinical practice guidelines to determine if the guidelines are being practiced. Research indicates that the adoption of clinical practice guidelines continues to lag behind their production and dissemination . Adoptioformation; they require minimal effort on the part of the recipient, which greatly supports their adoption [Proceedings of the American Medical Informatics Association's 2002 Annual Symposium, screen savers have been shown to be effective as a reminder system in engaging physicians in bioterrorism CME activity, although the use of email has exceeded all other Internet applications [Over the past ten years, accessibility to educational opportunities has increased with advancements in technology, particularly the Internet. The Internet offers a delivery system for educational interventions and research activities that are more convenient to the physician learner than traditional live large group lectures and seminars . The Intadoption . Email wadoption . Other fications .Flanagan and colleagues demonstrated promise for email as a means of engaging physicians in online activities designed to reinforce guideline use. They found physician response rate to email solicitation to be 50% over a 14-month study period . Beyond This study is a subanalysis of data from a randomized controlled trial (RCT), described in detail elsewhere . The goaThe study was conducted between February 1, 2002 and December 31, 2002. The intervention included a series of four modules, feedback of performance data and a quality improvement toolbox. The education modules were based upon adult learning and behavior change theory . Our driThe subanalysis of this trial focuses on the use of email reminders to engage physicians in the online intervention. Physician recruitment occurred from November of 2001 to January of 2002. Following recruitment, the intervention was initiated in February of 2002 via email broadcast to recruited physicians. During 2002, four separate educational modules were offered. Each module was introduced with a series of email announcements followed by email reminders that contained tailored subject line (i.e. Dear Dr. John Smith) and text message containing the URL that would connect the physician directly to the educational module. The first three modules, emphasized: (1) young sexually active women are at high risk for asymptomatic infection that may lead to future serious health consequences; (2) newer urine-based screening allows diagnosis without a pelvic examination; and (3) infection may be effectively treated with a one-dose antibiotic. The fourth module reviewed previously introduced concepts. A total of 33 announcements and reminders were sent to recruited physicians between February 1, 2002 and December 31, 2002, which represents one reminder overall for each 1.5 weeks of the study duration. Initially, we were concerned that frequent email reminders would be considered intrusive. After a trial period, we found that we could increase the frequency of reminders without difficulty, thus fewer email reminders were sent during the initial phases of the study.For the subanalysis of this trial, the principal outcome measure is participation, defined as physician log-on at least once to the website. Data was collected electronically when physicians logged on to the intervention. In addition, several evaluation questions were used at the conclusion of the online educational activities to explore CME preferences. Descriptive analyses of patient and physician demographics are used to compare baseline characteristics of patients and physicians in the email participants versus the recruited non-participants. Statistical significance is determined with tests appropriate to the distribution of the data . Two-tailed tests are used for all analyses.Four hundred eighty physicians were recruited to participate, representing 380 physician offices. Of the 463 recruited physicians, 445 were successfully contacted by email using the addresses they had furnished at the time of recruitment. Of these 445 recruited physicians, 210 (47.2%) physicians from 190 offices logged on to at least one of the educational modules. Of the 210 physicians who logged on at least once during the 45-week study period, one hundred twenty-four (59%) returned again to log-on for Module 2, eighty-seven (41%) logged on for Module 3, and forty-four (21%) logged on to Module 4.Two hundred and ten physicians of 445 logged on at least once to the website, leaving 235 physicians as non-participants. Figure The participant characteristics n = 210) were compared with those of recruited but non-participating physicians (n = 235)  and national meetings (50.0%). MDs were more likely to prefer web-based CME (37.0%) to local (35.1%) or national (16.6%) meetings. Female physicians reported a preference for web-based CME (50.0%), whereas male physicians preferred local (35.0%) and national (27.5%) meetings over web-based CME (25.0%).The results of this study indicate that email reminders may be useful in engaging nearly half of a group of practicing primary care physicians recruited to participate in an online women's health educational series. This data is consistent with McMahon et al.'s findings in comparing the use of email, fax and mail, finding that email reminders were more useful to increase response rates . The stuFindings from follow-up evaluation question data indicate that CME providers interested in targeting specific groups of physicians may benefit from using alternative methods of CME recruitment and delivery. CME providers targeting DOs may want to explore ways to engage DOs in web-based learning activities or consider focusing activities that target DOs to local or national meetings. Providers of CME who are interested in engaging male physicians and graduates of U.S. medical schools may find email reminders useful, but they may also want to explore additional methods of recruitment.th reminder. Based on our experience, it would seem reasonable that providers and researchers with limited resources consider focusing their announcements/reminders on the first 3–10 encounters. Data from time of log-on underscores the advantages of asynchronous online interventions for busy clinicians. Traditional "live" online symposia scheduled for the middle of the day might appeal to the physicians who logged on between 10 AM and 2 PM (10:00–14:00), but data from this intervention suggest that many physicians have more available time later in the day for online educational activity. The investigators findings of Monday being a frequent day for log-on was unexpected, but may offer an opportunity for future study designs to include weekend email broadcasting rather than a Thursday broadcast.Persistent email reminders did increase physicians' response rates to online education, but response rate decreased with the number of reminders. The first three reminders produced the largest responses, with decline after the 10The topic of the online educational activity may influence response to email announcements and reminders. While baseline Chlamydia screening rates were relatively low in both groups, the significant difference between the groups may indicate that those who are likely to perform better according to clinical practice guidelines are more likely to participate in online educational strategies that reinforce their use. Or the higher screening rates may be associated with a higher degree of interest in the overall topic area of women's health.Also related to the topic addressed in this online study, previous studies of preventive practices of female physicians have indicated they are more likely than males to promote preventive practices  and screComparisons of characteristics of participant physicians and non-participant recruited physicians may be useful to those designing online recruitment and engagement strategies for future studies. Those using email reminders to communicate with physician populations including large numbers of DOs, however, may benefit from considering blended methods of CME recruitment and delivery. Using various methods of reaching providers, may also enhance DO participation. CME providers targeting DOs may want to explore additional ways to engage DOs in web-based learning activities or consider focusing activities that target DOs at local or national meetings.Physicians' online clinical information seeking and engagement in online education continues to grow . ResearcReminding physicians often via email about online educational opportunities appears to increase engagement in a community-based primary care physician audience. The early and consistent implementation of this push technology may increase physicians' utilization of interventions designed to improve practice.MA participated in the statistical analysis and drafted the manuscript. BCC participated in the statistical analysis and drafting of the manuscript. LC participated in all phases of the project. TW participated in the draft of the manuscript. CS participated in the design and coordination of the study and the drafting of the manuscript. MNR participated in the coordination of the study. NWW participated in the design and implementation of the study. JJA conceived of the study and participated in all phases of the study. All authors read and approved the final manuscript.The authors declare that they have no competing interests.The pre-publication history for this paper can be accessed here:


ELA2), causing increased intracellular concentration of this serine protease, inhibits neutrophil differentiation in severe congenital neutropenia (SCN). Since the clinical symptoms of agranulocytosis and SCN are similar, we hypothesized that it may origin from a common genetic variation in ELA2 or that sulphasalazine may affect human neutrophil elastase activity and protein expression.Drug-induced agranulocytosis, a severe side effect marked by a deficit or absolute lack of granulocytic white blood cells, is a rare side-effect of the anti-inflammatory drug sulphasalazine. Mutations in the human neutrophil elastase gene (ELA2 in DNA from 36 patients who had suffered from sulphasalazine-induced agranulocytosis, and compared them with 72 patients treated with sulphasalazine without blood reactions. We also performed in vitro studies of the blood cell lines HL60 and U937 after sulphasalazine exposure with respect to cell survival index, neutrophil elastase protein expression and activity.We screened for genetic differences in ELA2, which previously have been reported to be associated with SCN, was found in this material. Protein expression of human neutrophil elastase in lymphoma U937 cells was not affected by treatment with concentrations equivalent to therapeutic doses. Cell survival of lymphoma U937 and promyelocytic leukemia HL-60 cells was not affected in this concentration range, but exhibited a decreased proliferative capacity with higher sulphasalazine concentrations. Interestingly the promyelocytic cells were more sensitive to sulphasalazine than the lymphoma cell line.None of the mutations in ELA2 mutations do, however, not seem to be involved in the etilogy of sulphasalazine-induced agranulocytosis. Why sulphasalazine is more toxic to promyelocytes than to lymphocytes remains to be explained.Neutrophil elastase expression and  Sulphasalazine (SA) has anti-inflammatory, immunosuppressive and antibiotic actions, and is a component in the therapy of Crohn's disease, ulcerative colitis and rheumatoid arthritis. Bacterial enzymes in the colon split sulphasalazine into sulphapyridine and 5-aminosalicylic acid before it is absorbed. Sulphapyridine acts as a sulphonamide antibiotic, whereas 5-aminosalicylic acid is believed to be the anti-inflammatory metabolite. Common side/toxic effects are vomiting, skin rash and headache. The incidence of the hematological adverse effects associated with sulphasalazine is generally low, but the reactions can be severe and sometimes fatal. The risk of sulphasalazine-induced agranulocytosis, i.e. profoundly depressed circulating neutrophils is highest within the first three months of sulphasalazine-treatment, with a fatality rate of 6.5 % . ClinicaELA2, encoding human neutrophil elastase, have been identified in a majority of the cases with CN and two-thirds of the cases with SCN [Severe congenital neutropenia (SCN) and cyclic neutropenia (CN) occur both as inherited and as sporadic diseases. SCN has a constant low neutrophil number if left untreated, whereas CN manifests with cyclic oscillations of neutrophil number with a 21-day cycle. Recently, diverse heterozygous mutations in ELA2, one third which of had experienced sulphasalazine-induced agranulocytosis. We, furthermore, tested for cytotoxic doses of sulphasalazine, and studied protein expression of human neutrophil elastase in sulphasalazine-treated blood cell lines.In this study, we hypothesized that sulphasalazine-induced agranulocytosis, with clinical symptoms similar to congenital neutropenia, may arise from genetic variation in the human neutrophil elastase gene. We genotyped 108 sulphasalazine-treated patients for Patients were treated with sulphasalazine  for inflammatory joint diseases and inflammatory bowel disease. The cases with sulphasalazine-induced agranulocytosis were originally collected through the Swedish Medical Products Agency's register of adverse side effects . The conELA2 were amplified by PCR using primer pairs listed in Table ELA2.Genomic DNA was extracted from whole blood using standard techniques. Fragments covering exons 2–5 of The lymphoma cell line U937 and the promyelocytic cell line HL-60 (American tissue culture collection) were cultured in Dulbeccos modified Eagles Medium, DMEM (Sigma) supplemented with 10 % fetal bovine serum , L-glutamine and penicillin-streptomycin (Sigma).6) of U937 cells were grown in 75 cm2 dishes in complete medium containing 0, 125 and 250 μM sulphasalazine for 24 h. For protein isolation, cells were washed in PBS and lysed in buffer containing 1% Triton X-100, 50 mM Tris-HCl pH 8.0 and protease inhibitor cocktail (Sigma) and were kept on ice for 30 min. Lysates were centrifuged for 10 min at 10 000 × g, and protein concentration was determined using BioRad protein assay. Criterion precast gels  were used to perform SDS-page with 20 μg protein loaded per well. After gel transfer to a nitrocellulose membrane, the membranes were blocked over night in 5 % dry milk in TBS-Tween. Primary antibody against human neutrophil elastase  was diluted 1:1000 in 5 % dry milk in TBS-T. After 2 h incubation, and four sets of washing, a secondary antibody was added (1:5000) and blots were developed using ECL . Western blot analysis of human neutrophil elastase expression was performed twice.Equal numbers  as a substrate. For each assay we took 25 μl sample, mixed with 100 μl buffer containing 100 mM Tris-HCl pH 8.5, 1 M NaCl, 500 mM MgCl2 and 0.1 % Triton X-100. To this, 50 μl of substrate was added, to a final concentration 1 μM. After 30 min of incubation in room temperature, absorbance was read at 405 nm and the concentration was calculated from a standard curve of elastase (Sigma).Cells (HL-60 and U937) treated with 0, 125, 250 and 500 μM of for 24 h were lysed with 100 μl of buffer containing 100 mM Tris-HCl pH 7.4, 1 mM MgCl50).For the cell viability assay, we used a fluorometric microculture cytotoxicity assay (FMCA) previously described by Larsson et al . Briefly2-test with one degree of freedom, using Minitab 14. A p-value less than 0.05 was denoted with (*), p < 0.01 with (**) and was considered as statistically significant.Two-tailed Student's t-test was used to compare subject characteristics and results from cell culture between cases and controls. Frequencies of subject characteristics male versus females was tested with Chip = 0.023). The white blood cell count (WBC) before sulphasalazine-treatment did not differ between cases and controls, nor did the dose of sulphasalazine. Bone marrow aspirates had been taken from 10 patients (cases). In all samples, the myelopoesis was seriously reduced and a maturation arrest at the promyelocyte-myelocyte stage of neutrophilic differentiation was seen.The characteristics of the subjects are presented in Table ELA2 was found in this material, although we found a silent single nucleotide polymorphism, called S173 [None of the previously reported mutations in led S173  that corled S173 . No corr50) of sulphasalazine was approximately 370 μM for HL-60 cells and 820 μM for U937 cells.By western blot analysis, we analyzed neutrophil elastase protein expression in U937 cells. No difference in human neutrophil elastase expression was detected after treatment with 125 and 250 μM sulphasalazine Figure , but at ELA2) are implicated as the primary abnormality [ELA2, which, however, was equally represented among cases and controls.Idiosyncratic drug-induced agranulocytosis can be due to several different mechanisms of action, including immunological, toxic and genetic ,8. Toxicormality . The focELA2 act in a dominant manner, interfering with sub-cellular trafficking of neutrophil elastase, and leading to an accumulation of neutrophil elastase in the cytosol [ELA2 may disrupt the AP3β-recognition site [GFI1, a transcriptional repressor of ELA2, causes over-expression of neutrophil elastase in mice, thus, making them neutropenic [Heterozygous mutations in  cytosol . For nor cytosol . When G- cytosol . In theo cytosol , and mution site . Furthertropenic .50 values of 370 μM and 820 μM, respectively. Human neutrophil elastase expression in lymphoma U937 cells did not differ after sulphasalazine at 125 and 250 μM, indicating that human neutrophil elastase production is not affected by sulphasalazine at subtoxic levels.During maintenance therapy with sulphasalazine, trough serum sulpha concentration is on average approximately 100 μM at the Department of Clinical chemistry and pharmacology, Uppsala University hospital. To avoid toxic effects, trough serum concentration of sulpha should stay below 600 μM . Our in ELA2 mutations were found, and therapeutic concentrations of sulphasalazine did not increase the expression of human neutrophil elastase. High concentrations of sulphasalazine were toxic to white blood cells in vitro; however, there is no evidence that this toxicity is mediated through human neutrophil elastase. Promyelocytic cells were more sensitive to sulphasalazine than lymphoma cells, and the reason for this difference may also explain sulphasalazine-induced agranulocytosis.In conclusion, neutrophil elastase does not appear to be involved in the etiology of sulphasalazine-induced agranulocytosis. No causative The author(s) declare that they have no competing interests.AJ carried out the molecular genetic studies, participated in the sequence alignment, drafted the manuscript and carried out the in vitro experiments. MW participated in the design of the study and performed the statistical analysis. HM conceived the study, and AJ, MW and HM participated in its design and coordination. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The management of acute myocardial infarction (AMI) has improved over the last 50 years with the more frequent use of effective medicines and procedures. The clinical benefit of the speciality of the attending physician is less clear. The United Kingdom National Service Framework for coronary heart disease (CHD) suggested that patients with CHD are likely to benefit from cardiological supervision. We set out to assess the effect of access to cardiologists on survival among AMI patients admitted in two UK hospitals.The study was conducted in a university hospital and a district general hospital in England. Information was obtained on age, sex, ethnicity, Carstairs socioeconomic deprivation category derived from postcode of residence, comorbidity, distance from hospital and medication from all patients admitted with acute myocardial infarction in two acute trusts between July 1999 and June 2000. Record linkage to subsequent Hospital Episode Statistics and Registrar General's death records provided follow up information on procedures and mortality up to eighteen months after admission. Cox proportional hazard models were used to investigate the main hypothesis controlling for confounding. The main outcome measure was 18-month survival after myocardial infarction.Access to a cardiologist was univariately associated with improved survival . This effect remained after controlling for the effect of patient characteristics . The effect disappeared after controlling for access to effective medication .Access to a cardiologist is associated with better survival compared to no access to a cardiologist among a cohort of patients already admitted with AMI. This effect is mainly due to the more frequent use of effective medicines by the group referred to cardiologists. Hospitals may improve survival by improving access to effective medicines and by coordinating care between cardiologists and general physicians. The management of acute myocardial infarction (AMI) has improved over the last 50 years with the more frequent use of effective medicines and procedures. The clinical benefit of the speciality of the attending physician is less clear. The effect of the speciality of the attending physician on mortality in AMI has been studied mainly in the United States (US) with conflicting results arising from the studies -6. The eThe National Service Framework (NSF) for coronary heart disease (CHD) published in March 2000, suggested that patients with CHD are likely to benefit from cardiological supervision. To provide this level of care, all acute hospitals will eventually need a minimum of two cardiologists . A recenThere is a need to establish whether the involvement of a cardiologist in the management of AMI patients affects the quality and outcome of care, and if so to identify ways to improve the outcome of care for patients unable to gain access to a cardiologist. This study aims to assess the effect of access to cardiologists on survival among AMI patients accounting for access to effective investigation, medication, procedures and the underlying condition of the patient at presentation.A retrospective cohort design was used.st July 1999 and 31st June 2000 with a discharge diagnosis of AMI were included in the analysis. A diagnosis of AMI was based on evidence of raised cardiac enzymes and/or other indicators of myocardial necrosis and on a physician's judgement of ECG changes indicative of AMI.All patients admitted to two hospitals in Eastern England between 1Hospital Episode Statistics were used to extract records of all patients admitted with the ICD10 diagnostic codes for Acute Myocardial Infarction  in any diagnostic field. The records were restructured to produce one record per patient using the new NHS number. For records with missing NHS number, a unique identifier was created using date of birth, sex and post code. The unique identifier was also used as a check for the records with NHS numbers. Records of all Finished Consultant Episodes with OPCS 4 codes of either Coronary Artery Bypass Grafting (K40–46) or Percutaneous Transluminal Coronary Angiography (K49–50) were extracted. The process was repeated for angiography (K63 – 65). Record linkage with subsequent Hospital Episode Statistics and Registrar General's records provided follow up information on procedures and death up to eighteen months after the index AMI.All cases were reviewed by examining the case notes. Detailed information on variables summarised below was obtained.List of variables extracted from patients' case notes• Hospital where patient was first admitted• Whether the patient was seen by a cardiologist or not, determined by evidence of a cardiology review in a patients case note• The average distance from residence to hospital first seen was determined by mapping the distance in miles using the RAC™ website distance calculator• A history of comorbidity – defined as the presence of diabetes, metastatic malignancy, cerebrovascular accident (CVA), asthma, chronic obstructive airway disease, renal impairment, endocrine disorder, chronic infection, dementia• Physical impairment with poor mobility• Procedures – exercise testing, angiography, CABG, PTCA• Appropriate medication – β blockers, aspirin, ACE inhibitors, thrombolysis table • A history of Smoking Previous MI Hypertension• Impaired left ventricular function based on echocardiography result or angiography• Severity of AMI using the number of vessels affected (vessels were considered affected if a lesion of 50% or more was noted in the angiography report)• Demographic factors: age, sex, ethnicity, socioeconomic status and Carstairs socio-economic deprivation category derived from postcode of residence2 test. Continuous variables were tested using the Student t test comparing patients seen by cardiologists and those seen by other physicians.Baseline patient characteristics were tabulated. Categorical variables were tested for statistical significance using the χThe relative odds of drug and procedure use by speciality of physician were calculated. Specific variables included the use of thrombolytic therapy, β blockers, aspirin, ACE inhibitors among clinically appropriate groups, and the use of exercise testing, coronary angiography, angioplasty and coronary artery bypass grafting (CABG).Cox proportional hazards models were used to investigate the effect on survival of seeing a cardiologist. Multivariate models were fitted to control for the effect of patient and hospital characteristics. Controlled factors included: age, sex, comorbidity, hospital, distance from patients residence to hospital and Carstairs socio-economic deprivation category in the first instance. The effect of angiography, revascularisation and the use of effective medicines (aspirin and/or β blockers and/or thrombolysis – eligibility criteria listed below) were subsequently introduced into the model to investigate whether these affected outcome. The factors were included in the model either because they are known to confound the association between type of physician and survival or are known to be associated with survival and were not comparable between the two groups.Eligibility criteria for appropriate use of effective medicines .Thrombolytic therapy• No warfarin therapy on admission• ST-segment elevation on initial ECG• Less than 12 hours since onset of chest pain• Systolic BP less than 180 mmHg and diastolic BP less than 110 mmHg at presentation• No severe CVA, gastrointestinal disease or chronic liver diseaseAspirin• No haemorrhagic complication• No severe CVA, gastrointestinal disease or chronic liver disease or renal failure• No warfarin therapy on admissionβ blockers• No chronic lung disease• No cardiogenic shock, hypotension, complete heart block or decompensated heart failureThe characteristics of the two hospitals are summarised figure The main outcome was eighteen-month survival defined as time between date of AMI and death.Statistical analysis was carried out using Stata (Version 6.0).In general for Cox regression analysis, the number of events i.e. deaths (and similarly the number of non-events) per variable modelled should be at least 10 .Ethical approval was obtained from the two local research ethics committees of the hospitals involved in the study. Permission from the director of research and Caldicott guardians of data in each hospital was also obtained.Medical records were obtained for 94% of eligible patients (476 of 506 patients). Four patients did not have enzyme changes of myocardial infarction or were clear cases of miscoding. The mean age of the cohort was 69.3 years (SD 13.2) and 34.5% were female. The patients with missing records did not differ from those with records in terms of age or sex using information from routine data . There were no significant differences in the proportion of data missing between the two hospitals including those for eligibility to effective medications and co morbidities.Patients in our sample seen by a cardiologist were younger, with a higher proportion of males to females. They were more likely to have a history of CHD prior to myocardial infarction, but less likely to have a history of congestive heart failure or hypertension Table . PatientThe likelihood of receiving effective medication  was higher among patients seen by a cardiologist compared with those not seen by a cardiologist. Furthermore, patients seen by a cardiologist were more likely to have undergone exercise testing, angiography and revascularisation procedures Table . The useUnivariate analysis indicated that patients seen by a cardiologist had better survival .The survival of patients seen by a cardiologist was still better than that for those not seen by a cardiologist  after controlling for the confounding effect of pre-existing comorbidity, age, sex, hospital first seen, deprivation and distance Table . The effThe effect of seeing a cardiologist on survival became non-significant once access to angiography, revascularisation procedures and effective medicines (aspirin and/or β blockers and/or thrombolysis) had been adjusted for. The hazard ratio was 0.70 95% CI 0.33 – 1.46). The fully adjusted model indicated that the most important factor affecting survival was access to effective medication. . The usAll cases diagnosed by the managing clinician as AMI with ECG changes and found to have enzyme changes indicating myocardial necrosis were included in the analysis after the case notes were reviewed. This may have involved some misclassification due to misdiagnosis, but this is likely to occur at random, affecting only a small number of cases, and can only underestimate the effect of each factor.Limitations of this study include potential for bias in the allocation of patients to treatments and physicians (ie cardiologist/non cardiologist) that were not measured. Another possible limitation is bias arising from medical case notes which were unobtainable. Records from routine data were used to examine whether those with missing records differed in any systematic way from those with available records; it was found that they did not differ in age or sex. The study did not use any criteria for judging clinical appropriateness of the procedures used. Incomplete recording of information in the case notes hampered the determination of appropriateness for effective medication. However there was no difference in the proportion of missing data between the two hospitals.Since doctors may selectively be referring younger patients with lower comorbidity to a cardiologist, we controlled for age and comorbidity in the analysis. However, residual confounding from age and comorbidity could still account for some of the observed difference in survival.All patients admitted to the Coronary Care Unit (CCU) in one of the hospitals are seen by a cardiologist and have a higher chance of accessing thrombolysis, angiography and revascularisation. A cardiologist also sees the majority of patients admitted to the CCU in the second hospital. The protocol for the management of AMI in both hospitals stipulates a cardiology review of all AMI patients. Access to a cardiologist may be a proxy measure of access to effective treatment and it may not be the trigger for effective treatment. These limitations mean that the findings should be interpreted with a degree of caution. In addition our inability to use formal appropriateness criteria limits the interpretation of findings.Despite these limitations the results indicate that, in the short term, acute trusts can improve survival of patients by increasing the use of effective medicines among general physicians.We observed better survival among patients seen by a cardiologist compared with patients with no access to a cardiologist, among a cohort of patients already admitted with AMI. This effect was entirely explained by the more frequent use of effective medicines by cardiologists in the multivariate analysis. About eight hospitals in the UK Royal College of Physicians survey have no cardiologist and another 30% have a single cardiologist . It willNone declaredAll authors contributed in writing the paper, in addition, IA collected the data and conducted the analysis, DK conceived the idea, BA provided advice on statistical analysis, JP provided input in the conduct of the study, PW contributed in refining the research question and discussing the findings of paper.The pre-publication history for this paper can be accessed here:


Since 3D structural data of the LV is now obtainable using standard transesophageal echocardiography (TEE) devices intraoperatively, the present study describes a method to transfer this data into a commercially available FEM analysis system: ABAQUS© Software was used for semi-automatic endocardial border detection, reconstruction, and volume-rendering of the clinical 3D echocardiographic data. A newly developed software program MVCP FemCoGen©, written in Delphi, reformats the TomTec file structures in five patients for use in ABAQUS and allows visualization of regional deformation of the LV.In this prospective study TomTec LV Analysis TEEThis study demonstrates that a fully automated importation of 3D TEE data into FEM modeling is feasible and can be efficiently accomplished in the operating room.For complete intraoperative 3D LV finite element analysis, three input elements are necessary: 1. time-gaited, reality-based structural information, 2. continuous LV pressure and 3. instantaneous tissue elastance. The first of these elements is now available using the methods presented herein. Intraoperative TEE is currently available in most cardiac surgical operating rooms. In some centers, intraoperative 3D echocardiography is used to evaluate geometry and to plan surgical interventions prior to LV remodeling surgery. However, quantitation of LV geometry is limited to rather imprecise measures such as ejection fraction. Thus the cardiac surgeon has no sophisticated, immediate, quantitative analysis of the preoperative 3D LV geometry. Intraoperative quantitative analysis of the dynamic behavior of the LV might provide optimal information upon which to base precise patient-specific planning of the surgical intervention, as well as to assess the adequacy of the completed surgical repair.Because the LV cannot be realistically described by a symmetric mathematical model, the modern approach consists of using a FEM mesh which approximates LV geometry  or wholeInitial attempts at FEM in the heart have been carried out with 3D segmentation and tracking using sophisticated and expensive cardiac MRI , but untFEM modeling of 3D intraoperative echo data provides an excellent tool for incorporating material properties, volumetric data and boundary pressures to more accurately record and then to simulate LV dynamic performance. Accurate simulation will be the foundation of surgical planning. The limitation until now in applying FEM intraoperatively has been the technical complexity of this technique. The purpose of this study is to take the first step towards introducing FEM into the operating room environment. The goal is to facilitate transfer of geometric data from 3D ultrasound data set into FEM.-6 m-3 kg-1 at a respiratory rate sufficient to maintain end-tidal CO2 levels between ~4.4*103 m kg-1 s-1 and ~5.1*103 m kg-1s-1.After obtaining institutional review board approval, LV images from clinical TEE data sets were obtained in five patients via the midesophageal window using a Philips 5500/7500 or and Acuson Sequoia ultrasound system. After induction of general anesthesia and airway protection, the esophagus was intubated using an omniplane TEE probe. 3D TEE data sets of the LV structures including mitral annulus and leaflets, chordae tendinae, papillary muscles and ventricular wall were obtained using the automated Philips/Acuson acquisition protocol at 10° increment. Images were gaited for both beat-to-beat variability and respiratory motion. In order to facilitate acquisition in the shortest possible timeframe, ventilation was modified to provide a tidal volume of 5*10© software module [All images were stripped of patient identifiers. For LV geometry reconstruction, the TomTec LV-Analysis TEEe module  was emple module . It alsoThe first landmark was set in the middle of the mitral valve at the level of its annulus. Care was taken to avoid having the mitral valve cusps cross this landmark. Two additional landmarks were placed in the middle of the aortic valve at the level of its annulus and at the endocardial level of the LV apex. With this landmarking procedure, a time-resolved LV geometric analysis with 18 models per heart cycle was obtained see Fig. .The rendered LV geometry resulting from the TomTec analysis tool was transferred to an ABAQUS input file using software written in Delphi. In this program, the TomTec file structure was reformatted to an ABAQUS system (version 6.3) input file based on standard ABAQUS FEM elements.© cardiac simulator [ABAQUS creates a time series of LV model files and requires continuous intraventricular pressure and tissue elastance parameters to process the model. For this analysis LV pressure was modeled using wave forms obtained from Columbia University's HeartSimimulator . A singlThe time required for each step in this process was recorded for each patient data set.© [th image out of a set of 18 images per heart cycle) are displayed and can be visualized using ABAQUS viewer options. Each mesh element can be analyzed separately. This is shown in Fig. Both, the Philips Sonos 5500/7500 or the Acuson Sequoia ultrasound systems required less than 10 minutes acquistion time per patient. The application of the TomTec LV analysis algorithms with manual placement of the necessary landmarks took approximately 7 minutes per patient. In five patient data sets conversion from TomTec data to the FEM model was carried out in less than a minute for a heart cycle using the conversion tool MVCP FemCoGenThe general intention of this study was to demonstrate the feasibility of transporting individual patient's LV geometry data into a FEM model. Standard laptop computer technology was utilized to accomplish the transfer from common TEE-machines (Philips Sonos 5500/7500 and Acuson Sequoia).© package and ABAQUS FEM system, plus the recently developed MVCP FemCoGen©. Accomplishing this transfer will form the foundation for intraoperative surgical planning and quantitative outcome assessment of valvular and LV reconstructive surgery.The software running on the laptop was the commercially available TomTec LV Analysis TEEThe scope of this study was to produce a prototype in which the feasibility of the method could be assessed. In a fully operational system, we could postulate clinical applications such as enhanced/automated wall motion abnormality detection, assessment of regional relaxation which encompases the entire ventricle, assessment and guidance of ventricular remodeling operations, and serial assessment of recovery of regional wall function post myocardial stunning.FEM meshes have been used for approximately 30 years  in the aThe total time required for acquisition to a completed FEM model was approximately 24 minutes and can be accomplished during the time period when the patient is being prepared for cardiopulmonary bypass . Thus the feasilbility in terms of duration is clearly demonstrated.© Software is under review by the US FDA, but despite of lack of validation TEE is the only practical technology in the cardiac operating room for the forseeable future. Ultrasound tissue Doppler technologies may be developed in the future to allow automation of the registration process.In terms of procedure accuracy, reproducibility and duration, the primary limitation is the dependence of the TomTec software on manual entries of the three registration landmarks. This requirement is iterative. Manual entries must be done for multiple frames within the TEE data sets. Inter- and intraobserver variability is a general problem for ultrasonic imaging. The validation of the TomTec border detection has not been published. TomTec LV Analysis TEEA limitation of the present study is that it is focused on the deployment of the transfer method. The entire process will require extensive validation. The validation strategy will most likely involve comparision with preoperative cardiac MRI as well as comparison with bypass and post bypass tissue geometry in the same patients. Creating models from MRI based data sets analogous to the TomTec LV analysis and transfering these models to ABAQUS might lead to a new validation strategy which is not been possible up to now. The tool for modeling presented here facilitates vector-subtraction analysis for different points within the cardiac cycle. Quantification is therefore immediately available for both global and regional wall motion, shape and volume analysis. The future use of such instantaneous analysis has a number of potential applications for LV function assessment and surgical planning. This technology could enable a comprehensive automated regional wall motion analysis. A significant challenge in the evaluation and management of patients with coronary artery disease is determining the viability of myocardium. A biomechanical FEM of the LV myocardium can be imported to evaluate dynamic mechanical properties of regions of the myocardium. This approach could provide the basis for a new index of regional myocardial viability.For complete intraoperative 3D LV finite element analysis, three input elements are necessary: 1. time-gaited, reality-based structural information, 2. continuous LV pressure and 3. instantaneous tissue elastance. The first of these elements is now available using the methods presented herein. The later two parameters will be required for robust modeling and analysis. Pressure data will be easily available in the cardiac operating room. Strategies for computing elastance are presently under development. With all three parameters, it will be possible to begin to develop the computational strategies which will allow virtual procedures to be performed utilizing 3D display technology and a haptic-feedback robotic "instruments". Whether this new intraoperative information will be useful in assessing the effectiveness of surgical interventions such as LV remodeling remains to be studied.FEM analysis has not been feasible for LV in the intraoperative setting. The major roadblock was the complexity and the practicality of transfer of structural 3D data to a FEM analysis program. This study describes a method to rapidly transfer 3D structural data from the TEE device into a FEM analysis program. Once mesured pressure and calculated elastance are added to the model, near real-time dynamic stress-strain information in the operating room will be achievable.®, NSN did the data acquisition and the medical part. Both authors read and approved the final manuscript.JFV did the technical part implementing the FEM model in ABAQUS