Information technology (IT) adoption enables biomedical research. Publications are an accepted measure of research output, and network models can describe the collaborative nature of publication. In particular, ecological networks can serve as analogies for publication and technology adoption. We constructed network models of adoption of bioinformatics programming languages and health IT (HIT) from the literature.We selected seven programming languages and four types of HIT. We performed PubMed searches to identify publications since 2001. We calculated summary statistics and analyzed spatiotemporal relationships. Then, we assessed ecological models of specialization, cooperativity, competition, evolution, biodiversity, and stability associated with publications.Adoption of HIT has been variable, while scripting languages have experienced rapid adoption. Hospital systems had the largest HIT research corpus, while Perl had the largest language corpus. Scripting languages represented the largest connected network components. The relationship between edges and nodes was linear, though Bioconductor had more edges than expected and Perl had fewer. Spatiotemporal relationships were weak. Most languages shared a bioinformatics specialization and appeared mutualistic or competitive. HIT specializations varied. Specialization was highest for Bioconductor and radiology systems. Specialization and cooperativity were positively correlated among languages but negatively correlated among HIT. Rates of language evolution were similar. Biodiversity among languages grew in the first half of the decade and stabilized, while diversity among HIT was variable but flat. Compared with publications in 2001, correlation with publications one year later was positive while correlation after ten years was weak and negative.Adoption of new technologies can be unpredictable. Spatiotemporal relationships facilitate adoption but are not sufficient. As with ecosystems, dense, mutualistic, specialized co-habitation is associated with faster growth. There are rapidly changing trends in external technological and macroeconomic influences. We propose that a better understanding of how technologies are adopted can facilitate their development. Information technology (IT) innovation and adoption have been significant enablers of recent progress in biomedical research. Biologists were early adopters of computing technology and continue to use it as a primary way of delivering data, tools and knowledge to their communities Publication in peer-reviewed journals continues to be a well-accepted measure of research output and adoption, and bibliometrics--a quantitative study of textual information--has increasingly used network models to investigate the collaborative nature of research publication. Some network models have been disease-specific in areas like neglected tropical diseases Ecological network models can serve as apt analogies for technology adoption. Individual researchers, research institutions, and companies also inhabit “ecosystems” In this study, we constructed network models of IT adoption based on the biomedical literature and assessed their ecological properties. Both IT and the literature are vast in scope. Thus, we first focused on two specific areas of IT--programming languages commonly used in bioinformatics research and HIT systems commonly implemented in clinical settings. We further focused on literature published since the first months of 2001 which witnessed seminal publications in bioinformatics related to the initial sequencing of the human genome http://codesearch.google.com) listing of languages and selected seven: Fortran, JavaScript, Mathematica, Perl, Python, R, and Visual Basic. From the “Information Systems” category in MeSH, we selected four sub-categories: “Clinical Laboratory Information Systems” (LIS) [L01.700.508.300.110], “Hospital Information Systems” (HIS) [L01.700.508.300.408], “Radiology Information Systems” (RIS) [L01.700.508.300.780], and “Reminder Systems” (RS) [L01.700.508.300.790] for further investigation.The field of IT is vast in scope. Using the Medical Subject Headings (MeSH) ontology, we selected two well-known areas of “Information Science” [L01] for this study: “Programming Languages” [L01.224.900.780] and “Information Systems” [L01.700.508.300]. Because “Programming Languages” is a terminal branch of the ontology, we used the Google Code Search , date (DA), place (PL), authors (AU), and journal (TA) fields. The date was truncated to the four-digit year. We calculated summary statistics, including publications per year, cumulative publications over time, the fraction of the decade's publications per year per technology, and compound annual growth rates (CAGR) for publications as measures of adoption rates. We expected correlation between research publications and other modes of publication such as popular books and software code, though we expected less correlation with downstream industrial products such as patents and job listings. We first searched Google Labs' Ngram Viewer We then calculated the geographical distribution of publications to generate statistics and maps, the latter as a means of investigating spatial networks. From the MEDLINE files, we tabulated frequencies of the country of origin for published studies. We color-coded countries according to which technology was most commonly published. Using the frequency data, we generated maps to display the extent to which technology adoption was influenced by geography.http://www.cytoscape.org). Then, we generated attribute files defined by “node  =  type” statements . We used these files to visualize and analyze the networks over time and by technology. From this process, we tabulated network topology statistics.We next generated publication networks. We converted the MEDLINE data into node-edge-node triplets  that we imported as undirected graphs using Cytoscape software (http://cran.cnr.berkeley.edu). At the level of technology families, we calculated (5) biodiversity using -∑p*log(p) as a measure of entropy, where p is the probability that a publication discusses a certain technology. We also estimated (6) stability as the linear fit and Pearson correlation in successive years of publication numbers across technologies. Stability was estimated by comparing the number of publications for each language in 2010 and 2002 versus 2001 to indicate long- and short-term stability. To explore whether past publication frequencies could describe stability and predict future frequencies, we also calculated a Pearson correlation matrix for each technology across the ten years from 2001 to 2010.Finally, we applied species- and system-level ecological metrics to the publication data. At the level of individual technologies, we (1) assessed specialization as the fraction of publications per technology occurring in a single journal. We assessed (2) mutualism and competition based on technologies published in similar journals. We then calculated (3) cooperativity as the number of authors per publication, and for languages, we assessed (4) evolution as the temporal progression of time-to-event for version releases The literature search identified 2416 total publications. Among HIT, we identified 418 for HIS, 226 for RS, 153 for LIS, and 133 for RIS. Among programming languages, we identified 443 for Perl, 255 for Bioconductor, 244 for Python, 197 for Visual Basic, 166 for Fortran, 95 for Javascript, and 86 for Mathematica. Publication attributes were always reported, except place (PL) which ranged in reporting frequency from 93% (Python) to 99% (four technologies).We first analyzed the frequency of technology publications in the literature over time. Overall, there are substantially more HIS publications versus other HIT. Adoption of HIS appears to be variable over time . CumulatBecause the scientific literature is a specialized corpus, we compared frequency trends for publications of technologies with other broader sources. We observed some divergence between Google Labs' Ngram Viewer and the scientific literature . For exaFinally, we assessed correlations between frequency counts of technology publications with counts from websites in various socioeconomic domains. Some web sources, such as Amazon (r = 0.04), the Library of Congress (r = −0.08), and the United States Patent and Trademark Office (r = 0.03) were amenable to longitudinal analysis, so we compared web search results with cumulative publication totals. Other web sources, such as Craigslist San Francisco (r = 0.10) and Nature Jobs (r = 0.71) were more amenable to “snapshot” analysis, so we compared web search results with 2010 publication totals. The correlation between Nature Jobs listing counts and 2010 publications was the only one greater than 0.20 . Still oWe then examined the role of geography in technology adoption. The distribution of publications is similar between programming languages and HIT, with the United States, England, and the Netherlands occupying the top three positions for both families of technology . Within A world map shows countries of origin for publications of any technology and displays expected clusters in industrialized North America, Europe, East Asia, and Asia-Pacific . MathemaWe next assessed the temporal and topological characteristics of technology publication networks. Network diagrams of studies as nodes and common authors as edges  showed tTemporal network diagrams were generated of studies published for specific programming languages . Nodes oNext, we examined the species-level ecological characteristics of different technologies. As previously discussed, based on total publications , some teWe first assessed specialization as the highest fraction of publications for each technology published in a single journal . The fraCooperativity among scripting languages and HIT was comparable. Cooperativity ranged from 4.8 for Bioconductor to 3.4 for Fortan, and from 4.9 for LIS to 4.0 for RIS. Older, commercial languages lagged. Interestingly, among languages, specialization and cooperativity were positively correlated (r = 0.93), while among HIT they were negatively correlated (r = −0.98). Finally, for programming languages, we also performed time-to-event analysis of rates of evolution, as measured by time to new version release . Across Relationships between cooperativity and specialization versus network node and edge counts were either statistically significant or marginally significant  . RelatioBiodiversity was estimated for languages and for HIT using entropy calculations . Data inDespite the potential benefits of IT innovation, the adoption of new technologies can be unpredictable and challenging. It has been recognized that adoption and implementation are different phenomena In this study, we calculated statistics, constructed network models for analysis and visualization, and described ecological characteristics of biomedical IT adoption, specifically programming languages used in bioinformatics and health IT systems, based on the literature from the last decade. Adoption of HIT has been variable, while scripting languages have experienced rapid adoption. We found that, as with biological species, dense, mutualistic co-habitation is associated with faster growth. We propose that understanding why and how technologies are adopted could aid in their development and lead to scientific and socioeconomic benefit.The history of programming languages spans more than half a century We observed that Perl experienced rapid early adoption, while Python and Bioconductor have experienced accelerated adoption more recently. The fraction of publications per year has grown most rapidly for Python and most slowly for Mathematica. We compared these adoption rates to 20 year compound annual growth rates for other technologies Medical informatics has been described as having a “long and delayed adolescence” which continues to “find itself in search of self-definition” In our data, adoption of HIS was variable over time. The fraction of publications per year has grown most rapidly for LIS and most slowly for RIS. HIS have grown to have the greatest presence, perhaps due to demand, while RS were second, perhaps due to generalizability. Relative to the programming languages, growth in HIT publications were more modest. Using Google Ngram Viewer and search, the frequency of HIS books exceeds that of other HIT. Interestingly, the RIS adoption rate (CAGR = 4%) was similar to increases in biopsy procedures during the past decade performed by radiologists (8%) A seminal study by Coleman On a more theoretical level, a study by Granovetter Even when innovations are successfully adopted in one location, they often disseminate slowly, if at all In this study, a world map shows countries of origin for publications and displays expected clusters in North America, Europe, East Asia, and Asia-Pacific. Within types of technology, there is considerable variation in the relative fractions of publication frequencies. There was little geographical correlation, further supporting the hypothesis that technology adoption is a virtual process.George Box is credited with saying that all models are wrong, but some are useful. We chose a network approach to model technology adoption, though other strategies such as agent based models Our network diagrams of studies as nodes and common authors as edges show the largest connected components represent modern scripting languages. Temporal network diagrams showed that nodes of similar time periods tend to be neighbors, though this is less frequently true among more mature languages. The two largest connected components among HIT represent HIS, and two of the next three biggest components represent LIS. Among programming languages, the largest connected component represents Bioconductor. The next largest, which surprisingly is also the only hybrid component, represents Perl and Python. Interestingly, based on a linear model, Bioconductor has more edges than expected and Perl has fewer, perhaps due to Bioconductor's high specialization and cooperativity and Perl's slower initial evolution. For Bioconductor and Perl, the largest connected components include well-defined topical clusters.At the level of individual technologies, several ecological models can be useful to describe research collaboration: (1) we assessed specialization as the fraction of publications per technology occurring in a single journal; (2) we assessed mutualism and competition based on technologies published in similar journals; (3) we calculated cooperativity as the number of authors per publication; (4) and finally, for languages, we assessed evolution as the progression of time-to-event for new version releases.More specialized IT may be prone to more rapid adoption. For example, early adopters of digital pathology were laboratories that needed to provide pathology services at great distances and needed technology to increase efficiency. The creation of standards for virtual slide pathology has facilitated adoption Associations between other ecological strategies, such as cooperation and competition, and behaviors such as growth rate, the ability to survive in different environments, and the distribution of other species that co-inhabit an ecosystem have been observed across species. Appropriate strategies emerge: a niche with little co-habitation is associated with a slow growth rate, while ecological diversity with intense co-habitation can be associated with a faster rate There are several biodiversity analogies relevant to technology: genetic diversity is like diversity within a language , species diversity is like differences among languages , and ecological system diversity is like the degree of difference among a system of languages . Here, in two limited model “ecosystems”, we quantitatively examined species and system diversity. Ecological studies of food webs have reached inconsistent conclusions about the relationships between complexity or diversity with stability or persistence The range of IT methodologies, applications, and--more than ever--interactions in biomedical research and clinical practice has become extraordinarily complex. The cost and effort of implementing new technologies as well as the potential missed opportunities, in terms of scientific productivity and patient care, due to unsuccessful implementations demand that IT systems become better understood. Because peer-reviewed publications are a widely accepted and comprehensive permanent record of biomedical research, they present an invaluable resource for inquiry. However, as complex as IT and the research literature have become, traditional methods for analyzing and interpreting the data may no longer suffice. Networks are becoming increasingly appreciated for their ability to model complex social systems such as research co-authorship. Recently, network models have also been applied successfully to analyze ecological systems, but just as importantly, the behaviors of ecological systems have provided insights into the structure of network models. In the cases of both abstract networks and real world social and ecological systems, emergent behaviors arising from populations of individuals may be different than the simple sum of their parts.We built this study on several key premises: first, that the biomedical literature could be used as a detailed and comprehensive description of technology adoption; second, that network models could be applied to understand the complex topology of IT publications; and third, that ecological models could further inform and enable interpretation of technology adoption and publication networks. There were many possible ways to conduct this analysis. We chose to model a publication as an organism in a population, where publications related to different types of technologies were analogous to organisms of different species. These publications, regardless of technology discussed, formed relationships based on shared authorship just as organisms might form relationships with other organisms of the same or different species. An implicit assumption is that publications and organisms are independent and can “take on a life of their own”. Groups of publications subsequently formed niches, often within the same or similar journals, just as groups of organisms might form a niche in a lake or a cave. These behaviors could be measured using abstract bibliometric network statistics such as co-authorship and density as well as ecological metrics such as specialization and cooperatively. As these niches combined to form “ecosystems”, in this case programming languages or HIT, emergent properties were observed related to system diversity and stability that are being studied with great interest in real-world deserts, oceans, and cities.We constructed a mapping of technology, network, publication, and ecosystem entities . We alsoIn this study, we performed quantitative analyses on a large set of biomedical publications spanning a decade with a focus on relevant biomedical information technologies. The study reproduced several previously reported relationships of publication and ecosystem networks. The study also extended these findings by unifying them, quantitatively and conceptually, by applying them to the dynamic problem of technology adoption. In particular, this study found that programming language and HIT growth was similar to reports of other technologies There were also several implicit assumptions and associated limitations in this study. The programming languages and HIT were chosen based on perceived importance and lack of semantic ambiguity. Notable exclusions included the C and Java languages and HIT such as electronic medical records and decision support systems. No technology in this study experienced decreases in adoption. From ontological and implementation perspectives, programming languages and HIT are not, themselves, directly comparable. Additional studies would be needed to determine whether these results are reproduced in other classes of technologies and methodologies, such as databases, controlled vocabularies, computer hardware, and laboratory instruments. There are also well documented challenges around precision and recall of MEDLINE search terminology Future work will be needed to assess the role of the complex forces in today's technological society that could affect adoption of programming languages and HIT. In ecology, an indicator species is one that is affected early by external trends In this study, we performed statistical analyses and constructed ecological models of information technology adoption based on the biomedical literature. We focused on programming languages used in bioinformatics research and health IT systems implemented in clinical settings. Adoption of HIT has been variable, while scripting languages have experienced rapid adoption and have grown to form large connected network components. We found that spatiotemporal relationships can facilitate adoption but are not sufficient. Dense, mutualistic “ecosystems” are associated with faster technology adoption. We propose that a better understanding of which technologies get adopted, as well as how and why, can potentially facilitate their design and distribution as well as lead to socioeconomic benefits such as intellectual property production and employment opportunities.Figure S1Culturomics trends. We compared frequency trends for publications of technologies with Google Labs' Ngram Viewer. We observed some divergence from the scientific literature. For example, (A) among HIT, books on electronic medical records (not included in this study) have increased since the mid-1990s, but (B) the frequency of HIS books exceeds that of other types. Among programming languages, (C) the number of Perl books spiked and fell dramatically in the early part of the decade, but (D) the frequency of JavaScript books still exceeds those for Bioconductor.(PPT)Click here for additional data file.Figure S2Plot of search results in Nature Jobs versus numbers of publications for programming languages. The unadjusted p-value is significant and suggests a relationship between research output and socioeconomic benefit, but it may be the result of multiple hypothesis testing.(PPT)Click here for additional data file.Figure S3Geographic variation. (A) Within technology families (languages shown here), there is considerable geographical variation in the relative publication frequencies. (B) Among programming languages, England publishes more frequently on scripting languages, while the US publishes more frequently using commercial products. Specifically, 75% of Bioconductor publications and 66% of Perl publications originated in England, while 46% of Visual Basic publications and 47% of Mathematica publications originated in the United States. The two countries were nearly equal in JavaScript (44% versus 42%) and Fortran (40% versus 43%) publications.(PPT)Click here for additional data file.Figure S4Color-coded countries according to the frequency of published technologies. Panels depict (A) RS, (B) RIS, (C) LIS, (D) HIS. Countries shown in red indicate a frequency of greater than 60%, orange indicates 50–60%, yellow indicates 40–50%, green indicates 30–40%, cyan indicates 20–30%, blue indicates 10–20%, and purple indicates less than 10%.(PPT)Click here for additional data file.Figure S5Summary of common journals of publication suggest different secondary specializations. Python is commonly used in neuroinformatics studies, Mathematica in engineering and imaging, JavaScript in medical informatics, and Visual Basic in behavioral research.(PPT)Click here for additional data file.Figure S6Publication stability. To explore whether past publication frequencies describe stability and predict future frequencies, we calculated a Pearson correlation matrix for each technology across the ten years from 2001 to 2010. We found that while publication frequencies were correlated with frequencies from previous years (r>0.80), the correlation with data from three years earlier was variable, suggesting that the relative popularity of technologies is unstable and that current states are not predictive of future states, even within a short year time horizon.(PPT)Click here for additional data file.


There are a number of limitations to using conventional diagnostic markers for patients with clinical suspicion of infection. As a consequence, unnecessary and prolonged exposure to antimicrobial agents adversely affect patient outcomes, while inappropriate antibiotic therapy increases antibiotic resistance. A growing body of evidence supports the use of procalcitonin (PCT) to improve diagnosis of bacterial infections and to guide antibiotic therapy. For patients with upper and lower respiratory tract infection, post-operative infections and for severe sepsis patients in the intensive care unit, randomized-controlled trials have shown a benefit of using PCT algorithms to guide decisions about initiation and/or discontinuation of antibiotic therapy. For some other types of infections, observational studies have shown promising first results, but further intervention studies are needed before use of PCT in clinical routine can be recommended. The aim of this review is to summarize the current evidence for PCT in different infections and clinical settings, and discuss the reliability of this marker when used with validated diagnostic algorithms. Emerging bacterial resistance to antimicrobial therapeutics calls for more stringent efforts to reduce antibiotic overuse . TowardsIn this diagnostic dilemma, procalcitonin (PCT) has stimulated great interest as a potentially more specific marker for bacterial infection. PCT is produced ubiquitously in response to endotoxin or mediators released in response to bacterial infections -1β, tumor necrosis factor (TNF)-α, and IL-6) and strongly correlates with extent and severity of bacterial infections . BecauseBased on this evidence, PCT has been put forward as a promising candidate marker for diagnosis and for antibiotic stewardship in patients with systemic infections . ImportaThe aim of this review is to summarize the current evidence for PCT in different infections and clinical settings, and discuss the strengths and limitations of PCT, and the reliability of this marker when used with validated diagnostic algorithms.A plethora of observational studies have investigated the diagnostic potential of PCT in different clinical situations and different types and sites of infections. Table For the diagnosis of blood stream infections and bacteremia, studies found a high diagnostic performance of PCT -15. To dIn UTIs, evidence for the utility of PCT comes primarily from the pediatric literature, where it has a similar sensitivity but superior specificity compared to CRP for the prediction of pyelonephritis in children with febrile UTIs . It corrFew studies have investigated the use of PCT in intra-abdominal infections -36. WhilEscherichia coli lipopolysaccharide (LPS) injections[Different studies have evaluated the utility of PCT in patients with febrile neutropenia -41. A renjections. While onjections.The clinical implications of the above mentioned observational studies may be limited by differences in disease definitions and patient groups, use of insensitive (semi-quantitative) PCT assays, and different methodological issues such as observer bias, selection bias and issues of sample availability, co-infection and colonization. To overcome these limitations, several randomized-controlled studies have investigated the use of PCT to assist in decisions about initiation and/or duration of antibiotic therapy (antibiotic stewardship). Thereby the benefit of PCT was measured by clinical outcomes, assuming that if the patient recovers without antibiotics, there was no relevant bacterial illness in need of antibiotic therapy. Importantly, all intervention studies used fully automated highly sensitive PCT assays, the results of which can be obtained in the clinical routine of an emergency department within one hour thus permitting bed-side decision making. Recently, different options for PCT testing have become available, including the KRYPTOR , the VIDAll published studies on antibiotic stewardship used similar clinical algorithms with recommendations for or against antibiotic treatment based on PCT cut-off ranges. For moderate risk patients with respiratory tract infections in the emergency department Figure , algoritThe first intervention study testing PCT as a guide for antibiotic decisions included patients with different types and severities of respiratory infections . ClinicaArguably, the most important (over-) use of antibiotics occurs in primary care. As many as 75% of patients with upper and lower respiratory infections receive antibiotics, despite the mostly viral origin of the condition . Two mulIn more high risk patients in the ICU setting, different trials have investigated the use of PCT, mainly for discontinuation of antibiotics. The first small proof of concept study  found a Sepsis is not a well-defined disease, but a consequence of different infectious disease entities and far too complex to be reduced to a single cut-off of any surrogate marker. Limitations of every PCT measurement include false-positive and false-negative results ,11. DiffFor upper and lower respiratory tract infection in ICU patients with sepsis and post-operative infections, randomized-controlled studies have shown the efficacy of using PCT algorithms to guide antibiotic decisions. For other types of infections, only observational studies are available which are importantly limited by the lack of a true gold standard. Most intervention studies were conducted in European countries including Switzerland, Germany, France and Denmark (and two in China) and validation in other countries and continents is therefore warranted. Importantly, PCT levels must always be evaluated in the context of a careful clinical and microbiological assessment. As the kinetics of PCT are of particular diagnostic and prognostic interest, repeated measurements should be performed if feasible, especially in persistently sick patients if antibiotics are withheld. The limitations of every PCT measurement include false-positive and false-negative results . UnspeciEmerging bacterial resistance to antimicrobial agents calls for more effective efforts to reduce the unnecessary and prolonged use of antibiotics in self-limiting non-bacterial and resolving diseases . PatientAB: antibiotic; CAP: community-acquired pneumonia; CRP: C-reactive protein; ECOPD: exacerbation of chronic obstructive pulmonary disease; ED: Emergency department; ICU: intensive care unit; IFN: interferon; IL: interleukin; LPS: lipopolysaccharide; PCT: procalcitonin; TNF: tumor necrosis factor; RCT: randomised-controlled trial; UTI: urinary tract infection; WBC: white blood cells.Drs Schuetz, Albrich, and Mueller reported receiving support from BRAHMS Inc and Biomerieux to attend meetings and fulfill speaking engagements. Dr Mueller reported serving as a consultant and receiving research support from BRAHMS and BioMérieux Inc.PS drafted the initial manuscript. WCA and BM commented on the manuscript. All authors approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/9/107/prepub


Fibrosing mediastinitis (FM) and IgG4-related disease (IgG4-RD) are two fibroinflammatory disorders with potentially overlapping clinical and radiological features. In this paper, we looked for histopathologic features of IgG4-RD and enumerated infiltrating IgG4-positive plasma cells within mediastinal tissue biopsies from FM patients. We identified 15 consecutive FM surgical mediastinal tissue biopsies between 1985 and 2006. All patients satisfied the clinical and radiological diagnostic criteria for FM. All patients had either serological or radiological evidence of prior histoplasmosis or granulomatous disease, respectively. Formalin-fixed paraffin-embedded tissue sections of all patients were stained for H&E, IgG, and IgG4. Three samples met the predefined diagnostic criteria for IgG4-RD. In addition, characteristic histopathologic changes of IgG4-RD in the absence of diagnostic numbers of tissue infiltrating IgG4-positive plasma cells were seen in a number of additional cases . We conclude that up to one-third of histoplasmosis or granulomatous-disease-associated FM cases demonstrate histopathological features of IgG4-RD spectrum. Whether these changes occur as the host immune response against Histoplasma or represent a manifestation of IgG4-RD remains to be determined. Studies to prospectively identify these cases and evaluate their therapeutic responses to glucocorticoids and/or other immunosuppressive agents such as rituximab are warranted. IgG4-related disease (IgG4-RD) is recognized to include a growing number of fibroinflammatory disorders –5. HistoIgG4-RD was first described in the context of autoimmune pancreatitis presenting with obstructive jaundice due to a space-occupying lesion within the pancreas , 8. SincFibrosing mediastinitis (FM), also called sclerosing mediastinitis, is a rare syndrome characterized by an aggressive fibroinflammatory process within the mediastinum –15. ProgHistoplasma capsulatum infection can often be documented. In endemic areas of North America, the majority of FM cases are thought to represent a rare hypersensitivity reaction to this infection  was calculated for each case.The presence and number of IgG- and IgG4-positive cells was evaluated in all 15 FM cases. To enumerate IgG and IgG4-positive plasma cells, the entire slide was scanned at low power for the areas with the highest IgG4-positive plasma cell density. For each case, the three high power fields (hpf) with the highest density were photographed using a magnification of 40x , or esophageal compression. Patients with mediastinal malignancies and/or prior mediastinal radiation therapy were excluded , 20.A histopathological diagnosis of FM required the presence of extensive tissue fibrosis. This fibrous tissue typically infiltrates and obliterates adipose tissue with or without patchy mononuclear immune cell infiltration in the absence of malignancy.conclusive diagnosis of infection was assumed in the presence of a positive fungal stain (Grocott methenamine silver (GMS)) or culture of the biopsy tissue specimens and/or serologic titer ≥1 : 32 and/or presence of an M or H band by complement fixation/immunodiffusion. A suggestive diagnosis was defined as a serologic titer >1 : 8 and/or radiological features  suggestive of previous granulomatous infection.A Patients with radiological features of prior granulomatous disease, histological evidence of granulomatous inflammation, or a localized calcified mass lesion within the mediastinum were classified as previous granulomatous disease .definite case of IgG4-RD: at least two of the following three histological features: (1) lymphoplasmacytic infiltrate, (2) storiform-type fibrosis, or (3) obliterative phlebitis/arteritis plus ≥50 IgG4-positive cells/hpf with an IgG4+/IgG+ ratio ≥40%. Probable case of IgG4-RD: one histological feature plus ≥50 IgG4-positive cells/hpf with an IgG4+/IgG+ ratio ≥40%. Unlikely case of IgG4-RD: remaining cases. This definition is based on the consensus recommendations provided by a panel of experts during the International Symposium on IgG4-Related Disease, Boston, MA, October 2011 .IgG4-RD was defined using the following definition: The Mayo Clinic Institutional Review Board (IRB) approved the study.All 15 patients underwent surgical resection/debulking (7 patients) or surgical biopsy (8 patients) at Mayo Clinic, Rochester, MN, between 1985 and 2006 .Histoplasma capsulatum in 6 of 13 cases. The organisms were typically detected in the necrotic areas of granulomas  and a surrounding dense fibrotic rim was identified. GMS staining detected characteristic yeast forms for anulomas .+/IgG+ ratios are summarized in Three cases met the predefined diagnostic histological criteria for definite IgG4-RD (FM IgG4-RD) . The absUnfortunately, serum IgG4 levels were not available for any of these patients and none of them was treated with glucocorticoids or other immunosuppressants. The demographic, clinical, and radiological characteristics are summarized in The precise etiology of FM remains indeterminate. It likely represents a clinical-pathological syndrome attributable to various triggers including infectious pathogens causing granulomatous mediastinitis, drug toxicity and idiopathic immune-mediated cases –15. The By definition, IgG4-RD is currently considered an idiopathic fibroinflammatory disorder , 4, 6, 9The clinical, radiological, and pathological presentation of FM as a metabolically active space-occupying fibro-inflammatory disease process within the mediastinum is highly compatible with the disease manifestations of IgG4-RD in other organs such as the pancreas and the salivary glands. Herein we demonstrate that a subset of histoplasmosis/granulomatous-disease-associated FM cases exhibits the histopathological and immunological characteristics consistent with a definite diagnosis of IgG4-RD: lymphoplasmacytic infiltration, storiform fibrosis, obliterative phlebitis/arteritis, and an accumulation of IgG4-positive plasma cells (≥50 cells/hpf and ≥40% of IgG4/IgG-positive plasma cells). Therefore, this subgroup of FM cases may be part of the ever-expanding disease spectrum of IgG4-RD, and perhaps respond favorably to immunosuppressive therapy with glucocorticoids or rituximab. Interestingly, the tissue samples of these patients also contained a large number of CD20-positive B-lymphocytes . AlternaDue to the retrospective design our analysis of the clinical, radiological and serologic data is constrained by the data documented in the medical records by a diverse team of care providers. Furthermore, the infrequent utilization of diagnostic tissue biopsies and surgical debulking procedures in FM patients restricted our analysis of the histopathologic pattern and number of IgG4-positive plasma cells to a relatively small subset of FM patients . However, we have previously demonstrated that these 15 patients were representative of a large FM cohort treated at a Midwestern tertiary referral center . Our stuIn summary, we conclude that there is an overlap of the histopathologic features between histoplasmosis/granulomatous-disease-associated FM and IgG4-RD. A subset, approximately 20%, of these FM cases may indeed be part of the IgG4-RD spectrum. Although the exact pathogenesis and natural history of these cases remains unknown and may differ from classic IgG4-RD, the prospective identification of this subgroup of patients with characteristic IgG4-RD histopathology and a hyper-IgG4 immune response would be extremely valuable. This strategy can perhaps facilitate the identification of a subset of FM patients more likely to respond to immunosuppressive therapy. Consequently, we propose the prospective identification of this subgroup of FM patients based upon the presence of an elevated serum IgG4 level >140 mg/dL and/or characteristic histopathological findings and accumulation of IgG4-positive plasma cells within the mediastinal tissue. As the use of chest computed tomography has largely reduced the need for routine surgical tissue biopsies to establish a diagnosis of FM, based on the vast experience of the successful use of endoscopic needle biopsies for the diagnosis of IgG4-RD in the pancreas, we recommend to obtain transbronchoscopic ultrasound-guided needle biopsies if surgical biopsies are not needed for diagnosis , 32. Thi


Background. Syndromes are defined by traditional Chinese medicine as consisting of different pattern elements. Few scales have been designed for differentiating pattern elements of dementia and have shown major flaws. Thus, a new pattern element scale (PES) was developed. This study aimed to evaluate the utility of the PES in dementia patients. Methods. A total of 171 dementia patients were enrolled, and their pattern elements were ascertained, first by clinicians using the PES, then compared with results by two experts to be used as a standard criterion independently. Reliability of the subscales of the PES was assessed by receiver operator characteristic curves. Correlations between the subscales of the PES and cognition were calculated by canonical correlation analysis. Results. The PES consisted of 11 pattern element subscales. The area under the curves of all subscales was 0.7 or above. Phlegm muddiness, blood stasis, and yang hyperactivity subscales showed optimal sensitivity and specificity in discriminating pattern elements. Other subscales showed relatively lower sensitivity but higher specificity. Memory and language were significantly correlated to qi deficiency and the blood stasis pattern element. Conclusion. The PES can accurately and easily discriminate pattern elements and is a helpful tool for traditional medical subtyping of dementia. N-methyl-D-aspartate receptor antagonist, have a modest clinical effect on the symptoms and do not prevent the deterioration associated with dementia [Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that leads to cognitive and behavioral impairments. As shown in previous studies, AD constitutes 60 to 80% of all cases of dementia . The ultdementia , 3. Therdementia .The Complete Work of Jingyue, published in 1624, contains the earliest known description in the world of an herbal therapeutic strategy for dementia [The Records for Syndromes' Differentiation, published in 1687, develops herbal remedies for dementia [yin deficiency, qi deficiency, yang hyperactivity, and marrow deficiency. Each pattern element has its own clinical features, which are usually abstracted from medical history, symptoms, and tongue-pulse signs of the disease. Because there is no recognized standard method to discriminate the pattern elements, it is difficult to compare treatment effects between different studies.Herbal medicine has long been used in a traditional form in China as therapy for dementia. dementia . FollowiAt present, there are few scales specifically designed for the research of discriminating syndromes in dementia patients, and these scales have major flaws –9. Firstqi deficiency, yin deficiency, yang deficiency, blood deficiency, marrow deficiency, endogenous heat, and yang hyperactivity (See the appendix). Each subscale contains seven items, and every pattern element subscale has a maximum score of 30 points. When the score was 6 points and above, it was considered to efficiently diagnose this pattern element of each subscale. The subscales rate the major pattern elements of dementia, and the PES can be completed in a relatively short period of time. This study aimed to provide further information about the reliability and parallel validity of the PES for discriminating the pattern elements in people with dementia.Initially the PES was composed of 11 pattern element subscales, including phlegm muddiness, kidney deficiency, spleen deficiency, blood stasis, A total of 171 patients with dementia, including AD and vascular dementia (VaD), were enrolled from Dongzhimen Hospital, Daxing District Psychiatric Hospital and three communities around Dongzhimen Hospital, in Beijing, China, between April 2011 and February 2012.Diagnostic and Statistical Manual of Mental Disorders, fourth edition [The diagnosis of dementia was based on the  edition . The fol edition ; (2) two edition ; (6) cli edition ; (7) a s edition ; and (8) edition , and the edition .All patients were evaluated by two experts who discriminated the pattern elements independently. In the case of discrepancies in the evaluation of pattern elements, a third expert was consulted, the pattern elements were discussed, and a final decision was made. The diagnosis by the experts was recognized as a standard criterion. The PES was administered to all participants by five trained clinicians who discriminated pattern elements according to authors' instructions. The five clinicians were blinded to the pattern elements that were discriminated by experts. Sensitivity and specificity were evaluated with experts' diagnosis as the standard criterion using the receiver-operator characteristic (ROC) curves for each subscale, respectively  and negative predictive value (NPV) were calculated based on the prevalence among the selected sample.The parallel validity between the judgment of the experts and discrimination of pattern elements with the PES was also calculated by kappa value using the chi-square test. The correlations between scores of the subscales (including 11 pattern elements) of the PES and cognition score as measured by MMSE  were calculated using canonical correlation analysis.This study was undertaken in accordance with the principles of the Declaration of Helsinki. The protocol was approved by the Dongzhimen Hospital Institutional Ethics Committee. The patients and their caregivers provided written informed consent.A total of 171 participants of dementia were enrolled in this study. The sample included 92 (54%) participants with probable AD, 32 (19%) with a diagnosis of probable VaD, 40 (23%) with mixed dementia, and 7 (4%) with other dementia. The sample was composed of 85 males and 86 females. The mean age was 73.0 ± 8.8 years old. The mean year of formal education was 9.07 ± 4.52. The mean MMSE score was 16.25 ± 6.20, and the severity of dementia was as follows: 59 (34.5%) with mild dementia, 57 (33.3%) with moderate dementia, and 55 (32.2%) with severe dementia.yang hyperactivity showed an optimal sensitivity, with 83.5%, 94.7%, and 90.5%, respectively, and the specificity was 83.8%, 85.3%, and 92.0%, respectively, for discriminating pattern elements. The sensitivity of yin deficiency, yang deficiency, qi deficiency, marrow deficiency, and blood deficiency subscales was poor (58.8%–68.3%). More interestingly, the specificity of these subscales was excellent (>90%), which suggests a lower false positive rate. It indicates that these subscales have a lower capability to discriminate those pattern elements. The subscales of endogenous heat and blood deficiency showed acceptable sensitivity, 72.7% and 71.4%, respectively, and the specificity was relatively high . Tests for sensitivity and specificity of each subscale were demonstrated, respectively, in yin deficiency, qi deficiency, and marrow deficiency, with each higher than 75.0%; however, the other six subscales showed much lower PPVs (11.9%–65.2%). PPV and NPV were calculated based on the baseline rate of each pattern element of the sample . The NPV The kappa values are shown in r = 0.507, P < 0.001). Further analysis showed that memory and language were significantly negatively correlated with qi deficiency and blood stasis, which indicated that higher scores on the qi deficiency and blood stasis subscales are associated with severe impairment of memory and language. As shown in Tables At present, there are three widely used differentiating scales of traditional syndromes for dementia in China. Fu  publisheGiven that early epidemiological studies showed that VaD was the main cause of dementia in China, and the prevalence of VaD was much higher than AD –21, reseyang hyperactivity, and yin deficiency subscales was higher than 0.9, which showed an excellent capacity to discriminate pattern elements. The subscales for phlegm muddiness, blood stasis, and yang hyperactivity showed a high degree of sensitivity (>83.5%), and the specificity was excellent (>83.8%); therefore, those three subscales are suitable for case screening in epidemiological surveys and strict inclusion criteria in clinical investigations. The sensitivity of the yin deficiency, yang deficiency, qi deficiency, marrow deficiency, and spleen deficiency subscales was poor (58.1%–68.3%) but with higher specificity (>80.0%); these subscales are also suitable for strict inclusion criteria in clinical investigations.The findings of the current study demonstrated that the 11 subscales of the PES showed high reliability for discriminating pattern elements. The AUC for each of the subscales was higher than 0.7 and achieved the minimum requirements for diagnostic tests . The AUCThe subscale for blood stasis had a good parallel validity (kappa = 0.79), while the subscales for kidney deficiency and spleen deficiency had much poorer validity (0.248–0.273). The other subscales showed a medium parallel validity . yang deficiency, spleen deficiency, blood deficiency, and endogenous heat showed relatively lower PPVs. The phlegm muddiness and kidney deficiency showed relatively lower NPVs. The possible reason may be a result of the high prevalence. The PPVs and NPVs were related to the baseline rate of prevalence; higher prevalence may induce relatively lower PPVs, and higher prevalence may induce relatively lower NPVs . Becauseqi and blood stasis was negatively correlated to memory and language, indicating that higher scores related to deficiency of qi and blood stasis are associated with more severe impairment of language and memory. The different results may be because the scores in previous studies were calculated based on dementia and nondementia, and the result was the correlation between the pattern elements and the disease. In the present study, the correlations were based only on scores from patients with dementia, and the result was the correlation between the severity of cognition and pattern elements in dementia patients. This result indicated that scores on the subscales of the PES have an inherent correlation with the objective scale examination of dementia. Therefore, pattern elements were not only correlated with disease but were also correlated with cognition in the same patients. Studies have reported that memory functions are correlated with kidney essence vacuity and turbid phlegm blocking the upper orifice in mild cognitive impairments and AD patients. Turbid phlegm blocking the upper orifice was correlated with executive function and global cognition, as measured by the MMSE in VaD patients. There are many treatments in Chinese medicine for replenishing kidney essence or removing phlegm, which can improve memory and cognitive function –29. The There are limitations in the present study. First, there were no normal controls or patients with mild cognitive impairment recruited in the present study; thus, differences in the pattern elements distributions of different groups were unclear. Second, because of time limits, the test-retest reliability, the internal consistency between clinical feature items, and the cut-off scores for different levels of severity  of the subscales were not determined. More participants and followup tests are needed in future studies.yang hyperactivity subscales were shown to be superior to other subscales in terms of parallel validity and diagnostic properties. In summary, the present study shows that the PES, a brief tool for traditional medical subtyping for dementia, is helpful to accurately and easily discriminate pattern elements. From this scale, the phlegm muddiness, blood stasis, and


These results suggested that spinal PreM-INs function to significantly modulate hand-muscle activity during precision grip, but the contribution of other neural structures is also needed to recruit an adequate combination of hand-muscle motoneurons.Grasping is a highly complex movement that requires the coordination of a number of hand joints and muscles. Previous studies showed that spinal premotor interneurons (PreM-INs) in the primate cervical spinal cord have divergent synaptic effects on hand motoneurons and that they might contribute to hand-muscle synergies. However, the extent to which these PreM-IN synaptic connections functionally contribute to modulating hand-muscle activity is not clear. In this paper, we explored the contribution of spinal PreM-INs to hand-muscle activation by quantifying the synaptic linkage (SL) and functional linkage (FL) of the PreM-INs with hand-muscle activities. The activity of 23 PreM-INs was recorded from the cervical spinal cord (C6–T1), with EMG signals measured simultaneously from hand and arm muscles in two macaque monkeys performing a precision grip task. Spike-triggered averages (STAs) of rectified EMGs were compiled for 456 neuron–muscle pairs; 63 pairs showed significant post-spike effects . Conversely, 231 of 456 pairs showed significant cross-correlations between the IN firing rate and rectified EMG . Importantly, a greater proportion of the neuron–muscle pairs with SL showed FL  compared with the pairs without SL , and the presence of SL was significantly associated with that of FL. However, a significant number of pairs had SL without FL (SL∩!FL,  Grasping is a highly complex movement that requires the coordination of a number of hand joints and muscles. The large number of degrees of freedom (DOF) of hand anatomy enable its flexible and varied movement, but this requires a high computational load and causes the “DOF problem”  and functional linkage (FL) with hand-muscle activity . Experiments were performed in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the Animal Research Committee at the National Institute for Physiological Sciences, Japan.Electrophysiological recordings were obtained from two adult macaque monkeys  or sevoflurane (1.5–3.0% in 2:1 O2:N2O) under aseptic conditions, and a custom-made recording chamber was implanted over the laminectomy . The test window was set at a duration of 12 ms  after the spinal neuron spike. Potential cross-talk between simultaneously recorded EMGs was evaluated by combining a cross-correlation method ] of PreM-INs was calculated as the inverse of the interspike interval:ti is the time of the ith spike. The instantaneous firing rate was then low-pass filtered  and down-sampled to 1000 Hz. Rectified EMGs were also low-pass filtered  and down-sampled to 1000 Hz. Continuously recorded 90-s data points, which contained ~10 successive trials including whole-task phases, were used to calculate the cross-correlation. Cross-correlation significance was defined by a Monte Carlo method . The transposed signal cross-correlations were compiled for 456 neuron–muscle pairs, and the lower and upper limits were set at −0.29 and 0.25, respectively. These analyses were performed off-line using MATLAB (MathWorks).To quantify the FL between neuronal activity and hand-muscle activity, we calculated cross-correlations between the neuronal and muscle activities Figure . First, Among the 210 spinal neurons recorded from the two monkeys , 23 neurons produced 63 significant PSEs  in hand and arm muscles, and were identified as PreM-INs (18 excitatory and five inhibitory). The neurons had either post-spike facilitation (PSF) or post-spike suppression (PSS) effects on at least one muscle; no neuron had both PSF and PSS simultaneously. As an example, a single PreM-IN STA is shown in Figure A) is shown in Figure p < 0.05, t-test). This result indicates that PreM-IN activity had significant covariation with muscles other than those on which they had output effects.A majority of PreM-INs , including 17 excitatory and two inhibitory PreM-INs, had significant cross-correlations with at least one muscle (FL). In total, 246 of 456 neuron–muscle pairs had significant cross-correlations. Interestingly, FL polarity was positively biased; most FLs were positive , and only a few pairs showed negative FLs . Moreover, all PreM-INs with significant FLs had positive FLs regardless of whether they were excitatory or inhibitory PreM-INs; two excitatory PreM-INs concurrently had negative FLs ; a greater proportion of pairs with significant SL than pairs without significant SL also showed significant FL , and only 20/63 pairs with significant SL lacked the significant FL. This clear association between SL and FL suggested that spinal PreM-IN output effects significantly modulate target muscle activities.Among a total of 456 neuron–muscle pairs, 266 pairs showed either a SL (PSF or PSS) or a FL (positive or negative), and 43 pairs concurrently showed both SL and FL . On the other hand, for the inhibitory PreM-INs, only one of 11 neuron–muscle pairs with significant SL (PSS) showed a significant FL, and the association was not significant . This result suggested that excitatory PreM-INs constituted the prime movers of the target muscle activity; inhibitory PreM-INs were involved to a lesser extent.Interestingly, SL and FL association depended on whether the PreM-INs were excitatory or inhibitory Figures . In the p < 0.0025 (PSL), and cross-correlation significance was tested using p < 0.01 (PFL). Therefore, the chance level of SL∩!FL and !SL∩FL was set to PSL* (1 − PFL) and (1 − PSL)*PFL, respectively. A binomial test showed that the number of SL∩!FL (n = 20) and !SL∩FL (n = 203) significantly exceeded the chance level . These results indicated that SL and FL were clearly associated, but a significant number of incongruities between SL and FL also existed.Although there was a significant association between SL and FL, there were many exceptions: 20 pairs had SL without FL (SL∩!FL), and 203 pairs had FL without SL (!SL∩FL). To test whether these incongruities occurred by chance, we quantified the chance level of these incidences. PSE significance was tested using The existence of hand-muscle synergy and the modular control of primate grasping has been suggested (Brochier et al., The contribution of spinal interneurons to muscle synergy has been extensively investigated in the hind-limb movement of frogs (Giszter et al., The clear association between SL and FL was specific to excitatory PreM-INs and was not found in inhibitory PreM-INs Figures . This suIn addition to the significant association between SL and FL, our results also showed a significant number of incongruities, i.e., !SL∩FL and SL∩!FL Figures , 3. SeveAnother possible explanation for the incongruities is the involvement of other premotor systems Figure . If a prIn this study, we explored how PreM-IN output effects contribute to hand-muscle activation by investigating SL and FL between PreM-INs and hand-muscle activity in monkeys performing a precision grip task. Our results showed that SL and FL between PreM-IN and their target muscle activities were significantly associated, indicating that spinal PreM-INs contribute to hand-muscle activity modulation during control of grasping. However, a significant number of incongruities between SL and FL were also found, suggesting the contribution of other neural structures in recruiting an adequate combination of hand-muscle motoneurons. Further studies are needed to elucidate the relative importance of multiple premotor systems to the control of hand-muscle activity during grasping.The co-existence of associations and incongruities between SL and FL may reflect that the modular control of hand movements is characterized by both fixed and flexible control (Macpherson, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The volumetric ratio of the coarse aggregate (Vagg) and the water-to-binder (W/B) ratio were selected as the main test variables. Two W/B ratios (25% and 40%) were used and the value of Vagg varied between 0% and 40.0%, and 0% and 46.5% for W/B ratios of 25% and 40%, respectively. The test results demonstrated that the slope of the ascending branch of the stress-strain curve of Ca(OH)2-activated Hwangtoh concrete was smaller, and it displayed a steeper drop in stress in the descending branch, compared with those of ordinary Portland cement (OPC) concrete with the same compressive strength. This trend was more pronounced with the increase in the W/B ratio and decrease in Vagg. Based on the experimental observations, a simple and rational stress-strain model was established mathematically. Furthermore, the modulus of elasticity and strain at peak stress of the Ca(OH)2-activated Hwangtoh concrete were formulated as a function of its compressive strength and Vagg. The proposed stress-strain model predicted the actual behavior accurately, whereas the previous models formulated using OPC concrete data were limited in their applicability to Ca(OH)2-activated Hwangtoh concrete.This study examined the stress-strain behavior of 10 calcium hydroxide (Ca(OH) For these reasons, the development of concrete with nil or minimal cement has attracted significant attention since the late 1980s.With the increasing importance of leadership in energy and environmental design (LEED) certifications for buildings and reducing greenhouse gas (GHG) emissions, many concrete industry players are strongly focusing on minimizing the use of ordinary Portland cement (OPC). Although OPC has played a prominent role in building and infrastructure development as the basic component of concrete and mortar, the production of a ton of OPC is commonly associated with the following environmental issues –4: (1) C2)-activated Hwangtoh mortars are comparable to those of OPC mortars with the same mixing proportions. However, more extensive use of Hwangtoh concrete in structural engineering applications warrants precise evaluations of its inherent characteristics including mechanical properties, inelastic deformation behavior, and durability. In particular, the compressive stress-strain relations of concrete incorporating a new binder should definitely be evaluated for use in the rational analysis and design of structural elements because the cohesion between pastes and aggregate particles significantly influences the extent of increase in strain due to the applied load [2-activated Hwangtoh concrete are available in existing literature.Hwangtoh has gained more interest recently as a source material for low-cement concrete, especially in Korea and China, because it is known to be eco-friendly, with high absorption capacity and self-purifying characteristics, as well as offering health benefits by virtue of emitting far infrared radiation –7. Hwangied load . The str2-activated Hwangtoh concrete under compression. To formulate the key factor determining the slopes of the ascending and descending branches of the curves, 10 concrete mixes were prepared with a range of water-to-binder (W/B) ratios by weight and fine aggregate-to-total aggregate ratios (S/a) by volume. The developed model was then compared with existing models [2-activated Hwangtoh concrete were compared with those of OPC concrete collected from a variety of specimens [The objective of the present study is to propose a simple and rational model for obtaining the nonlinear stress-strain curves for Ca(OH)g models –11 that pecimens  with com2. This Hwangtoh contained less calcium oxide (CaO) but was rich in both silicon oxide (SiO2) and aluminium oxide (Al2O3) as inferred from Hwangtoh acquired high pozzolanic reactivity as a result of its calcination at a temperature of 850°C using the Hoffman method. The calcinated Hwangtoh, which was used as a source material, was activated by 7.5% Ca(OH)2/g, respectively. The specific gravity, fineness modulus, and water absorption of the sand (used as the fine aggregate) were 2.42%, 2.51%, and 1.7%, respectively, and those of the crushed granite (used as the coarse aggregate with a maximum size of 19 mm) were 2.6%, 6.75%, and 1.1%, respectively. The specific gravity and maximum particle sizes of Ca(OH)2 were 2.24 and 21.2 μm, respectively.The measurement of the physical properties of materials revealed the specific gravity and specific surface area of Hwangtoh to be 2.8 and 3200 cmEc) and smaller strain (ε0) values at peak stress than do mortars and pastes, indicating that the volumetric ratio of the coarse aggregates (Vagg) directly affects the stress-strain curve of concrete [2-activated Hwangtoh binder were prepared with a range of W/B and S/a ratios, as listed in W/B ratios were 25% and 40%, and within each of these ratios, the S/a ratio of the mixes for each W/B ratio varied from 30% to 100% in intervals of 15%. The concrete specimen with an S/a ratio of 100% indicates a mortar without coarse aggregates. As a result, Vagg ranged between 0% and 40.0%, and 0% and 46.5% for W/B ratios of 25% and 40%, respectively. The unit water content was fixed at 180 kg/m3 for all concrete mixes. To achieve workability of the mixes for casting, a polycarboxylate-based, high-range water-reducing agent was added with binder ratio by weight of 1.5% and 1.2% for concrete mixes with W/B ratios of 25% and 40%, respectively.In general, with increase in the compressive strength of concrete, the initial slope of its stress-strain curve increases, whereas the descending branch of the curves after peak stress has a more rapidly decreasing slope . Moreoveconcrete , 16. Con3 capacity and equipped with rubber wiper blades. The initial slump of fresh concrete was measured in accordance with the ASTM C143 provision [−4 per min was employed. Testing was continued until the final crushing of the concrete. All test data were captured by a data logger and stored automatically. Using the measured stress-strain curve, the Ec was calculated at 40% peak stress in accordance with the ASTM C469 provision [All concrete specimens were mixed using a pan mixer of 0.35 mrovision . Immediarovision .Vagg. As the applied load increased, the initial crack propagated toward the top and bottom surfaces of the specimens. As a result, the failure of specimens after peak stress was governed by the time when the longitudinal crack joined the top and bottom surfaces of the specimen. The width of the longitudinal cracks increased sharply at 80%–85% of the peak stress, which was accompanied by a rapid increase in the longitudinal and transverse strains, as shown in Vagg decreased. With rapid increase in transverse strain, the volumetric change of the specimens started to shift from compression to tension. This threshold point was found to occur at approximately 80% and 95% of the peak stress for concrete mixes with Vagg of 0% and 40%, respectively. This implies that the rate of increase in transverse strain due to the opening of longitudinal cracks decreases as Vagg increases. After the peak stress, failure tended to occur along the longitudinal cracks, which commonly formed in the pastes between the aggregate particles. The drop in stress subsequent to peak stress was more rapid in concrete mixes with Vagg = 0% than those with Vagg = 40%. Longitudinal cracking started at 50%–60% of the peak stress within the mid-height section of the specimen. The stress at which cracks developed was independent of fc′), Ec, and strains of the Ca(OH)2-activated Hwangtoh concrete specimens. The value of fc′ increased by 1.89–2.52 times as the W/B ratio decreased from 40% to 25%. The rate of this increase also increased gradually as Vagg decreased. At both W/B ratios, the concrete specimens developed lower fc′ than did OPC concrete with no supplementary cementitious materials, as shown in fc′ corresponding to an increase in the W/B ratio was similar in both concrete types. The best-fit curve for fc′ confirmed that a W/B ratio not exceeding approximately 30% is required for structural applications of Ca(OH)2-activated Hwangtoh concrete. The fc′ of the test concrete also decreased as Vagg decreased  was very short compared to those for mixes with coarse aggregates. These trends were more pronounced for a W/B ratio of 25% than for 40%, leading to the inference that the mechanical interlocking of the coarse aggregate along the cracks relives the brittle fracture (as indicated by the descending branch) and improves the compressive strength of the concrete.The stress-strain curves obtained for the concrete mixes are plotted in concrete –11, the f pastes , causingfc′ and Ec of the Ca(OH)2-activated Hwangtoh concrete is shown in fc′ not exceeding 50 MPa, as well as predictions made by Carreira and Chu's model [wc) of normal-weight concrete was assumed to be 2300 kg/m3. The Ec of the concrete was commonly lower than the best-fit curves determined for OPC concrete and predictions of Carreira and Chu's model [2-activated Hwangtoh binder than OPC.The relationship of 's model . In thei's model . The dev's model , possiblEc of concrete can be expressed as a function of fc′ and wc [wc on the Ec of the tested Ca(OH)2-activated Hwangtoh concrete because the variation in the wc values (in the test) was very minimal at the same W/B ratios, ranging between 2419 and 2431 kg/m3, 2321 and 2335 kg/m3 for W/B ratios of 25% and 40%, respectively. Moreover, Ec was affected by Vagg  owing to the considerably higher modulus of elasticity in aggregates than in pastes when individually subjected to load. In addition, an increase in the continuous cracks joining the bond microcracks that developed at the interface between the pastes and aggregate particles leads to a faster rate of increase in strain [Ec, influential parameters such as fc′ and Vagg were repeatedly combined and adjusted through a trial-and-error approach until a relatively high correlation coefficient (R2) was obtained. Based on a regression analysis of the test results, the Ec of Ca(OH)2-activated Hwangtoh concrete with fc′ < 40 MPa can be empirically expressed as follows Ec=3ε0 of concrete increases with increase in fc′. This trend was also verified for the test case from the data listed in ε0 have mostly been empirically developed only as a function of fc′. However, Ca(OH)2-activated Hwangtoh concrete demonstrated higher values of ε0 than did OPC concrete with the same fc′, as shown in ε0 values also increased slightly as Vagg decreased because the increase in paste volume reduced the Ec and accelerated the nonlinearity of the stress-strain curves, especially after the development of longitudinal cracks. However, none of the predicted equations [Vagg on the strain although the former is evidently the secondary factor causing the increasing strain rate. Based on a regression analysis of the test results, the ε0 of Ca(OH)2-activated Hwangtoh concrete can be written as follows (see MacGregor and Wight  establisquations –11 consilows see :(2)ε0=02-activated Hwangtoh concrete is parabolic and hump-shaped with its vertex at the peak stress point. This physically means that the tangential modulus of elasticity has the maximum value at the origin, gradually decreases to zero at the peak stress point, and becomes negative through the descending branch of the curve. In this study, the same assumption and the following nonlinear equation [Y( = fc/fc′) is the normalized stress, X( = εc/ε0) is the normalized strain, and fc is the concrete stress corresponding to strain εc. Equation  Y = 1 when X = 1, representing the peak stress point; (3) dfc/dεc = 0 whenX = 1 or at the peak stress point. Hence, the factor β1 in Xquation [Y=(β1+1)Xquation [Y=(β1+1)Xβ1 for the descending branch using the secant modulus at 0.5 fc′ as the reference point, as follows:Xd = ε0.5/ε0 and ε0.5 is the strain corresponding to 0.5 fc′ after peak stress. The values of β1 in the nonlinear equations   β1 for fc′ and Vagg, as inferred from ε0 to propose a simple equation for ε0.5, yielding the following equation:The slope of the descending branch of the curve depends on β1, which determines the slopes of the ascending and descending branches. For given fc′ and Vagg, the material properties of Ec, ε0, and ε0.5 were calculated using  is the reference value for the compressive strength of concrete. A higher value of β1 in β1, whiced using  and 5)))β1, whig branch  and the g branch :7)β1=0β1=0β1, r  εc≤ε0β1=0.43ex2-activated Hwangtoh concrete can be generalized as follows:ε0 and β1 are obtained using ed using  or 8), , 2-activW/B ratios and Vagg values. The figure also displays the curves pertaining to previous models [γe,m) and standard deviation  of the normalized root-mean-square errors (NRMSE) calculated for each stress-strain curve. In general, the previous models commonly overestimate the slope of the ascending branch and underestimate the value of ε0. This trend is more pronounced with the increase in fc′ and decrease in Vagg. Furthermore, the equations proposed by [Vagg. Consequently, the previous models yield high values for γe,m (>0.238) and γe,s (>0.050) and are limited in their applicability to Ca(OH)2-activated Hwangtoh concrete, and the error associated with them gradually increases as Vagg decreases.s models –11 that posed by  and Wee 2-activated Hwangtoh concrete are in better agreement with test results, showing relatively higher accuracy for both ascending and descending branches, judging from the considerably lower NRMSE values . These results are consistent with the actual responses: in particular, they accurately reflect the effect of Vagg on ε0 and the slopes of the ascending and descending branches. Hence, the proposed model is useful for accurately evaluating the compressive stress-strain behavior of low- and medium-strength Ca(OH)2-activated Hwangtoh concrete.In contrast to the previous models for OPC concrete, the predictions obtained from the proposed model for Ca(OH)2-activated Hwangtoh concrete with different W/B and Vagg values. The Ec and ε0 values of the specimens were compared to those of OPC concrete compiled by Yang et al. Based on the experimental data, a simple equation was established to reasonably predict the stress-strain relations of Ca(OH)2-activated Hwangtoh concrete under compression, though further verification is required for strengths of more than 40 MPa because of the limited data used for empirical fitting. From the experimental and comparative observations, the following conclusions may be drawn.W/B, the fc′ of Ca(OH)2-activated Hwangtoh concrete was commonly lower than that of OPC concrete; however, the test concrete gained strength development comparable to that of structural concrete at a W/B less than 30%.For the same Vagg, the slope of the ascending branch of the stress-strain curve and fc′ decreased, whereas ε0 and the declining slope of the descending branch of the curve increased. This observation was more pronounced as the W/B ratio increased.With decrease in fc′, Ca(OH)2-activated Hwangtoh concrete had lower Ec and larger ε0, showing greater discrepancy as Vagg decreased. Hence, the Ec and ε0 of Ca(OH)2-activated Hwangtoh concrete could be formulated as a function of fc′ and Vagg.Compared to OPC concrete with the same 2-activated Hwangtoh concrete, whereas the proposed stress-strain model predicted the actual behavior quite accurately, as evidenced by the much lower NRMSE values.Previous models formulated using OPC concrete data revealed limitations in their applicability to Ca(OH)The present study examined the stress-strain behavior of Ca(OH)


Diabetics who have acquired an ankle fracture may be easily missed given their atypical presentation. As such, it is not infrequently seen that these patients are either initially misdiagnosed or ineffectively managed resulting in unnecessary hospital length of stay and procedures. Multiple review articles and retrospective studies have been previously published in the literature, but complete guidelines to assist in accurate diagnosis and cost-effective management for this complex problem do not currently exist. Through a critical analysis of the current literature, a proposed diagnostic and management algorithm and scoring system that can be used to quantify risks in the surgical management are presented for consideration. Both diabetes and ankle fractures are increasing in incidence worldwide. In 2003, it was estimated that 194 million people in the world have been diagnosed with diabetes and this is predicted to exponentially increase to over 333 million by 2025 [Publications were identified by conducting a comprehensive keyword search of Medline, EMBASE, and CINAHL databases between the months of September 2010 to March 2011 by the primary author (Joshua Yee). Search terms included “diabetes,” “ankle,” and “fracture.” Available abstracts of all articles  published in the English language in the above databases searched within the above timeframe where included for initial review to determine suitability. Inclusion criteria for full-text review were that articles must be relevant to diabetic ankle fracture diagnosis and management. Manual search of the all the references in the full-text publications was also completed to further identify additional publications for potential inclusion. All included full-text publications for review were further defined as either a notable or supportive. A publication was defined to be notable if the study design  and level of prognostic strength  were met. Notable publications were subjected to further critical analysis. Exclusion criteria were the following: publications not published in English; all conferences, lectures, review articles, and publications that were neither published nor published in the above databases. Duplicate results that occurred in different databases were truncated to a single result.A total of 352 abstracts were initially screened. From these abstracts, 59 articles met our inclusion criteria for further full text review. 293 articles were excluded. Nine additional articles were found after reviewing all the full-text references . NineteeThe AFDA algorithm consists of two parts: a diagnostic and management part Figures  and 3, hRisk factors for diabetes include previous history of impaired glucose intolerance; high-risk ethnic groups ; positive family history or gestational diabetes; age greater than or equal to 45 with either a body mass index (BMI) greater or equal to 25 or presence of hypertension; and established cardiovascular risk factors or disease. If risk factors are present, screening for diabetes is suggested using either HBA1c , two-hour plasma glucose  during an oral glucose tolerance test, or fasting blood glucose  [If the presence of diabetes has been excluded, other causes of ankle redness, swelling, and/or pain should be considered, which can include: gout, infection, septic arthritis, deep vein thrombosis (DVT), and haemarthrosis , 6. FurtSince the introduction of the Ottawa ankle rules , there hThe AFDA management algorithm and score will assist the treating specialist in the optimal decision making for managing diabetic ankle fractures. If a fracture requires fixation, the AFDA score  can be cIf Charcot's arthropathy is present in conjunction with the diabetic ankle fracture, Eichenholtz's  staging The AFDA scoring system  is basedWith the use of AFDA algorithm, it can hopefully provide a standardized approach and guide to management for diabetic ankle fractures. The scoring system, in particular, can assist in objectively quantifying risk for both the patient and affected ankle joint so as to allow the treating specialist to have confidence in achieving the best possible outcome. As the score increases, the risks of failure in standard fixation methods increase and consideration of more robust and rigid fixation techniques or fusion should be incorporated. From our review of the literature, we suggest that if the patient scores five or more, rigid fixation/arthrodesis should be considered from the outset. If rigid fixation/arthrodesis fails, despite adequate measures in hope for an optimal outcome, amputation can be considered.The current evidence of which AFDA is derived from is based primarily on heterogeneous study designs and our center's experience. As such, it will require further validation reviews or trials, incorporating followup and functional outcome scores. Once validated, AFDA can be used as a protocol and research tool for the diagnosis and management of diabetic ankle fractures.


Patients with CF experience pulmonary exacerbations. These are often initially empirically treated with intravenous antibiotics, with antibiotic choice refined after susceptibility testing.We completed a 5-year retrospective review of children attending the Paediatric CF Unit, Nottingham. The respiratory sampling, antibiotic prescribing and susceptibility testing guidance were audited. Episodes were classified according to the concordance between the antibiotics prescribed and antibiotic susceptibility testing.Pseudomonas aeruginosa, 103 antibiotic courses were commenced that coincided with an isolation of P. aeruginosa. P. aeruginosa was fully susceptible, partially susceptible or fully resistant on 33%, 44.7% or 16.5% of occasions respectively. The antibiotic prescriptions were never changed following antibiotic susceptibility testing. We found no association between change in FEV1 (p = 0.54), change in BMI (p = 0.12) or time to next exacerbation (p = 0.66) and concordance between antibiotic susceptibility and the antibiotics administered.Of 52 patients who had previously isolated This study contributes to mounting evidence questioning the utility of routine antibiotic susceptibility testing. While early infection with P. aeruginosa, may be eradicated by the expeditious use of antibiotic therapy P. aeruginosa is accompanied by significant decline in clinical status, including lung function The natural history of progression of lung disease in cystic fibrosis (CF) usually consists of a sequential acquisition of infecting organisms Conventionally, antibiotic selection has been directed by the results of antibiotic susceptibility testing. However there is uncertainty regarding the states in which the organism exists within the CF lung and the antibiotic susceptibilities of the organism growing in planktonic, adherent and biofilm states vary significantly At the time of writing, the clinical guideline of Nottingham Children's Hospital Children and Young Persons CF Unit reflects the strategy of many units in the UK in recommending respiratory sampling at each clinical contact 2P. aeruginosa (as defined by greater than 50% of months with samples positive for P. aeruginosa over the last 12 months) We completed a retrospective case-note audit of patients attending the Children and Young Persons CF Unit, Nottingham UK for each attendance between January 2005 and November 2010. We identified those patients who had chronic pulmonary infection with The adherence to the respiratory sampling, antibiotic susceptibility testing and antibiotic prescribing guidance was audited. We determined the effect of adherence to the guidance upon outcome.P. aeruginosa is identified by morphotype. The BSAC  methods for antimicrobial susceptibility testing are used for interpretation Our practice is to undertake respiratory sampling at the commencement of a treatment course of antibiotics, with the initial selection of antibiotics being either empirical or guided by the most recent culture result from the previous clinical contact. Antibiotics selection should then be refined once the results of susceptibility testing are reported. Antibiotic susceptibility testing is performed in our unit using disc diffusion testing against a standard panel of antibiotics — ceftazidime, ciprofloxacin, piptazobactam, meropenem, aztreonam, gentamicin, amikacin, tobramycin and colistin. The isolation of multiple strains of P. aeruginosa was isolated from a patient with CF which was later reported to be resistant to the antibiotic(s) prescribed and where the antibiotics were not changed. We classified episodes according to the concordance between the antibiotics prescribed and antibiotic susceptibility profiles of the isolated organism. If the organism was ‘fully susceptible’ or ‘fully resistant’ to both antibiotics administered this was recorded . In cases where the organism was reported as susceptible to one antibiotic but resistant to the other in the combination, this was recorded as ‘partially susceptible’. In cases where more than one strain of P. aeruginosa was identified, the antibiotic profile was determined to be fully susceptible (or fully resistant) if the antibiotics prescribed matched (or otherwise) the susceptibility profile of the isolated organism. The combination of two strains of bacteria was considered to be ‘partially susceptible’ in all combinations other than the situation where the bacteria were fully susceptible or fully resistant . Changes in FEV1, BMI (body mass index) during treatment and the time to next exacerbation were compared. Where BMI data was missing this was calculated from the last clinic height and the current weight. Two groups of analyses were performed; the first using the unit of analysis (UoA) as the first episode for each patient so that each patient would only contribute once, and for the second the unit of analysis was each exacerbation, to ensure that no data were lost. Differences between groups were tested using Kruskal–Wallis test.We planned to identify episodes where a strain of 3P. aeruginosa isolated at least once, of whom 4 had been transferred to adult services and 8 patients had not experienced a pulmonary exacerbation or their notes were ‘missing’. The remaining 40 patients had received 306 antibiotic courses combined, of which 169 (55.2%) were given intravenously. Of these, 23 patients had received 103 courses of intravenous antibiotic therapy that followed an isolation of P. aeruginosa either on admission or at a clinic attendance that prompted admission. This group forms the basis of the further analysis.  with patients receiving an average of 4 intravenous courses (range 1–17) in the period of interest.Of the episodes where Reports for antibiotic susceptibility testing were available for 97 (94.2%) episodes. In no case was the antibiotic prescription changed upon receipt of the antibiotic susceptibility report. Of the 103 episodes, the organism was found to be fully susceptible to the antibiotics administered on 34 (33%), fully resistant on 17 (16.5%) and partially susceptible on 46 (44.7%) of occasions. On three occasions the antibiotic prescription was changed mid-way through an intravenous treatment course. On two occasions this was due to a poor clinical response, however the antibiotic change did not alter the concordance categorisation. On a third occasion a family member wished the antibiotics to be changed and again, the antibiotic was changed to another to which the organism was similarly resistant.1 (% predicted) (Considering the outcomes of FEVedicted) , BMI (Fiedicted)  or time edicted) , there w1 percent predicted was not associated with the concordance between sensitivity profile and the antibiotics prescribed (p = 0.5353), neither was outcome dependent upon antibiotic concordance for change in BMI (p = 0.1202), or time to next exacerbation of intravenous antibiotic course (p = 0.6603).Analysing all 103 episodes, the outcome in terms of change in FEV1 (p = 0.1759), BMI (p = 0.7785) or time to next exacerbation or intravenous antibiotic course (p = 0.2239) was associated with antibiotic susceptibility concordance.Analysing the data using the patient as the unit of analysis so that each patient contributes only their first treatment course to the data set, neither FEV41), BMI or time to the next exacerbation.We found that our practice adhered closely to the guideline recommending respiratory sampling at each clinical contact and that antibiotic susceptibility testing was performed in 94.2% of cases. However on no occasion was the empirical antibiotic changed upon receipt of the antibiotic susceptibility profile. We found that, despite 66% of antibiotic courses consisting of antibiotics to which the organism was not fully susceptible, the antibiotic concordance was not associated with clinical outcome in terms of lung function (FEVA similar study consisting of a retrospective analysis of patient data from the control group of a randomised trial of inhaled tobramycin, restricted the prescription of intravenous antibiotics to ceftazidime and tobramycin. They found no correlation between antibiotic susceptibility to tobramycin and ceftazidime and clinical outcome The antibiotic susceptibility reports in these studies detail susceptibility profiles for antibiotics in isolation. In order to answer the question of whether combination antibiotic susceptibility testing conferred a clinical benefit, a randomised trial compared combination susceptibility testing with conventional testing. There was no significant difference in clinical or bacteriological outcome In order to more closely reflect the anticipated mode of growth of the organism within the CF lung, attempts have been made to consider antibiotic regimens based on biofilm susceptibilities. Generating simulated antibiotic regimens based on biofilm and conventional susceptibility testing yields different antibiotic selections that on some occasions were contradictory Our report is likely to represent a significant proportion of clinical practice in the UK and reflects the ‘real world situation’. Not only was the response to all antibiotic selections included, but we were also able to determine the effect for patients who receive intravenous antibiotics at regular intervals, irrespective of whether they would meet criteria of an infective exacerbation. We are also the first to report such findings in the paediatric population.Our findings are limited by the small number of patients who contribute to the data set. However, these patients represent a wide spectrum of severity of disease and the corresponding analysis at the patient level, serves to support our findings and reduce the likelihood that we have encountered a unit of analysis error.in vitro. In addition, inconsistencies in the diagnosis of pulmonary exacerbations The concern regarding the applicability of conventional antibiotic susceptibility continues to increase and further questions arise as a result. The most likely explanation for the poor association between susceptibility and response is that the mode of growth of the organism is difficult to represent in vitro model of the in vivo condition and further understanding of how the organism behaves in the clinical setting. In the meantime the mounting evidence questioning the utility of routine susceptibility testing suggests that a more refined approach should be considered.The effective management of pulmonary exacerbations is critical to the continued improvements in CF care, and is an area in which we currently fall short. Twenty-five percent of patients experiencing an exacerbation do not recover their baseline lung function after treatment