A pathology order interface based on the transmission of texts obtained from pathology requisitions and just-in-time construction of HL7 messages.

Background: A pathology order interface using Health Level 7 standards (HL7) generally has an HL7 client program that gathers information from the clinical electronic medical record system, packages the information in the form of HL7 message, and sends the message using secure communication protocols to an HL7 interface engine located on the pathology side. We describe an alternative approach that transmits the texts obtained from requisitions, with subsequent just-in-time construction of HL7 messages. Materials and methods: The order interface is between a dermatology clinic EMR and pathology information system. A text acquisition and processing program runs in the background in desktop computers in dermatology clinic so that a copy of pathology requisition text is obtained each time when the clinic prints a pathology requisition. Discrete elements of the data are extracted from this text, prepended to the text and saved on a shared drive within the dermatology office intranet. This text file is then transferred to pathology intranet using secure File Transfer Protocol (sFTP). Once received, an HL7 message construction program extracts the discrete data elements to construct an HL7 message. The HL7 message is then forwarded to an HL7 interface engine and entered into the pathology information system as an order. Results: Using an actual case as an example, the content and format of the information flowing through different steps of the interface are demonstrated. Conclusions: The construction of such an interface does not involve the clinic EMR vendor, thus avoiding its associated cost and potential delay. This interface has advantages over our other order interfaces constructed using the conventional approach in that it does not require a change of order process and it avoids duplicate orders.

Odorant Receptor Inhibition Is Fundamental to Odor Encoding.

Most natural odors are complex mixtures of volatile components, competing to bind odorant receptors (ORs) expressed in olfactory sensory neurons (OSNs) of the nose. To date, surprisingly little is known about how OR antagonism shapes neuronal representations in the detection layer of the olfactory system. Here, we investigated its prevalence, the degree to which it disrupts OR ensemble activity, and its conservation across phylogenetically related ORs. Calcium imaging microscopy of dissociated OSNs revealed significant inhibition, often complete attenuation, of responses to indole-a commonly occurring volatile associated with both floral and fecal odors-by a set of 36 tested odorants. To confirm an OR mechanism for the observed inhibition, we performed single-cell transcriptomics on OSNs exhibiting specific response profiles to a diagnostic panel of odorants and identified three paralogous receptors-Olfr740, Olfr741, and Olfr743-which, when tested in vitro, recapitulated OSN responses. We screened ten ORs from the Olfr740 gene family with ∼800 perfumery-related odorants spanning a range of chemical scaffolds and functional groups. Over half of these compounds (430) antagonized at least one of the ten ORs. OR activity fitted a mathematical model of competitive receptor binding and suggests normalization of OSN ensemble responses to odorant mixtures is the rule rather than the exception. In summary, we observed OR antagonism occurred frequently and in a combinatorial manner. Thus, extensive receptor-mediated computation of mixture information appears to occur in the olfactory epithelium prior to transmission of odor information to the olfactory bulb.

Integrated 1D and 2D model for better assessing runoff quantity control of low impact development facilities on community scale.

This study proposes a modelling framework of integrated one-dimensional (1D) and two-dimensional (2D) hydrodynamic modelling to evaluate the effectiveness of sponge city construction at community scale. Through a case study in Zhuhai, we integrate Stormwater Management Model (SWMM) and Cellular Automata Dual-DraInagE Simulation (CADDIES) 2D model to analyze the rainfall-runoff process involving green infrastructures. SWMM is applied to analyze the change of surface runoff control effects before and after the implementation of sponge city low impact development (LID) facilities, and CADDIES is adopted to simulate the propagation of excess runoff on the surface. The results show that the LID facilities can effectively reduce the runoff volume of small and medium-sized rainfall events since the maximum runoff reduction rate is 94.4%. For long-term operation, the LID can capture 52.9% of annual rainfall volume and reduce annual runoff by 28.0%. However, the CADDIES 2D model simulations indicate that LID facilities have little effect on flood alleviation in specific regions under extreme rainfall conditions. In addition, we compared the modelling performance using four different terrain Digital Elevation Model (DEM) resolutions and found that 1 m terrain DEM resolution can produce comparable results to 0.25 m DEM with a fraction of computational time. We also find that the MIKE FLOOD model and the integrated model of SWMM and CADDIES 2D can obtain similar simulation results, the p-value = 0.09 which is >0.05, but SWMM-CADDIES integrated model is more suitable for small-scale simulation.

An evaluation of the mid-ventilation method for the planning of stereotactic lung plans.

BACKGROUND AND PURPOSE: Stereotactic ablative body radiotherapy for lung plans requires 4DCT. Most radiotherapy centres use this to determine an internal target volume (ITV), despite studies suggesting that planning on a mid-ventilation (Mid-V) phase can reduce target volumes. The purpose of this study is two-fold: to determine whether the Mid-V approach provides adequate coverage and to discuss methods to enable the Mid-V approach to be applied more widely. METHOD: 4D scans of 79 patients were outlined on every phase. The mid-V phase was identified. Margins were determined from the range of motion, and plans generated with a 55 Gy prescription. A grid-based method was used to get the probability of tumour coverage in the presence of systematic and random uncertainties, with and without blurring for breathing motion. RESULTS: For the Mid-V plans with the margins calculated from the van-Herk formula, after blurring doses for breathing, the coverage (dose covering 95% of the CTV 95% of the time) was greater than for plans with isotropic 5 mm margins uncorrected for breathing (58.2 Gy v 57.3 Gy). Similar results were obtained for a linear margin chosen as 0.15 of the breathing range. Deformable contour propagation in a commercial outlining system (ProSoma) identified the same mid-V phase in the majority of cases. CONCLUSION: Our results confirm that a mid-V approach can be used to reduce the PTV size, with no loss of tumour coverage. We propose the use of a simplified margin formula equal to the margin ignoring breathing plus 0.15 of the range of motion.

The physician's role in perioperative management of older patients undergoing surgery.

Life-sustaining and life-improving surgical interventions are increasingly available to older, frailer patients, many of whom have multimorbidity. Physicians can help support perioperative multidisciplinary teams with assessment and preoperative optimisation of physiological reserve, comorbidities and associated geriatric syndromes. Similar structured support can be useful in the postoperative period where older patients are at increased risk of delirium, medical complications, increased functional dependency and where discharge planning can prove more difficult than in younger cohorts. Comprehensive geriatric assessment has been shown to improve outcomes and is now embedded in most UK-based services for traumatic hip fracture. Perioperative comprehensive geriatric assessment has been explored in other surgical disciplines and procedures and, where evaluated, has been associated with improved outcomes. The need to support older patients with frailty undergoing surgery exceeds the capacity of specialist geriatricians. Other groups of healthcare professionals need to nurture the core competencies to support this group perioperatively.

Drug-associated arrhythmia in the military patient.

Members of the Armed Forces may be exposed to drugs, or combinations of drugs, with the potential to prolong the QRS or QT intervals. The effect of this is to increase the likelihood of developing dangerous ventricular tachyarrhythmias, including ventricular tachycardia, torsades de pointes or ventricular fibrillation. Common examples of the pharmacological agents associated include antibiotics, antiemetics and antimalarials. Genetic predisposition, electrolyte disturbance, anaesthesia and trauma may exacerbate the proarrhythmic effect of these medications. Screening of recruits does not detect all those with a genetic predisposition to drug-associated arrhythmias, so vigilance in preventing this iatrogenic disorder and recognising and appropriately managing it when present is important. This article explains the physiological basis of arrhythmogenesis, outlines the clinical features and provides guidance on investigation and management, with particular reference to military patients.

Heme oxygenase-1 gene promoter polymorphism is associated with the development of necrotizing acute pancreatitis.

OBJECTIVES: Acute pancreatitis is a severe and frequently life-threatening disease, which can lead to pancreatic necrosis, acute lung injury, systemic inflammatory response syndrome, and other complications. In this study, we hypothesized that the expression of heme oxygenase-1 determined by the number of guanidinium thiocyanate (GT) repeats can influence the occurrence of acute pancreatitis. METHODS: Patients with acute pancreatitis (n = 131) and age- and sex-matched healthy controls (n = 108) were studied. The polymerase chain reaction products were analyzed by ABI 3130 genetic analyzer and the exact size of the polymerase chain reaction products was determined by GeneMapper software. A short allele was defined as containing 27 GT repeats or fewer, whereas a long allele was more than 27 repeats. RESULTS: The subjects were categorized into 3 groups on the basis of the genotype results: 1 short and 1 long, 2 short, and 2 long alleles (L/L). Patients with necrotizing disease more frequently were carriers of LL genotype compared with those who had edematous acute pancreatitis. Furthermore, logistic regression analysis revealed that the presence of L/L allele type doubles the risk for developing pancreatic necrosis in patients with acute pancreatitis. CONCLUSIONS: The polymorphism of the GT repeats in the heme oxygenase-1 promoter region may be a risk factor for developing severe and necrotizing acute pancreatitis.

Characterization of the receptor binding residues of kisspeptins by positional scanning using peptide photoaffinity probes.

Kisspeptins, endogenous peptide ligands for GPR54, play an important role in GnRH secretion. Since in vivo administration of kisspeptins induces increased plasma LH levels, GPR54 agonists hold promise as therapeutic agents for the treatment of hormonal secretion diseases. To facilitate the design of novel potent GPR54 ligands, residues in kisspeptins that involve in the interaction with GPR54 were investigated by kisspeptin-based photoaffinity probes. Herein, we report the design and synthesis of novel kisspeptin-based photoaffinity probes, and the application to crosslinking experiments for GPR54-expressing cells.

MicroRNA profiling in lung cancer reveals new molecular markers for diagnosis.

OBJECTIVE: To identify new molecular diagnostic markers for non-small cell lung carcinoma (NSCLC) by analyzing microRNA (miRNA) expression profile differences in samples from NSCLC patients and adults with nonneoplastic diseases. STUDY DESIGN: miRNA expression was studied in archival formalin-fixed, paraffin-embedded tissues by microarray and confirmed by real-time PCR analysis of NSCLC and normal lung tissues. An algorithm for discriminating normal, squamous cell carcinoma (SQCC), and adenocarcinoma (ADC) tissue was derived from miRNA expression studies and applied towards characterization of poorly differentiated NSCLC samples. RESULTS: Microarray data from a genome-wide scan revealed 34 differentially expressed miRNAs, 5 of which enabled algorithmic discrimination of normal tissue from carcinoma (SQCC or ADC), as well as SQCC from ADC. Expression of miR-21 was significantly increased in both tumor types, whereas levels of miR-451 and miR-486-5p were reduced. SQCC was distinguished from normal tissue and ADC by high-level miR-205 expression and decreased miR-26b. Comparison of miRNA profiles to histological and immunohistochemical findings in 19 poorly differentiated specimens demonstrated the potential clinical utility of miRNA profiling to provide important insights into the classification of SQCC and ADC. CONCLUSION: This study presents a novel algorithm for specimen classification in cases of poorly differentiated NSCLC.

Decorin protein core affects the global gene expression profile of the tumor microenvironment in a triple-negative orthotopic breast carcinoma xenograft model.

Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that decorin protein core modulated the differential expression of 374 genes within the stromal compartment of the tumor xenograft. Further, our top gene ontology classes strongly suggests an unexpected and preferential role for decorin protein core to inhibit genes necessary for immunomodulatory responses while simultaneously inducing expression of those possessing cellular adhesion and tumor suppressive gene properties. Rigorous verification of the top scoring candidates led to the discovery of three genes heretofore unlinked to malignant breast cancer that were reproducibly found to be induced in several models of tumor stroma. Collectively, our data provide highly novel and unexpected stromal gene signatures as a direct function of systemic administration of decorin protein core and reveals a fundamental basis of action for decorin to modulate the tumor stroma as a biological mechanism for the ascribed anti-tumorigenic properties.

The metastasis suppressor KISS1 lacks antimetastatic activity in the C8161.9 xenograft model of melanoma.

The objective of this study was to use the established xenograft model of human melanoma (C8161.9) to test a pharmacological approach to the effect of the metastasis suppressor KISS1. A KISS1 analog was used to inhibit the metastatic development of C8161.9 cells in nude mice. Further experiments were performed to test the validity of the C8161.9 model and test the connection between KISS1 expression and loss of metastatic potential. New clones of C8161.9 cells were obtained, with or without KISS1 expression, and were tested for metastasis formation. The absence of benefit in survival with the KISS1 analog compared with PBS prompted us to revisit the C8161.9 model. We found that the cells expressing KISS1, used in the previous study and obtained by transfection and single-cell cloning, were defective for both formation of orthotopic tumors and metastases. In mixing experiments, these cells could not suppress orthotopic tumor growth of KISS1-negative C8161.9 cells, suggesting that the suppression of metastasis by C8161.9-KISS1 cells may be intrinsic to the selected clone rather than related to KISS1 expression. Isolation of clones from parental C8161.9 cells in soft agar yielded cell populations that phenotypically and genotypically mimicked the KISS1-positive clone. In addition, new clones expressing KISS1 did not show any decrease in metastatic growth. These data demonstrate the heterogeneity of cell types in the C8161.9 cell line and the high risk of artifact linked to single-cell selection. A different xenograft model will be necessary to evaluate the use of KISS1 analogs as antimetastatic therapy.

Open-Source web-based Geographical Information System for health exposure assessment.

This paper presents the design and development of an open source web-based Geographical Information System allowing users to visualise, customise and interact with spatial data within their web browser. The developed application shows that by using solely Open Source software it was possible to develop a customisable web based GIS application that provides functions necessary to convey health and environmental data to experts and non-experts alike without the requirement of proprietary software.

Has estimation of numbers of cases of pandemic influenza H1N1 in England in 2009 provided a useful measure of the occurrence of disease?

BACKGROUND: Surveillance indicators of influenza activity have generally provided robust comparative trend data for England. These indicators became less reliable, however, for monitoring trends in activity, or comparisons with previous years, during the influenza pandemic in 2009 because of changes in the perception of risk and changes in the systems of healthcare delivery. An approach was developed to estimate the number of cases of influenza-like illness (ILI) occurring because of infection with pandemic influenza virus. METHODS AND FINDINGS: The number of cases was estimated each week in England on the basis of total number of patients consulting healthcare services with ILI; estimates of the proportion of individuals in the community experiencing an ILI-seeking health care; and the proportion of these positive on laboratory testing. Almost 800,000 cases (range 375,000-1·6 million) of symptomatic ILI cases were estimated to have occurred over the course of the two waves of pandemic activity in England. More cases were estimated to have occurred in the second wave than in the first. CONCLUSIONS: These results underestimate the total number of infections as they do not include asymptomatic infections nor those with mild illness not meeting the definition of a case of ILI. Nevertheless, the case number estimates provide a useful indicator of the trend in influenza activity and weekly data were extensively used in media reports. Although surveillance methods differ between countries, the approach of synthesising available data sources to produce an overall estimate of case numbers could be applied more widely to provide comparative data.

Hepatitis C and B testing in English prisons is low but increasing.

BACKGROUND: Prisons are important settings for blood-borne virus control because of the high prevalence of hepatitis C and B viral infections (HCV and HBV), and behaviours associated with transmission among prisoners. METHODS: Data from sentinel laboratories in England were used to identify testing for hepatitis C (anti-HCV) and hepatitis B [hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antigen (HBc)] among male and female prisoners between 2005 and 2008. RESULTS: Between 2005 and 2008, 10 723 prisoners from 39 prisons in England were tested for anti-HCV, anti-HBc and/or HBsAg. Overall, 24.2% prisoners tested positive for anti-HCV. Anti-HCV testing increased 47% over 4 years (P < 0.001), whilst the proportion testing positive decreased significantly from 26% in 2005 to 23% in 2008 (χ(2)= 10.0, df = 3, P = 0.030). In total, 13.9% people tested positive for anti-HBc. Of 5151 people tested for anti-HBc, 4433 were also tested for HBsAg; of these 2.4% were HBsAg positive. HBsAg testing increased 35% between 2005 and 2008, with no significant change in the proportion testing positive. Between 2005 and 2008, 2.4% (CI: 2.32-2.43%) of the prison population (24 prisons) were estimated to have been tested for anti-HCV. CONCLUSIONS: Although hepatitis testing has increased, only a small proportion of the prison population were tested. More testing is required to identify infected prisoners and refer them for appropriate treatment.

Variations in the epidemiology of primary, secondary and early latent syphilis, England and Wales: 1999 to 2008.

OBJECTIVE: To investigate factors associated with variations in diagnoses of primary, secondary and early latent syphilis in England and Wales. METHODS: Data were derived from two sources: diagnoses made in genitourinary medicine clinics reported on form KC60, and information collected through National Enhanced Syphilis Surveillance (NESS). Multinomial regression modelling was used for data analysis. RESULTS: Between 1999 and 2008, 12,021 NESS reports were received, 54% of KC60 reports. The dominant profile of the epidemic was one of white men who have sex with men aged 35-44, often co-infected with HIV, centred in larger cities. During this period, the proportion of primary cases increased over time, while the proportion of secondary cases fell. Primary cases exceeded secondary cases by 2004. The proportion of early latent cases remained relatively stable over time and tended to be lower than that of primary and secondary infection. Patients who attended because they had symptoms of infection, had been identified through partner notification, were HIV positive, and were UK born were more likely to present with primary or secondary infection than with early latent infection. A higher proportion of early latent cases were seen among patients who were Asian, had contacted sexual partners through saunas, bars and the internet, had untraceable partners, and had acquired infection in Manchester. CONCLUSIONS: The continuing syphilis epidemic indicates that control has only been partially effective, with ongoing transmission being sustained. Intensive and targeted efforts delivered locally are required to interrupt further transmission.

Integrating evidence based medicine into undergraduate medical education: combining online instruction with clinical clerkships.

BACKGROUND: Incorporation of evidence based medicine into the undergraduate curriculum varies from school to school. The purpose of this study was to determine if an online course in evidence based medicine run concurrently with the clinical clerkships in the 3rd year of undergraduate medical education provided effective instruction in evidence based medicine (EBM). DESCRIPTION: During the first 18 weeks of the 3rd year, students completed 6 online, didactic modules. Over the next 24 weeks, students developed questions independently from patients seen during clerkships and then retrieved and appraised relevant evidence. Online, faculty mentors reviewed student assignments submitted throughout the course to monitor progress. Mastery of the skills of EBM was assessed prior to and at the conclusion of the course using the Fresno test of competency. EVALUATION: Paired data were available from 139 students. Postcourse test scores (M= 77.7; 95% CI = 59-96.4) were significantly higher than precourse scores (M= 66.6; 95% CI = 46.5-86.7), p< .001. Paired evaluations demonstrated an average improvement of 11.1 +/- 20.0 points. All of the students submitted 4 independently derived questions and successfully retrieved and appraised evidence. CONCLUSIONS: Medical students successfully acquired and independently applied EBM skills following extended, online, faculty mentored instruction. This method of instruction provided uniform instruction across geographic sites and medical specialties and permitted efficient use of faculty time.

Investigation into the dissolution rate increase on storage of Wellbutrin SR 100 mg tablets.

The Food and Drug Administration (FDA) approved the New Drug Application for Wellbutrin sustained release (SR) 100 mg tablets on October 4, 1996. However, by 1998, the FDA expressed concern about the stability of this drug product based on an increase in the dissolution profile on storage. Data submitted in the annual report showed that this drug product could not meet the expiry of 18 months at the International Committee on Harmonization storage condition of 25 degrees C/60% relative humidity. The FDA mandated a 12-month expiry and GlaxoWellcome tightened this further by instituting an expiry of 9 months. The FDA also requested a long-term solution to the stability of Wellbutrin SR 100 mg tablets. Investigations via colloidal solutions revealed that the dissolution rate increase on storage occurred due to acid hydrolysis of the release controlling polymer. This drug product was successfully reformulated by slowing the initial dissolution rate and having an increased ratio of release controlling polymer to acid stabilizer. The reformulation used the same ingredients and manufacturing unit processes as the original formulation. The reformulated drug product was approved by the FDA on October 11, 2000 with an 18-month shelf-life. The shelf-life was extended to 36 months in an annual update to the FDA on December 1, 2005.

Fluorescent imaging of high-grade bladder cancer using a specific antagonist for chemokine receptor CXCR4.

We previously reported that the expression of CXC chemokine receptor-4 (CXCR4) was upregulated in invasive bladder cancers and that the small peptide T140 was a highly sensitive antagonist for CXCR4. In this study, we identified that CXCR4 expression was induced in high-grade superficial bladder tumors, including carcinoma in situ and invasive bladder tumors. To visualize the bladder cancer cells using urinary sediments from the patients and chemically induced mouse bladder cancer model, a novel fluorescent CXCR4 antagonist TY14003 was developed, that is a T140 derivative. TY14003 could label bladder cancer cell lines expressing CXCR4, whereas negative-control fluorescent peptides did not label them. When labeling urinary sediments from patients with invasive bladder cancer, positive-stained cells were identified in all patients with bladder cancer and positive urine cytology but not in controls. Although white blood cells in urine were also labeled with TY14003, they could be easily discriminated from urothelial cells by their shape and size. Finally, intravesical instillation of TY14003 into mouse bladder, using N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer model, demonstrated that fluorescent signals were detected in the focal areas of bladder of all mice examined at 12 weeks of BBN drinking by confocal microscopy and fluorescent endoscopy. On the contrary, all the normal bladders were found to be negative for TY14003 staining. In conclusion, these results indicate that TY14003 is a promising diagnostic tool to visualize small or flat high-grade superficial bladder cancer.

Structure-activity relationship study on artificial CXCR4 ligands possessing the cyclic pentapeptide scaffold: the exploration of amino acid residues of pentapeptides by substitutions of several aromatic amino acids.

Previously, downsizing of a 14-residue peptidic CXCR4 antagonist has led to the development of a highly potent CXCR4 antagonist [cyclo(-d-Tyr(1)-Arg(2)-Arg(3)-Nal(4)-Gly(5)-)]. In the present study, cyclic pentapeptide libraries that were designed by substitutions of several amino acids for d-Tyr(1) and Arg(2) in peptide were prepared and screened to evaluate binding activity for CXCR4. The above structure-activity relationship study led to the finding of several potent CXCR4 ligands.