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Originally motivated by the need for research reproducibility and data reuse, large-scale, open access information repositories have become key resources for training and testing of advanced machine learning applications in biomedical and clinical research. To be of value, such repositories must provide large, high-quality data sets, where quality is defined as minimising variance due to data collection protocols and data misrepresentations. Curation is the key to quality. We have constructed a large public access image repository, The Cancer Imaging Archive, dedicated to the promotion of open science to advance the global effort to diagnose and treat cancer. Drawing on this experience and our experience in applying machine learning techniques to the analysis of radiology and pathology image data, we will review the requirements placed on such information repositories by state-of-the-art machine learning applications and how these requirements can be met.

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Objectives: Precision medicine requires the measurement, quantification, and cataloging of medical characteristics to identify the most effective medical intervention. However, the amount of available data exceeds our current capacity to extract meaningful information. We examine the informatics needs to achieve precision medicine from the perspective of quantitative imaging and oncology. Methods: The National Cancer Institute (NCI) organized several workshops on the topic of medical imaging and precision medicine. The observations and recommendations are summarized herein. Results: Recommendations include: use of standards in data collection and clinical correlates to promote interoperability; data sharing and validation of imaging tools; clinician's feedback in all phases of research and development; use of open-source architecture to encourage reproducibility and reusability; use of challenges which simulate real-world situations to incentivize innovation; partnership with industry to facilitate commercialization; and education in academic communities regarding the challenges involved with translation of technology from the research domain to clinical utility and the benefits of doing so. Conclusions: This article provides a survey of the role and priorities for imaging informatics to help advance quantitative imaging in the era of precision medicine. While these recommendations were drawn from oncology, they are relevant and applicable to other clinical domains where imaging aids precision medicine.

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The Human Connectome Project (HCP) seeks to map the structural and functional connections between network elements in the human brain. Magnetoencephalography (MEG) provides a temporally rich source of information on brain network dynamics and represents one source of functional connectivity data to be provided by the HCP. High quality MEG data will be collected from 50 twin pairs both in the resting state and during performance of motor, working memory and language tasks. These data will be available to the general community. Additionally, using the cortical parcellation scheme common to all imaging modalities, the HCP will provide processing pipelines for calculating connection matrices as a function of time and frequency. Together with structural and functional data generated using magnetic resonance imaging methods, these data represent a unique opportunity to investigate brain network connectivity in a large cohort of normal adult human subjects. The analysis pipeline software and the dynamic connectivity matrices that it generates will all be made freely available to the research community.

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The Human Connectome Project (HCP) is an ambitious 5-year effort to characterize brain connectivity and function and their variability in healthy adults. This review summarizes the data acquisition plans being implemented by a consortium of HCP investigators who will study a population of 1200 subjects (twins and their non-twin siblings) using multiple imaging modalities along with extensive behavioral and genetic data. The imaging modalities will include diffusion imaging (dMRI), resting-state fMRI (R-fMRI), task-evoked fMRI (T-fMRI), T1- and T2-weighted MRI for structural and myelin mapping, plus combined magnetoencephalography and electroencephalography (MEG/EEG). Given the importance of obtaining the best possible data quality, we discuss the efforts underway during the first two years of the grant (Phase I) to refine and optimize many aspects of HCP data acquisition, including a new 7T scanner, a customized 3T scanner, and improved MR pulse sequences.

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SUMMARY: Few studies exist for bone densitometry of the whole foot. A phantom study demonstrated the sources of error and necessary controls for accurate quantitative computed tomography of the foot. A loss in bone mineral density (BMD) in the small foot bones may be an early indicator of diabetic foot complications. INTRODUCTION: Volumetric quantitative computed tomography (vQCT) facilitates the assessment of pedal bone osteopenia, which, in the presence of peripheral neuropathy, may well be an early sign of diabetic foot deformity. To date, sources and magnitudes of error in foot vQCT measurements have not been reported. METHODS: Foot phantoms were scanned using a 64-slice CT scanner. Energy (in kilovoltage peak), table height, phantom size and orientation, location of "bone" inserts, insert material, location of calibration phantom, and reconstruction kernel were systematically varied during scan acquisition. RESULTS: Energy (in kilovoltage peak) and distance from the isocenter (table height) resulted in relative attenuation changes from -5% to 22% and -5% to 0%, respectively, and average BMD changes from -0.9% to 0.0% and -1.1% to 0.3%, respectively, compared to a baseline 120-kVp scan performed at the isocenter. BMD compared to manufacturer-specified values ranged, on average, from -2.2% to 0.9%. Phantom size and location of bone-equivalent material inserts resulted in relative attenuation changes of -1.2% to 1.4% compared to the medium-sized phantom. CONCLUSION: This study demonstrated that variations in kilovoltage peak and table height can be controlled using a calibration phantom scanned at the same energy and height as a foot phantom; however, error due to soft tissue thickness and location of bones within a foot cannot be controlled using a calibration phantom alone.

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Iatrogenic transmission of transmissible spongiform encephalopathies (TSEs) has been demonstrated via surgical instruments and there is concern over the efficacy of conventional decontamination techniques used to reprocess reusable instruments. This paper describes the development of a novel cleaning method, 'electro-elution', to remove TSE disease-specific abnormal protein PrP(Sc) from the surface of stainless steel surgical instruments. The electro-elution process subjects the stainless steel instrument to an electrical current in the presence of an electrolytic buffer to remove protein deposits. Stainless steel discs were contaminated with infectious brain homogenate and subjected to a range of conditions to determine the ability of electro-elution to remove the deposits. To determine whether there was any residual PrP(Sc) remaining on the disc after electro-elution, a novel detection method, 'direct blotting', was also developed. Direct blotting utilizes a process of passive transfer of proteins directly from the surface of the instrument to a proteophilic membrane for detection. Our study shows that electro-elution has the ability to effectively remove, and possibly degrade, disease-associated PrP(Sc) from the surface of stainless steel surgical instruments.

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The CT Image Library (CTIL) of the Lung Screening Study (LSS) network of the National Lung Screening Trial (NLST) consists of up to three annual screens using CT imaging from each of 17,308 participants with a significant history of smoking but no evidence of cancer at trial enrollment (Fall 2002-Spring 2004). Screens performed at numerous medical centers associated with 10 LSS-NLST screening centers are deidentified of protected health information and delivered to the CTIL via DVD, external hard disk, or Internet/Virtual Private Network transmission. The collection will be completed in late 2006. The CTIL is of potential interest to clinical researchers and software developers of nodule detection algorithms. Its attractiveness lies in its very specific, well-defined patient population, scanned via a common CT protocol, and in its collection of evenly spaced serial screens. In this work, we describe the technical details of the CTIL collection process from screening center retrieval through library storage.

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While developing a new protein removal test for the quality control of surgical instrument cleaning, it was noted that alcohol firmly binds blood to stainless steel. Creutzfeldt-Jacob disease is one of the transmissible spongiform encephalopathies (TSE) that has been transmitted between humans and chimpanzees by electroencephalogram electrodes, previously 'sterilized' using ethanol and formaldehyde. Although ethanol has a bactericidal action, it also binds protein to metal. Prion proteins found in TSE are thought to be the causal agents of spongiform disease and it is likely that these proteins are also bound to the stainless steel of surgical instruments by alcohols. Where spongiform disease is a possibility, alcohol, and probably formaldehyde, should not be used to decontaminate neurosurgical instruments.

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As part of ongoing studies into the use of plant expression systems for making human therapeutic proteins, we have successfully expressed the major glycoprotein, gB, of human cytomegalovirus (HCMV) in transgenic tobacco plants. Viral glycoprotein was detectable in the protein extracts of mature tobacco seeds using neutralizing and non-neutralizing monoclonal antibodies specific for gB. Although several mammalian proteins have been expressed in tobacco, localization of these proteins in transgenic tobacco tissue has not been extensively examined. The objective of this study was to identify the site(s) of recombinant gB deposition in mature tobacco seeds. Using immunogold labelling and electron microscopy, we found specific labelling for gB in the endosperm of transgenic seeds, with gB localized almost exclusively in protein storage vesicles (PSV). This occurred in seeds that were freshly harvested and in seeds that had been stored for several months. These data indicate that gB behaves like a plant storage protein when expressed in tobacco seeds, and provide further support for the suitability of plants for producing recombinant proteins of potential clinical relevance.

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OBJECTIVE: To report a case of symptomatic bradycardia and hypotension that resulted from the therapeutic use of citalopram and to review any previous reports in the literature, from the manufacturer, and the Australian Drug Reaction Advisory Committee (ADRAC). CASE SUMMARY: A 60-year-old white woman who had been taking citalopram 20 mg/d for two weeks presented to the hospital with a heart rate of 39 beats/min, mild hypotension (systolic BP 105 mm Hg), and a normal electrocardiogram (QTc < 440 msec), following a presyncopal episode. The patient was admitted for cardiac monitoring, and citalopram was discontinued. The bradycardia and hypotension resolved in the 48-hour period following cessation of citalopram. No other medical or pharmacologic cause was found for the adverse drug reaction. DISCUSSION: Bradycardia has been reported rarely with citalopram in therapeutic doses, but this is the first detailed case with a dose of only 20 mg. The manufacturer reports bradycardia as an infrequent adverse effect (0.1-1%) of citalopram. There have been no reports to ADRAC or to the manufacturer in postmarketing surveillance. There is a case report of asymptomatic bradycardia in a patient whose dose was increased to 40 mg. In the case reported here, there was no QTc prolongation consistent with previous reports. The sinus bradycardia reported more often with therapeutic doses would appear to be distinct to QT abnormalities seen with citalopram overdose. CONCLUSIONS: Citalopram should be used with care in the elderly and in persons with a history of heart disease. Heart rate and blood pressure should be monitored in the first week of therapy and when doses are modified.

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Plant seeds offer unique opportunities for the production and delivery of oral subunit vaccines. We have used the immunodominant glycoprotein B complex of human cytomegalovirus (HCMV), introduced into tobacco plants, as a model system for studying the merit of this promising approach. Given the advantages of expressing proteins in seeds, a novel expression vector was developed incorporating regulatory sequences of glutelin, the major rice seed storage protein, to direct synthesis of recombinant glycoprotein B. Analysis of genomic DNA of 28 selected tobacco transformants by PCR amplification showed that 71% harboured the gB cDNA, a finding further documented by Southern blotting. Specific immunoassays of protein extracts from seeds of positive plants showed that all were producing antigenic glycoprotein B at levels ranging from 70-146 ng/mg extracted protein. In addition, similarity with native glycoprotein B produced in HCMV-infected cells was also demonstrated by inhibition of immunofluorescence on HCMV-infected human fibroblasts. These data are the first to report the expression of an immunodominant antigen of HCMV in plant tissues, indicating the fidelity with which this very large heterologous viral glycoprotein can be synthesized in this model system.

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Several conflicting theories have been proposed to explain the development of oedema. Pulse reverse osmosis (PRO) suggests that oedema occurs when the mean pulse capillary pressure exceeds the osmotic gradient between the plasma and the interstitial fluid. In order to test this concept mean arterial blood pressures and colloid osmotic pressures were taken in a group of healthy volunteers, a group of patients with bilateral ankle oedema and a group of treated hypertensives. Patients with oedema were found to have colloid osmotic pressures (COP's) which were significantly less than those of the healthy volunteers (p <0.001) and the treated hypertensives (p <0.001). The results support the oedema mechanism proposed by PRO and indicate that the relationship between blood pressure and COP may be a useful biochemical marker of oedema and its treatment. Further study is required to numerically quantify this relationship.

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The decision to use Digital Imaging and Communications in Medicine (DICOM), Health Level 7 (HL7), a common object broker such as the Common Object Request Brokering Architecture (CORBA) or ActiveX (Microsoft Corp, Redmond, WA) or any other protocol for the transfer of DICOM data depends on the requirements of a particular implementation. The selection of protocol is independent of the information model. Our goal as message standards developers is to design a data interchange infrastructure that will faithfully convey the computer-based patient record and make it available to authorized health care providers when and where it is needed for patient care. DICOM accurately and expressively represents the clinically significant properties of images and the semantics of image-related information. The DICOM data model is small and well-defined. The model can be expressed in Standard Generalized Markup Language (SGML) or Object Management Group Interface Definition Language or other common syntax-and can be implemented using any reliable communications protocol. Therefore our opinion is that the DICOM semantic data model should serve as the basis for a logically equivalent set of specifications in HL7, CORBA, ActiveX, and SGML for the interchange of biomedical images and image-related information.

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The Digital Imaging and Communications in Medicine (DICOM) Standard specifies a non-proprietary data interchange protocol, digital image format, and file structure for biomedical images and image-related information. The fundamental concepts of the DICOM message protocol, services, and information objects are reviewed as background for a detailed discussion of the functionality of DICOM; the innovations and limitations of the Standard; and the impact of various DICOM features on information system users. DICOM addresses five general application areas: (1) network image management, (2) network image interpretation management, (3) network print management, (4) imaging procedure management, (5) off-line storage media management. DICOM is a complete specification of the elements required to achieve a practical level of automatic interoperability between biomedical imaging computer systems--from application layer to bit-stream encoding. The Standard is being extended and expanded in modular fashion to support new applications and incorporate new technology. An interface to other Information Systems provides for shared management of patient, procedure, and results information related to images. A Conformance Statement template enables a knowledgeable user to determine if interoperability between two implementations is possible. Knowledge of DICOM's benefits and realistic understanding of its limitations enable one to use the Standard effectively as the basis for a long term implementation strategy for image management and communications systems.

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Pulse reverse osmosis (1) is a new theory of fluid balance and exchange which suggests that the mean blood pressure and osmotic gradient control fluid balance and that the pulse controls fluid exchange. In vitro testing has confirmed some of the physico chemical principles underlying the theory (2). The hypothesis suggests a relationship between mean capillary blood pressure and osmotic gradient. Imbalance in this relationship can be related to the development of hypertension, hypotension, oedema and shock. In an attempt to test this concept mean blood pressures and colloid osmotic pressures were measured and compared in a group of 50 healthy human volunteers. The results suggest a curvilinear correlation between the mean blood pressure and the COP.

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