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The value of a coronary artery disease prediction algorithm, the Framingham risk score (score), for detecting coronary artery calcium (CAC) was examined in 385 men and 472 women, aged 29 to 43 years. Scores were compared in subjects with and without CAC and were also used to predict presence of CAC. Receiver-operating characteristic curves were computed to compare different prediction models. The score model was compared with age only, natural logarithm of body mass index (lnBMI) only, and score plus lnBMI models. CAC was detected in 30% of men and 16% of women. The mean score was significantly higher in men and women with CAC. For every 2-point increase in the score, the odds of CAC increased by 30% in women and 20% in men. Significant associations between CAC status and risk factors were observed for age in women, and high- density lipoprotein cholesterol and blood pressure in men and women. The area under the receiver-operating characteristic curve for the score was 0.67 and 0.57 for women and men, respectively. When lnBMI was added to the score model, the area increased to 0.76 in women (lnBMI p <0.0001, score p <0.005). For men, the area increased from 0.57 to 0.67, and the score was no longer significant (p >0.60) in the model with lnBMI (p <0.0001). Score predicts CAC in asymptomatic young adults. Inclusion of lnBMI in the score model adds significantly to the prediction of CAC in women and men. The lnBMI model has a greater predictive value than the score in this young population. [ABSTRACT FROM AUTHOR]

Synonymous recoding of RNA virus genomes is a promising approach for generating attenuated viruses to use as vaccines. Problematically, recoding typically hinders virus growth, but this may be rectified using CpG dinucleotide enrichment. CpGs are recognised by cellular zinc-finger antiviral protein (ZAP), and so in principle, removing ZAP sensing from a virus propagation system will reverse attenuation of a CpG-enriched virus, enabling high titre yield of a vaccine virus. We tested this using a vaccine strain of influenza A virus (IAV) engineered for increased CpG content in genome segment 1. Virus attenuation was mediated by the short isoform of ZAP, correlated with the number of CpGs added, and was enacted via turnover of viral transcripts. The CpG-enriched virus was strongly attenuated in mice, yet conveyed protection from a potentially lethal challenge dose of wildtype virus. Importantly for vaccine development, CpG-enriched viruses were genetically stable during serial passage. Unexpectedly, in both MDCK cells and embryonated hens' eggs that are used to propagate live attenuated influenza vaccines, the ZAP-sensitive virus was fully replication competent. Thus, ZAP-sensitive CpG enriched viruses that are defective in human systems can yield high titre in vaccine propagation systems, providing a realistic, economically viable platform to augment existing live attenuated vaccines., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sharp et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Bovine Herpesvirus Type 1 (BoHV-1) infection causes infectious bovine rhinotracheitis and genital disease in cattle, with significant economic and welfare impacts. However, the role of cellular host factors during viral replication remains poorly characterised. A previously performed genome-wide CRISPR knockout screen identified pro- and antiviral host factors acting during BoHV-1 replication. Herein we validate a pro-viral role for a candidate from this screen: the cellular protein tetracopeptide repeat protein 4 (TTC4). We show that TTC4 transcript production is upregulated during BoHV-1 infection. Depletion of TTC4 protein impairs BoHV-1 protein production but does not reduce production of infectious virions, whereas overexpression of exogenous TTC4 results in a significant increase in production of infectious BoHV-1 virions. TTC4 itself is poorly characterized (especially in the context of virus infection), but is a known co-chaperone of heat shock protein 90 (HSP90). HSP90 has a well-characterized pro-viral role during the replication of diverse herpesviruses, and we therefore hypothesized that HSP90 is also pro-viral for BoHV-1. Drug-mediated inhibition of HSP90 using geldanamycin at sub-cytotoxic concentrations inhibited both BoHV-1 protein production and viral genome replication, indicating a pro-viral role for HSP90 during BoHV-1 infection. Our data demonstrates pro-viral roles for both TTC4 and HSP90 during BoHV-1 replication; possibly, interactions between these two proteins are required for optimal BoHV-1 replication, or the two proteins may have independent pro-viral roles., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Despite advances in healthcare, cardiovascular disease (CVD) remains the leading cause of death in the United States. Elevated levels of plasma cholesterol are highly predictive of CVD and stroke and are the principal driver of atherosclerosis. Unfortunately, current cholesterol lowering agents, such as statins, are not known to reverse atherosclerotic disease once it has been established. In preclinical models, agonists of nuclear receptor, LXR, have been shown to reduce and reverse atherosclerosis. Phytosterols are bioactive non-cholesterol sterols that act as LXR agonists and regulate cholesterol metabolism and transport. We hypothesized that stigmasterol would act as an LXR agonist and alter intestinal cholesterol secretion to promote cholesterol elimination. Mice were fed a control diet, or a diet supplemented with stigmasterol (0.3% w/w) or T0901317 (0.015% w/w), a known LXR agonist. In this experiment we analyzed the sterol content of bile, intestinal perfusate, plasma, and feces. Additionally, the liver and small intestine were analyzed for relative levels of transcripts known to be regulated by LXR. We observed that T0901317 robustly promoted cholesterol elimination and acted as a strong LXR agonist. Stigmasterol promoted transintestinal cholesterol secretion through an LXR-independent pathway., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In many regions of the world, urban water systems will need to transition into fundamentally different forms to address current stressors and meet impending challenges-faster innovation will need to be part of these transitions. To assess the innovation deficit in urban water organizations and to identify means for supporting innovation, we surveyed wastewater utility managers in California. Our results reveal insights about the attitudes towards innovation among decision makers, and how perceptions at the level of individual managers might create disincentives for experimentation. Although managers reported feeling relatively unhindered organizationally, they also spend less time on innovation than they feel they should. The most frequently reported barriers to innovation included cost and financing; risk and risk aversion; and regulatory compliance. Considering these results in the context of prior research on innovation systems, we conclude that collective action may be required to address underinvestment in innovation.

Rationale and Objectives: Although a checklist has been recommended for preventing satisfaction of search (SOS) errors, a previous research study did not demonstrate that benefit. However, observers in that study had to turn away from the image display to use the checklist. The current study tested a vocalized checklist to avoid this constraint., Materials and Methods: A total of 64 chest computed radiographs, half containing various "test" abnormalities, were read twice by 20 radiologists, once with and once without the addition of a simulated pulmonary nodule. Readers used a vocalized checklist-directing search. Receiver operating characteristic (ROC) detection accuracy and decision thresholds were analyzed to study the effects of adding the nodule on detecting the test abnormalities., Results: Adding nodules induced a substantial reluctance to report the other abnormalities (P < 0.001), as had been the case in the most recent study of the SOS effect in radiography., Conclusions: The vocalized checklist did not reduce nor eliminate the SOS effect on readiness to report further abnormalities. Although useful for organizing search and reporting, particularly among students, a vocalized checklist does not prevent SOS effects., (Copyright © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: Two decades have passed since the publication of laboratory studies of satisfaction of search (SOS) in chest radiography. Those studies were performed using film. The current investigation tests for SOS effects in computed radiography of the chest., Methods: Sixty-four chest computed radiographs half demonstrating various "test" abnormalities were read twice by 20 radiologists, once with and once without the addition of a simulated pulmonary nodule. Receiver-operating characteristic detection accuracy and decision thresholds were analyzed to study the effects of adding the nodule on detecting the test abnormalities. Results of previous studies were reanalyzed using similar modern techniques., Results: In the present study, adding nodules did not influence detection accuracy for the other abnormalities (P = .93), but did induce a reluctance to report them (P < .001). Adding nodules did not affect inspection time (P = .58) so the reluctance to report was not associated with reduced search. Reanalysis revealed a similar decision threshold shift that had not been recognized in the early studies of SOS in chest radiography (P < .01) in addition to reduced detection accuracy (P < .01)., Conclusions: The nature of SOS in chest radiography has changed, but it is not clear why., Advances in Knowledge: SOS may be changing as a function of changes in radiology education and practice., (Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.)

Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of metabolism to be identified through population screening. Early identification and treatment prevent the most dramatic clinical sequelae of the disorder, but new neurodevelopmental and psychological problems have emerged in individuals treated from birth. The additional unanticipated recognition of a toxic effect of elevated maternal phenylalanine on fetal development has added to a general call in the field for treatment for life. Two major conferences sponsored by the National Institutes of Health held >10 years apart reviewed the state of knowledge in the field of phenylalanine hydroxylase deficiency, but there are no generally accepted recommendations for therapy. The purpose of this guideline is to review the strength of the medical literature relative to the treatment of phenylalanine hydroxylase deficiency and to develop recommendations for diagnosis and therapy of this disorder. Evidence review from the original National Institutes of Health consensus conference and a recent update by the Agency for Healthcare Research and Quality was used to address key questions in the diagnosis and treatment of phenylalanine hydroxylase deficiency by a working group established by the American College of Medical Genetics and Genomics. The group met by phone and in person over the course of a year to review these reports, develop recommendations, and identify key gaps in our knowledge of this disorder. Above all, treatment of phenylalanine hydroxylase deficiency must be life long, with a goal of maintaining blood phenylalanine in the range of 120-360 µmol/l. Treatment has predominantly been dietary manipulation, and use of low protein and phenylalanine medical foods is likely to remain a major component of therapy for the immediate future. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication (sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase) and others under development. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medications and alternative medical foods available to tailor therapy. The primary goal of therapy should be to lower blood phenylalanine, and any interventions, including medications, or combination of therapies that help to achieve that goal in an individual, without other negative consequences, should be considered appropriate therapy. Significant evidence gaps remain in our understanding of the optimum therapies for phenylalanine hydroxylase deficiency, nonphenylalanine effects of these therapies, and long-term sequelae of even well-treated disease in children and adults.

As medical genetics has progressed from a descriptive entity to one focused on the functional relationship between genes and clinical disorders, emphasis has been placed on genomics. Genomics, a subelement of genetics, is the study of the genome, the sum total of all the genes of an organism. The human genome, which is contained in the 23 pairs of nuclear chromosomes and in the mitochondrial DNA of each cell, comprises >6 billion nucleotides of genetic code. There are some 23,000 protein-coding genes, a surprisingly small fraction of the total genetic material, with the remainder composed of noncoding DNA, regulatory sequences, and introns. The Human Genome Project, launched in 1990, produced a draft of the genome in 2001 and then a finished sequence in 2003, on the 50th anniversary of the initial publication of Watson and Crick's paper on the double-helical structure of DNA. Since then, this mass of genetic information has been translated at an ever-increasing pace into useable knowledge applicable to clinical medicine. The recent advent of massively parallel DNA sequencing (also known as shotgun, high-throughput, and next-generation sequencing) has brought whole-genome analysis into the clinic for the first time, and most of the current applications are directed at children with congenital conditions that are undiagnosable by using standard genetic tests for single-gene disorders. Thus, pediatricians must become familiar with this technology, what it can and cannot offer, and its technical and ethical challenges. Here, we address the concepts of human genomic analysis and its clinical applicability for primary care providers.

Interaction between institutional change and technological change poses important constraints on transitions of urban water systems to a state that can meet future needs. Research on urban water and other technology-dependent systems provides insights that are valuable to technology researchers interested in assuring that their efforts will have an impact. In the context of research on institutional change, innovation is the development, application, diffusion, and utilization of new knowledge and technology. This definition is intentionally inclusive: technological innovation will play a key role in reinvention of urban water systems, but is only part of what is necessary. Innovation usually depends on context, such that major changes to infrastructure include not only the technological inventions that drive greater efficiencies and physical transformations of water treatment and delivery systems, but also the political, cultural, social, and economic factors that hinder and enable such changes. On the basis of past and present changes in urban water systems, institutional innovation will be of similar importance to technological innovation in urban water reinvention. To solve current urban water infrastructure challenges, technology-focused researchers need to recognize the intertwined nature of technologies and institutions and the social systems that control change.

For years, clinicians have offered gene-by-gene carrier screening to patients and couples considering future pregnancy or those with an ongoing pregnancy early in gestation. Examples include ethnic-specific screening offered to Ashkenazi Jewish patients and panethnic screening for cystic fibrosis and spinal muscular atrophy. Next-generation sequencing methods now available permit screening for many more disorders with high fidelity, quick turnaround time, and lower costs. However, instituting these technologies carries with it perils that must be addressed. The basis for the selection of disorders on expanded carrier screening panels should be disclosed. The information provided about disorders with mild phenotypes, variable expression, low penetrance, and/or characterized by an adult onset should be complete and transparent, allowing patients to opt out of receiving these test results. Patients also must be made aware of the concept of residual risk following negative test results. Laboratories have a duty to participate in and facilitate this information transfer.

Noninvasive assessment of the fetal genome is now possible using next-generation sequencing technologies. The isolation of fetal DNA fragments from maternal circulation in sufficient quantity and sizes, together with proprietary bioinformatics tools, now allows patients the option of noninvasive fetal aneuploidy screening. However, obstetric care providers must become familiar with the advantages and disadvantages of the utilization of this approach as analysis of cell-free fetal DNA moves into clinical practice. Once informed, clinicians can provide efficient pretest and posttest counseling with the goal of avoiding patient harm. It is in the public's best interest that test results contain key elements and that laboratories adhere to established quality control and proficiency testing standards. The analysis of cell-free fetal DNA in maternal circulation for fetal aneuploidy screening is likely the first of major steps toward the eventual application of whole fetal genome/whole fetal exome sequencing.

Rationale and Objectives: We tested whether satisfaction of search (SOS) effects that occur in computed tomography (CT) examination of the chest on detection of native abnormalities are produced by the addition of simulated pulmonary nodules., Materials and Methods: Two experiments were conducted. In the first experiment, 70 CT examinations, half that demonstrated diverse, subtle abnormalities and half that demonstrated no native lesions, were read by 18 radiology residents and fellows under two experimental conditions: presented with and without pulmonary nodules. In a second experiment, many of the examinations were replaced to include more salient native abnormalities. This set was read by 14 additional radiology residents and fellows. In both experiments, detection of the natural abnormalities was studied. Receiver operating characteristic (ROC) curve areas for each reader-treatment combination were estimated using empirical and proper ROC models. Additional analyses focused on decision thresholds and visual search time on abnormality-free CT slice ranges. Institutional review board approval and informed consent from 32 participants were obtained., Results: Observers more often missed diverse native abnormalities when pulmonary nodules were added, but also made fewer false-positive responses. There was no change in ROC area, but decision criteria grew more conservative. The SOS effect on decision thresholds was accompanied by a reduction in search time on abnormality-free CT slice ranges., Conclusion: The SOS effect in CT examination of the chest is similar to that found in contrast examination of the abdomen, involving induced visual neglect., (Copyright © 2013 AUR. Published by Elsevier Inc. All rights reserved.)

Objectives In three experiments, we studied the detection of multiple abnormality types using the satisfaction of search (SOS) paradigm, the provision of a computer-aided detection (CAD) of pulmonary nodules and a focused nodule detection task. Methods 51 chest CT examinations (24 that demonstrated subtle pulmonary nodules and 27 that demonstrated no pulmonary nodules) were read by 15 radiology residents and fellows under two experimental conditions: (1) when there were no other abnormalities present except test abnormalities in the exams (non-SOS condition), and (2) when other abnormalities were present in the exams (SOS condition). Trials from the two conditions were intermixed. Readers were invited to return for two sessions: one in which the SOS condition was repeated with a simulated CAD; another in which only the non-SOS condition was presented. Detection accuracy was measured using receiver operating characteristic (ROC) analysis. Results An SOS effect (reduced detection accuracy for the test nodules in the presence of the diverse added abnormalities) was not found. Average accuracy was much higher when the CAD prompt was provided, without cost in the detection of the added abnormalities. Accuracy for detecting nodules appearing without intermixed SOS trials was also substantially improved. Conclusions CT interpretation was highly task dependent. Nodule detection was poor in the general search task. Therefore, CAD may offer a greater performance improvement than demonstrated in experiments assessing CAD using focused search. The absence of SOS may be due to limited nodule detection even without other abnormalities. Advances in knowledge CAD prompts of nodules increase the detection accuracy of nodules and decrease the time to detection-without impairing the detection accuracy-of non-nodule abnormalities.

Objective: To implement a 6-month quality improvement project in 15 primary care pediatric practices to improve short-term newborn screening (NBS) follow-up., Methods: At the start of the project, each practice completed a survey to evaluate office systems related to NBS and completed a chart audit. Practice teams were provided information about NBS and trained in quality-improvement methods, and then implemented changes to improve care. Monthly chart audits over a 6-month period were completed to assess change., Results: At baseline, almost half of practices completed assessment of infants for NBS; after 6 months, 80% of practices completed assessment of all infants. Only 2 practices documented all in-range results and shared them with parents at baseline; by completion, 10 of 15 practices documented and shared in-range results for ≥ 70% of infants. Use of the American College of Medical Genetics ACTion sheets, a decision support tool, increased from 1 of 15 practices at baseline to 7 of 15 at completion., Conclusions: Practices were successful in improving NBS processes, including assessment, documentation, and communication with families. Providers perceived no increase in provider time at first visit, 2- to 4-week visit, or during first contact with the family of an infant with an out-of-range result after implementation of improved processes. Primary care practices increased their use of decision support tools after the project.

Objectives: Over the last 20 years a number of small trials have reported that spironolactone effectively prevents acute mountain sickness (AMS), but to date there have been no large randomized trials investigating the efficacy of spironolactone in prevention of AMS. Hence, a prospective, double-blind, randomized, placebo-controlled trial was conducted to evaluate the efficacy of spironolactone in the prevention of AMS., Methods: Participants were sampled from a diverse population of western trekkers recruited at 4300 m on the Mount Everest base camp approach (Nepal side) en route to the study endpoint at 5000 m. Three hundred and eleven healthy trekkers were enrolled, and 251 completed the trial from October to November 2007. Participants were randomly assigned to receive at least 3 doses of spironolactone 50 mg BID, acetazolamide 250 mg BID, or visually matched placebo. A Lake Louise AMS Score of 3 or more, together with the presence of headache and 1 other symptom, was used to evaluate the incidence and severity of AMS. Secondary outcome measures were blood oxygen content and the incidence and severity of high altitude headache (HAH)., Results: Acetazolamide was more effective than spironolactone in preventing AMS (OR = 0.28, 95% CI 0.12-0.60, p < 0.01). Spironolactone was not significantly different from placebo in the prevention of AMS. AMS incidence for placebo was 20.3%, acetazolamide 10.5%, and spironolactone 29.4%. Oxygen saturation was also significantly increased in the acetazolamide group (83% ± 0.04) vs spironolactone group (80% ± 0.05, p < 0.01)., Conclusions: Spironolactone (50 mg BID) was ineffective in comparison to acetazolamide (250 mg BID) in the prevention of AMS in partially acclimatized western trekkers ascending to 5000 m in the Nepali Himalaya., (Copyright © 2011 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Recent state-of-the-art computed tomography and improved three-dimensional (3-D) postprocessing techniques have revolutionized the capability of visualizing airway pathology, offering physicians an advanced view of pathology and allowing for appropriate management planning. This article is a comprehensive review of trachea and main bronchi imaging, with emphasis on the dynamic airway anatomy, and a discussion of a wide variety of diseases including, but not limited to, congenital large airway abnormalities, tracheobronchial stenoses, benign and malignant neoplasms and tracheobronchomalacia. The importance of multiplanar reconstruction, 3-D reconstruction and incorporation of dynamic imaging for non-invasive evaluation of the large airways is stressed.

Objective: The 1983 US Orphan Drug Act established a process through which promising therapies are designated as orphan products and, later, with satisfactory safety and efficacy data, receive marketing approval and fiscal incentives. We examined accomplishments in drug development for inborn errors of metabolism (IEMs)., Methods: Food and Drug Administration data were used to identify orphan product designations and approvals for IEMs, and the trends for the past 26 years were summarized. Individual clinical development times (CDTs) from filing investigational new drug application to marketing approval were determined., Results: We examined 1956 orphan product designations from 1983 through 2008 and found 93 (4.8%) for IEMs. Of those, 24 (25.8%) received marketing approval. This proportion of approval was significantly (P = .036) higher than that for non-IEM orphan products (17%). Among the IEM products, disorders of complex molecules received the most designations and approvals (61 and 11, respectively). Among the subgroups, lysosomal storage diseases received the most designations and approvals (43 and 9, respectively), whereas mitochondrial diseases (other than fatty acid oxidation disorders) received 7 designations with no approvals. We then examined the CDTs for the approved IEM products and found a median of 6.4 years (range: 2.6-25.1 years). Biological products had significantly shorter CDTs than drugs (mean: 4.6 vs 11.0 years; P = .003)., Conclusion: For 26 years, the Orphan Drug Act has generated new therapies for IEMs. Why some IEMs have motivated successful drug development and others have not remains enigmatic; yet the needs of IEM patients without treatment are a certainty.

Rationale and Objectives: Computer-aided diagnosis (CAD) has been developed to ensure that the radiologist considers suspect focal opacities that may represent cancer in chest radiography. Although CAD was not developed to counteract the satisfaction of search (SOS) effect, it may be an effective intervention to do so. The objective of this study is to determine whether an idealized CAD can reduce SOS effects in chest radiography., Materials and Methods: Fifty-seven chest radiographs, half of which demonstrated diverse, native abnormalities were read twice by 16 observers, once with and once without the addition of a simulated pulmonary nodule. Simulated CAD prompts were provided during the interpretation, which unerringly pointed to the added simulated nodule. Area under the ROC curve for detecting the native abnormalities was estimated for each observer in each treatment condition. In addition to testing for the SOS effect in the presence of CAD prompts, results were compared to those of a previous SOS study., Results: Significantly more nodules were reported in the SOS with CAD experiment than in the original SOS experiment (49 versus 43, P < .01). An SOS effect was found even when CAD prompts were provided; ROC areas for detecting native abnormalities were reduced with added nodules [0.68 versus 0.65, P (one-tailed) < .05]. Comparison of the current experiment with CAD and the previous SOS experiments failed to show a significant difference of the magnitude of the SOS effect (P = .52). The threshold for reporting was more conservative with CAD prompts than in SOS studies (P = .052)., Conclusion: Our results indicate that the CAD prompts, even those that always point to their target lesion without false-positive error, fail to counteract SOS in chest radiography. The stricter decision thresholds with CAD prompts may indicate less visual search for native abnormalities.

This article reviews the pathological classification of cardiac and pericardial neoplasms, the incidence of the various tumor types, and the role of CT and MRI, including their major differences and clinical impact on patient management.

Rationale and Objectives: Image perception studies have been difficult to perform using clinical images because of the problems associated with obtaining proven abnormalities and appropriate normal controls. The objective of this research was to develop and evaluate interactive software that allows the seamless removal, archiving and insertion of abnormal areas from computed tomography (CT) lung image sets for use in image perception research., Materials and Methods: The software tools for removing, archiving, and adding lesions are described in detail. The efficacy of the software to remove abnormal areas of lung CT studies was evaluated by having radiologists select the one altered image from a display of four. The software for adding lesions was evaluated by having radiologists classify displayed CT slices with lesions as real or artificial along with their confidence level., Results: Observers could not reliably detect when images had been altered by the software. In the lesion-removal experiment, the observers correctly identified the altered display in only 15.8 +/- 2.8 of 56 sets. In the lesion-add experiment, the observers correctly identified the artificially placed lesions in 38.2 +/- 3.9 of 77 sets. The frequency distribution of the correct responses did not differ from that expected from chance selection., Conclusions: The results from both of these experiments demonstrate that radiologists could not distinguish between original and altered images. We conclude that this software can be used with volumetric CT lung images for creating normal control and target data sets for medical image perception research.

The measurement of parameters relating to the assessment of cardiac function and morphology are critically important prognostic determinates in patients with known or suspected cardiac disease, such as coronary artery disease and myocardial infarction. Similarly, the measurement of indices, such as ejection fraction and myocardial mass, are key in assessing the efficacy of therapy in patients with valvular, coronary artery and intrinsic myocardial diseases. Electron-beam computed tomography has been proven to be a reliable and accurate modality for measuring a host of parameters relating to cardiac function. This article reviews the unique technologic design of the electron-beam computed tomography scanner and specifically addresses how this technology has enabled electron-beam computed tomography to become the gold standard for the quantification of cardiac function.

We report a case of group F streptococcal pericarditis, the source of which was found to be an esophagomediastinal fistula arising from a midesophageal diverticulum. The patient presented subacutely and had no preexisting symptoms of esophageal disease. Antibiotic therapy, surgical drainage, pericardiectomy, and esophageal myotomy led to a successful outcome.

Coronary artery disease (CAD) is the number one killer of adults in the United States, claiming one-half million deaths annually. Early detection and prevention strategies clearly remain a top priority for health care providers in order to reduce the high mortality rate of heart disease. As an unequivocal reflection of arteriosclerosis, coronary arterial calcium (CAC) may provide a means to qualitatively assess the overall disease severity and likewise serve as a means to assess risk for CHD. It is known that patients with heavy calcium burdens have more advanced CAD, a concomitantly a higher likelihood of coronary stenoses, and a concomitant higher risk for acute cardiac events. Computed tomography has been shown to be an accurate, non-invasive method to quantify coronary calcification burden in patients. Evidence shows that calcium measurements by CT correlate well with histological plaque analyses, and that CAC measurements accurately reflect disease severity and can be useful to assess individual risk for CHD. The purpose of this article is to summarize the currently available evidence that has attempted to validate CAC screening as a screening exam and risk predictor for coronary heart disease.

As an unequivocal biomarker for arteriosclerosis, the presence of coronary calcium serves as a qualitative reflection of the severity of coronary artery disease (CAD). Greater calcium burdens correlate with more advanced disease, a higher likelihood of coronary stenoses, and a higher risk for coronary heart disease (CHD). Empirically, the quantification of coronary calcium not only provides an accurate reflection of disease severity, but also has great potential as a screening tool for CHD. Computed tomography (CT) has been shown to be capable of providing accurate, noninvasive measurements of coronary calcification. Evidence shows that calcium measurements by CT correlate well with histological plaque analyses, and that calcium burdens accurately reflect disease severity and can be used to assess individual risk for CHD. The purpose of this review article is to examine the accumulated evidence that has attempted to validate CT as a diagnostic tool for CAD and as a screening exam for CHD., (Copyright 2004 Wiley-Liss, Inc.)

Purpose: To compare coronary artery calcium scores from a multi-detector row helical computed tomographic (CT) scanner with those from an electron-beam CT scanner, with emphasis on subjects with calcium scores less than 400., Materials and Methods: Seventy-eight asymptomatic subjects (37 women, 41 men; age range, 39-78 years; mean age, 54.2 years) underwent multi-detector row CT and electron-beam CT. Volume and Agatston scores were calculated with a workstation. Statistical analyses included assessment of association between calcium scores from two scanners, calculation of percent absolute difference to assess score variability between scanners, equivalence analysis, construction of Bland-Altman plots to assess agreement between scores, and assessment of changes in score grouping and risk criteria based on score differences between scanners., Results: Electron-beam CT calcium scores were higher than multi-detector row CT scores. Linear association between calcium scores obtained from paired scans was significant (r = 0.96-0.99, P <.001). Mean percent absolute differences were 67.9% and 65.0% for volume and Agatston scores, respectively (48.6% and 46.3% for corresponding natural log-transformed scores). In subjects with a score of 11 or greater, mean percent absolute differences between electron-beam CT and multi-detector row CT scores ranged from 15% to 30% (<10% for natural log-transformed calcium scores). With a 20% equivalence limit, calcium scores from the two scanners were statistically equivalent (P <.05). Score grouping would have been subject to change in 12 (11 increased and one decreased; six with scores of 11 or greater), and possible risk management decisions would have been subject to change in eight (16%) of 51 subjects who underwent electron-beam CT versus multi-detector row CT scanning., Conclusion: Multi-detector row CT appears to be comparable to electron-beam CT for coronary calcification screening, except in subjects with a calcium score less than 11., (Copyright RSNA, 2004)

Purpose: To determine whether differences in body mass index (BMI) and image section levels representing the proximal through the distal sections of the heart are associated with attenuation differences in images of calcium phantoms scanned during computed tomographic (CT) imaging of study subjects., Materials and Methods: Mean attenuation values for three calcium phantoms (each with a different calcium hydroxyapatite concentration), as measured at each of four different image section levels, were obtained for 691 participants in the Muscatine CT Vascular Calcium Study. The subjects were grouped according to sex-specific BMI quartiles, and the degree of attenuation in each phantom was investigated as a function of image section level and BMI quartile. Spearman rank order correlation coefficients and one-, two-, and three-factor repeated-measures analysis of variance were used to examine the association between section level and BMI and the mean phantom attenuations., Results: Attenuation was, for the most part, significantly associated with both section level (P <.005) and BMI quartile (P <.0025-.05). The degree of attenuation tended to decrease in images obtained at the more distal cardiac levels and to increase with increasing BMI quartile., Conclusion: Differences in attenuation related to BMI and image section level appear to have a significant effect on current calcium scoring methods., (Copyright RSNA, 2004)

High-performance liquid chromatography (HPLC) has been applied to the multiplex detection of the two single nucleotide mutations commonly found in hereditary hemochromatosis (HH). HH is associated with a major G to A transition at position 845 (mutation Cys282Tyr) and a minor C to G transition at position 187 (mutation His63Asp) in the cDNA of the HFE gene. Two detection assays were developed based on HPLC analysis of restriction fragment length polymorphism (RFLP) or single nucleotide extension (SNE) products following multiplex PCR amplification. RFLP genotypes the two sites as dsDNA fragments of different lengths generated by restriction enzymes Rsa I/Bcl I. SNE extends primers 5'-adjacent to the sites of interest with a dideoxynucleotide triphosphate (ddNTP) to generate extended ssDNA. The identity of the added ddNTP reveals the identity of the original possible mutation site(s). Application of these methods with HPLC analysis provides simple and reliable genotyping for HH and can be applied to other single nucleotide polymorphism studies.

Coronary arterial calcification has unequivocally been shown to be a marker of atherosclerosis. To date, much research interest has been generated regarding the quantification of coronary calcification by electron beam computed tomography, and how best to use such measurements to identify and predict those at greatest risk for an adverse cardiac event. This article represents an attempt to provide an objective review of the literature regarding the potential role electron beam computed tomography (EBCT) has as an accurate and cost effective screening modality for coronary arterial disease, as well as a predictor for coronary heart disease.

The primary goal of performing cross-sectional imaging of the chest in the radiologic evaluation of lung cancer is to obtain information about the character and magnitude of the neoplasm. Patient prognosis and therapy decisions depend directly on identifying the size and full extent of the tumor. The ideal imaging modality therefore should provide reliable information that can be used to assist in accurately staging the malignancy. Traditionally, CT scanning has been used exclusively as part of the preoperative evaluation of primary lung carcinomas. Recent advances in CT scanning technology have greatly improved image acquisition times and image quality and consequently have enhanced the role of CT imaging in the evaluation of bronchogenic carcinomas. Single-breath CT acquisitions of the chest can now be accomplished in a matter of seconds. These rapid acquisitions improve image quality by decreasing respiratory motion, while enhancing patient compliance and throughput. Clearly, CT scanning has matured into an efficient and accurate diagnostic tool to stage primary lung malignancies noninvasively. In its present state of development, MR imaging has one distinct disadvantage that makes it significantly less attractive as a routine lung cancer examination, namely the inability to produce images of the lung that are high in spatial resolution. Also, the sensitivity and specificity of MR imaging, which are similar to those of CT scanning in identifying mediastinal and hilar metastases, offer no clinical advantages. Longer image acquisition times and time constraints force most MR imaging examinations to be abbreviated and limited in coverage. As a result, the necessary exclusion of important anatomic areas routinely visualized by CT scanning may limit the diagnostic power of MR imaging. Finally, MR imaging requires greater physician supervision than CT scanning to direct imaging and to maintain examination quality and thoroughness. Although MR imaging can contribute significantly to the radiologic evaluation of patients with lung cancer, its role is somewhat limited, and it is most useful as a complement to CT scanning. The additional versatility offered by pulse sequences that take advantage of the intrinsic relaxation of tissues greatly facilitates identification of tumor, particularly when local invasion is present. By virtue of the short T1 value of fat, MR imaging may improve the detection of mediastinal disease, particularly in cases in which the sensitivity of CT scanning cannot be optimized because of allergies to contrast or renal insufficiency. MR imaging is superior to CT scanning in demonstrating musculoskeletal anatomy and the neurovascular structures of the neck and mediastinum. Although MR imaging has a potential usefulness in the radiographic evaluation of lung carcinoma, technical shortcomings relegate this modality to a role that is primarily complementary to CT scanning. With time, technological improvements will undoubtedly redefine the role of MR imaging in the radiographic evaluation and staging of bronchogenic carcinomas.

Hereditary hemochromatosis is one of the most common hereditary disorders in Caucasians.The disease is linked to two single-nucleotide polymorphisms (SNPs) in the HFE gene.The two point mutations result in a change of Cys to Tyr at position 282 and His to Asp at position 63 in the resultant protein.We have developed a single-nucleotide extension (SNE) assay for hereditary hemochromatosis genetic testing, which employs capillary electrophoresis to simultaneously detect the SNE products generated from the two SNP sites. An upstream or a downstream primer adjacent to the possible mutation site is designed and extended one nucleotide further at the 3' end, complementary to the nucleotide at the possible mutation site.The extended nucleotide is one of four fluorescently labeled dideoxynucleotide triphosphates that also act as terminators. Analysis of the extended products by laser-induced fluorescence capillary electrophoresis (LIF-CE) directly reflects the identity of the possible mutation site. Using one primer upstream or downstream from the possible mutation site, three genotypes at one mutation site can be distinguished. Using both upstream and downstream primers provides a second level of specificity and increases the accuracy of the genetic test. The protocol can also be applied to the study of other SNP analyses and to simultaneous detection of multiple mutation sites.

Rationale and Objectives: Real-time computed tomography (CT) has the potential to expedite and improve CT-guided needle biopsies by allowing cross-sectional images to be viewed in real time as a needle is advanced toward the target lesion. A major concern about this procedure is the scattered and leaked radiation to which the operator is exposed. This study was undertaken to determine the exposure rates around a CT scanner during CT-guided needle biopsies and to identify the areas of greatest personnel exposure., Materials and Methods: Pig and human cadavers were used to simulate patients undergoing a CT-guided needle biopsy. Various anatomic biopsy sites were used. The radiologist's exposure was assessed by timing the procedure and measuring the exposure rates around the CT scanner with an ionization-chamber survey meter. Ion-chamber measurements multiplied by the time the radiologist spent performing several mock biopsies were compared with film dosimeter results. Doses to the hands, wrists, and whole body were measured with ring, wrist, body, and collar film dosimeters., Results: The average time required to perform a single biopsy was about 1 minute. The dose to the radiologist performing the simulated biopsies was calculated to be 123 mR, 68 mR, 14 mR, and less than 0.5 mR to the fingers, wrist, collar, and body, respectively, as calculated from ionization-chamber and time measurements. These exposure rates correlate well with the film dosimeter readings accumulated during the mock procedures., Conclusion: The dose received by the radiologist performing a CT-guided biopsy was comparable to that of other interventional procedures. In addition, operating from the head of the machine (ie, distal to the bed) appeared to markedly reduce personnel exposure, due to the shielding in the gantry of the CT scanner used in the study.

The purpose of this study was to evaluate the clinical efficacy of ultrasmall superparamagnetic iron oxide particles as a magnetic resonance (MR) contrast agent in differentiating metastatic from benign lymph nodes. Eighteen patients with primary lung malignancy and suspected regional lymph node metastases underwent MR imaging before and after Combidex(R) infusion in a multi-institutional study. All MR sequences were interpreted by one or more board-certified radiologists experienced in imaging thoracic malignancy. Each patient was evaluated for the number and location of lymph nodes, homogeneity of nodal signal, and possible change of MR signal post contrast. All patients underwent resection or sampling of the MR-identified lymph node(s) 1-35 day(s) post contrast MR imaging. In all, 27 lymph nodes or nodal groups were available for histopathologic correlation. Combidex had a sensitivity of 92% and a specificity of 80% in identifying pathologically confirmed metastatic mediastinal lymph nodes. Based on our preliminary data, Combidex MR imaging may provide additional functional information useful in the staging of mediastinal lymph nodes.

Background: To determine the relative utility of positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging with Combidex (MRI-C) in the non-invasive staging of non-small cell lung cancer (NSCLC) mediastinal lymph nodes (MLN), we compared the three tests' individual performance with surgical mediastinal sampling. In contrast to prior studies, cytology was not used., Methods: The MLN were evaluated using PET and CT in 64 NSCLC patients. MRI-C was performed in 9 of these patients. MLN with a PET standard uptake value greater than or equal to 2.5, or greater than 1 cm in the short axis by CT or lack of MRI-C signal change were considered positive for metastatic disease. All MLN were sampled and subjected to standard pathologic analysis. PET, CT, and MRI-C scans were interpreted blinded to the histopathological results. Sensitivity, specificity, and accuracy for each scan type to appropriately stage MLN was determined using pathologic results as the standard., Results: Thirty patients had stage I disease, 8 stage II, 9 stage IIIA, 7 stage IIIB, and 10 stage IV. Two-hundred-and-thirty MLN were sampled. Sixteen patients had metastatic mediastinal disease. Compared to the pathological results, PET, CT, and MRI-C had a sensitivity, specificity, and accuracy of 70%, 86%, 84%; 65%, 79%, 76%; 86%, 82%, and 83%, respectively. PET and MRI-C were statistically more accurate than CT (p<0.001). In cases where PET and CT did not identify MLN involvement with NSCLC, 8% (2/25) were pathologically positive., Conclusions: PET and MRI-C are statistically more accurate than CT. However, the differences are small and may not be clinically relevant. No technique was sensitive or specific enough to change the current recommendation to perform mediastinoscopy for MLN staging in NSCLC.

Coronary artery calcification is a marker for atherosclerotic disease. The calcifications frequently occur early in the disease process and often before the development of luminal narrowing or cardiac events. Electron beam CT has a high accuracy in detecting calcifications, and thus has prognostic value in predicting luminal narrowing and future cardiac events.

Coronary artery disease affects millions of Americans annually. In evaluating coronary artery disease, it is important to develop diagnostic methodology that can screen patients before the onset of symptoms or cardiac events and, in addition, evaluate the functional aspects of coronary artery disease, including any residual effects on the heart after events have occurred. Electron beam computed tomography allows the identification of coronary calcium, which is a marker for coronary atherosclerotic disease, and also allows the quantification of cardiac function, which may be altered from coronary atherosclerosis or the occurrence of a cardiac event. Thus, electron beam computed tomographic imaging is having a major impact on the diagnosis and follow-up on coronary artery disease.

Rationale and Objectives: The authors sought to determine whether the lateral chest radiograph is helpful in identifying left lower lobe pneumonia among inexperienced readers., Materials and Methods: The authors selected all patients who presented to a family practice training program with radiologic and clinical evidence of left lower lobe pneumonia (n = 65). They then selected an equal number of patients in whom chest radiographs were taken to "rule out pneumonia" and were found to be normal. Eight 1st-year family practice residents were asked to read the radiographs before and after a didactic session that emphasized lateral chest radiograph interpretation. The radiographs were presented under two viewing conditions: posteroanterior (PA) only versus PA and lateral. Receiver operating characteristic (ROC) curve methods were used to compare the effect of both the didactic session and the viewing condition on diagnostic accuracy., Results: There were no significant differences in performance before and after the didactic session and no differences between the two viewing conditions. After including only abnormal radiographs that demonstrated the "spine sign" (an apparent increased opacification of the lower vertebral bodies on the lateral view), the residents performed better when presented with both PA and lateral radiographs than when presented with the PA radiograph only (area under ROC curve, .8158 vs .7418, respectively; P = 0.24)., Conclusion: In patients with left lower lobe pneumonia whose radiographs demonstrated the spine sign, diagnostic accuracy improved when the lateral chest radiograph was viewed.

Background: Left lower lobe pneumonia may be obscured by the heart on the postero-anterior (PA) chest radiograph. In such cases, the lateral projection may be helpful, especially if it exhibits the "spine sign", which is an interruption in the progressive increase in lucency of the vertebral bodies from superior to inferior. We investigated whether the spine sign would help family physicians diagnose left lower lobe pneumonia on chest radiographs., Methods: We selected the chest radiographs of all patients with left lower lobe pneumonia who were seen between 1983 and 1995 at a family practice training program (N = 78) and an equal number of chest radiographs of patients without pneumonia. Six family physicians read these radiographs under two viewing conditions: PA only vs PA and lateral. We used receiver operating characteristic (ROC) curve methodology to compare the two viewing conditions., Results: There was no significant difference in performance between the two viewing conditions. The lateral view was helpful in some patients but misleading in others. Among patients with pneumonia, the lateral view was helpful when the spine sign was present, but it was misleading when the spine sign was absent., Conclusions: In this study of family physicians, the lateral chest radiograph did not improve overall diagnostic accuracy in patients with left lower lobe pneumonia. Among pneumonia patients with the spine sign, however, the lateral view was often helpful.

Aim: To define the utility of the frontal chest radiograph in the assessment of chest drain position., Patients and Methods: Fifty-six frontal chest radiographs in 45 patients with 61 chest drains (18 anterior, 9 interlobar, and 34 posterior position) were reviewed retrospectively to determine radiographic characteristics., Results: Eighty-nine percent of the anterior drains demonstrated a curved appearance at the insertion site, while 50% of posterior drains and all interlobar drains were straight at the insertion site. A curved intrapleural drain was a common finding when positioned anteriorly and posteriorly (67% and 59%, respectively). Interlobar drains were often straight throughout their course (89%). The tips of interlobar drains were usually positioned at the hilum (89%)., Conclusion: Results suggest that interlobar positioning can be suspected on the frontal chest radiograph. A curving chest drain with straight appearance at the insertion site was indicative of a posterior location.

Objectives: This study was designed to estimate the prevalence of coronary artery calcification in young adult men and women and to examine the association between the presence of coronary artery calcification and coronary risk factors measured in childhood and young adult life., Background: Electron beam computed tomography is a sensitive, noninvasive method for detecting coronary artery calcification, a marker of the atherosclerotic process. Coronary artery calcification is associated with coronary risk factors in older adults., Methods: Subjects (197 men, 187 women) had coronary risk factors measured in childhood (mean age 15 years) and twice during young adult life (mean ages 27 and 33 years). Each underwent an electron beam computed tomographic study at their second young adult examination., Results: The prevalence of coronary artery calcification was 31% in men and 10% in women. Increased body size, increased blood pressure and decreased high density lipoprotein (HDL) cholesterol levels were the coronary risk factors that showed the strongest association with coronary artery calcification. Significant odds ratios for coronary artery calcification, using standardized risk factor measurements at a mean age of 33 years in men and women, respectively, were 6.4 and 13.6 for the highest decile of body mass index, 6.4 and 6.4 for the highest decile of systolic blood pressure and 4.3 and 4.7 for the lowest decile of HDL cholesterol., Conclusions: Coronary artery calcification is more prevalent in men in this young adult population. Coronary risk factors measured in children and young adults are associated with the early development of coronary artery calcification. Increased body mass index measured during childhood and young adult life and increased blood pressure and decreased HDL cholesterol levels measured during young adult life are associated with the presence of coronary artery calcification in young adults.

Pulmonary aspergillosis represents a common, potentially lethal opportunistic infection that has four unique forms: allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, and invasive and semi-invasive aspergillosis. In individuals who are at risk, pulmonary aspergillosis is characterized by a spectrum of clinical and radiographic findings that are intrinsically related to the status of the immune system or the presence of structural lung disease. ABPA, occurring almost exclusively in asthma patients, is characterized radiographically by fleeting pulmonary alveolar opacities caused by deposition of immune complexes and inflammatory cells within the lung parenchyma. Mucus plugging and bronchial wall thickening can be expected in time. Aspergilloma, occurring in patients with structural lung disease, typically appears radiographically as a focal intracavitary mass and is characterized initially by an increase in the wall thickness of a preexisting cavity or cyst. Invasive aspergillosis, which occurs primarily in profoundly immunocompromised patients, may exhibit nonspecific patchy nodular opacities or lobar-type air-space disease in cases with vascular invasion. Computed tomography may reveal a halo or ground-glass attenuation and is more accurate in the detection of early disease. Cavitation often develops with time and typically results in the air crescent sign. Semi-invasive aspergillosis is radiographically similar to the invasive form but differs in clinical course, being associated with mild immunosuppression or chronic illness and typically progressing over the course of months rather than weeks.

Coronary artery calcification is a recognized marker for coronary atherosclerosis; however, the relationship between calcification and the success of balloon angioplasty at a calcification site has not been determined. The purpose of this study was to evaluate whether the presence of coronary artery calcification, as detected by electron bean computed tomography (EBCT), was predictive of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Site- specific coronary calcification was determined by EBCT in 20 patients with 24 lesions before, immediately after, and 2 to 18 month after PTCA. Calcification was scored using >130 Hounsfield units and >1.02-mm2 area criteria. Coronary calcium at the PTCA site was significantly greater in restenosed versus nonrestenosed patients (109.16 +/- 198.16 mm2 v 4.39 +/- 9.50 mm2) (P < .025). The amount of coronary calcium did not change as a result of the PTCA procedure (+2.72 +/- 22.31 mm2 v -4.81 +/- 7.82 mm2) (P = NS). The rate of progression of calcification was not greater in restenosed versus nonrestenosed patients (1.78 +/- 3.32 mm2/month v 0.09 +/- 0.19 mm2/mo) (P = NS). Site-specific coronary calcification as determined by EBCT appeared to be predictive of patients with an increased likelihood to restenose after PTCA. Further studies are needed to verify these observations in a considerably larger patient population.

Purpose: To assess the usefulness of indium-111 white blood cell and technetium-99m methylene diphosphonate bone single photon emission computed tomography (SPECT), computed tomography (CT), and magnetic resonance (MR) imaging in cranial osteomyelitis., Materials and Methods: Twenty-six cases (25 patients: 13 male, 12 female; mean age, 55 years) of suspected osteomyelitis were evaluated. Sixteen were postoperative. Final diagnosis was established by means of bone culture in 18 cases and clinical follow-up in eight., Results: Of 35 CT scans, 10 were true-positive (TP); three false-negative (FN); 13, true-negative (TN); one, false-positive (FP); and eight, equivocal. Of 36 SPECT scans, 19 were TP; 13, TN; one, FP; one, FN; and two, equivocal. Of 11 MR images four were TP; five, TN; and two, FN., Conclusion: CT is best for differentiation between soft-tissue and bone infection. MR imaging is best for assessment of the calvaria and skull base. SPECT is best for assessment of altered bone and may be the best technique for follow-up.

A reliable imaging technique is needed for follow-up of patients with temporal and facial osteomyelitis. Clinical outcome in 20 patients with suspected osteomyelitis of the temporal/mastoid, calvarium, and mandible facial bones was evaluated with 30 combined In-WBC/Tc-99m MDP bone single photon emission computed tomographic (SPECT) scans and 27 computed tomographic scans. Simultaneous dual-tracer 25-minute SPECT scans were acquired 18 to 20 hours after radiotracer injection by use of a three-detector system. Diagnosis of the 20 patients (age range, 3 to 74 years) included 8 with facial osteomyelitis, 6 with malignant otitis externa, 3 with mandibular osteomyelitis, and 3 with calvarial osteomyelitis. Diagnosis was confirmed by biopsy/culture results in 18 patients and by endoscopic and clinical evaluation in 2 patients with initial negative scans. Of the 30 In-WBC/MDP scans, 15 were true-positive, 13 true-negative, 1 false-negative, and 1 equivocal. Of a total of 27 CT scans, 9 were true-positive, 5 false-negative, and 1 equivocal in patients with biopsy-proven osteomyelitis. Three computed tomographic scans were false-positive and 1 was equivocal in patients without osteomyelitis, because of concurrent postoperative bone abnormalities. Additionally, 8 computed tomographic scans were true-negative. These results suggest that dual In-WBC/Tc-99m MDP bone SPECT scintigraphy provides an accurate imaging modality for diagnosis and follow-up of temporal and facial osteomyelitis when existing clinical or postoperative bone changes make it difficult to detect active osteomyelitis by computed tomographic scan.