An in vitro comparison of subjective image quality of panoramic views acquired via 2D or 3D imaging.

OBJECTIVES: The objective of this study is to compare subjective image quality and diagnostic validity of cone-beam CT (CBCT) panoramic reformatting with digital panoramic radiographs. MATERIALS AND METHODS: Four dry human skulls and two formalin-fixed human heads were scanned using nine different CBCTs, one multi-slice CT (MSCT) and one standard digital panoramic device. Panoramic views were generated from CBCTs in four slice thicknesses. Seven observers scored image quality and visibility of 14 anatomical structures. Four observers repeated the observation after 4 weeks. RESULTS: Digital panoramic radiographs showed significantly better visualization of anatomical structures except for the condyle. Statistical analysis of image quality showed that the 3D imaging modalities (CBCTs and MSCT) were 7.3 times more likely to receive poor scores than the 2D modality. Yet, image quality from NewTom VGi® and 3D Accuitomo 170® was almost equivalent to that of digital panoramic radiographs with respective odds ratio estimates of 1.2 and 1.6 at 95% Wald confidence limits. A substantial overall agreement amongst observers was found. Intra-observer agreement was moderate to substantial. CONCLUSIONS: While 2D-panoramic images are significantly better for subjective diagnosis, 2/3 of the 3D-reformatted panoramic images are moderate or good for diagnostic purposes. CLINICAL RELEVANCE: Panoramic reformattings from particular CBCTs are comparable to digital panoramic images concerning the overall image quality and visualization of anatomical structures. This clinically implies that a 3D-derived panoramic view can be generated for diagnosis with a recommended 20-mm slice thickness, if CBCT data is a priori available for other purposes.

European consensus on patient contact shielding.

Patient contact shielding has been in use for many years in radiology departments in order to reduce the effects and risks of ionising radiation on certain organs. New technologies in projection imaging and CT scanning such as digital receptors and automatic exposure control (AEC) systems have reduced doses and improved image consistency. These changes and a greater understanding of both the benefits and the risks from the use of shielding have led to a review of shielding use in radiology. A number of professional bodies have already issued guidance in this regard. This paper represents the current consensus view of the main bodies involved in radiation safety and imaging in Europe: European Federation of Organisations for Medical Physics, European Federation of Radiographer Societies, European Society of Radiology, European Society of Paediatric Radiology, EuroSafe Imaging, European Radiation Dosimetry Group (EURADOS), and European Academy of DentoMaxilloFacial Radiology (EADMFR). It is based on the expert recommendations of the Gonad and Patient Shielding (GAPS) Group formed with the purpose of developing consensus in this area. The recommendations are intended to be clear and easy to use. They are intended as guidance, and they are developed using a multidisciplinary team approach. It is recognised that regulations, custom and practice vary widely on the use of patient shielding in Europe and it is hoped that these recommendations will inform a change management program that will benefit patients and staff.

Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes.

Antigen transport from the airway mucosa to the thoracic lymph nodes (TLNs) was studied in vivo by intratracheal instillation of fluorescein isothiocyanate (FITC)-conjugated macromolecules. After instillation, FITC(+) cells with stellate morphology were found deep in the TLN T cell area. Using flow cytometry, an FITC signal was exclusively detected in CD11c(med-hi)/major histocompatibility complex class II (MHCII)(hi) cells, representing migratory airway-derived lymph node dendritic cells (AW-LNDCs). No FITC signal accumulated in lymphocytes and in a CD11c(hi)MHCII(med) DC group containing a CD8 alpha(hi) subset (non-airway-derived [NAW]-LNDCs). Sorted AW-LNDCs showed long MHCII(bright) cytoplasmic processes and intracytoplasmatic FITC(+) granules. The fraction of FITC(+) AW-LNDCs peaked after 24 h and had reached baseline by day 7. AW-LNDCs were depleted by 7 d of ganciclovir treatment in thymidine kinase transgenic mice, resulting in a strong reduction of FITC-macromolecule transport into the TLNs. Compared with intrapulmonary DCs, AW-LNDCs had a mature phenotype and upregulated levels of MHCII, B7-2, CD40, and intracellular adhesion molecule (ICAM)-1. In addition, sorted AW-LNDCs from FITC-ovalbumin (OVA)-instilled animals strongly presented OVA to OVA-TCR transgenic T cells. These results validate the unique sentinel role of airway DCs, picking up antigen in the airways and delivering it in an immunogenic form to the T cells in the TLNs.

Efficacy of a novel intradermal Lawsonia intracellularis vaccine in pigs against experimental infection and under field conditions.

BACKGROUND: The efficacy of a novel inactivated intradermal Lawsonia intracellularis vaccine, Porcilis® Lawsonia ID, was evaluated in two experimental vaccination-challenge studies and under field conditions on a farm with a history of recurrent acute ileitis. In addition, the efficacy of the vaccine was compared to that of a commercially available live attenuated vaccine. The novel inactivated vaccine consists of a freeze-dried antigen fraction that is dissolved just prior to use in either the adjuvant or in Porcilis® PCV ID; an existing intradermal vaccine against porcine Circovirus type 2. In the two experimental vaccination-challenge studies, groups of 25 piglets were vaccinated once at 3 weeks of age or left unvaccinated as challenge control. Vaccines tested were Porcilis® Lawsonia ID as standalone (study 1) or in associated mixed use with Porcilis® PCV ID (study 2) and an orally administered commercially available live vaccine (study 1). The pigs were challenged with virulent L. intracellularis at 4 weeks (study 1) or 21 weeks (study 2) after vaccination. Post-challenge, the pigs were evaluated for clinical signs, average daily weight gain, shedding and macroscopic as well as microscopic immuno-histological ileum lesion scores. In the field study, the mortality and key performance parameters were evaluated over a period of 8 months. RESULTS: The results of the two experimental vaccination-challenge studies showed that Porcilis® Lawsonia ID as single vaccine or in associated mixed use with Porcilis® PCV ID, induced statistically significant protection against experimental L. intracellularis infection, 4 weeks or 21 weeks after vaccination. This was demonstrated by lower clinical scores, improved weight gain, reduction of L. intracellularis shedding and reduction of macroscopic as well as microscopic ileum lesion scores when compared to the controls. The protection induced was superior to that of the commercially available live vaccine. In the field study Porcilis® Lawsonia ID was highly efficacious in reducing L. intracellularis associated mortality and improving key production parameters. CONCLUSION: The results support that this new intradermal vaccine is efficacious against L. intracellularis and may be used in associated mixed use with Porcilis® PCV ID.

Lengthening adalimumab dosing interval in quiescent Crohn's disease patients: protocol for the pragmatic randomised non-inferiority LADI study.

INTRODUCTION: Adalimumab is effective for maintenance of remission in patients with Crohn's disease (CD) at a dose of 40 mg subcutaneously every 2 weeks. However, adalimumab is associated with (long-term) adverse events and is costly. The aim of this study is to demonstrate non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening compared to standard dosing of every other week (EOW). METHODS AND ANALYSIS: The Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, multicentre, open label, randomised controlled non-inferiority trial. Non-inferiority is reached if the difference in cumulative incidence of persistent (>8 weeks) flares does not exceed the non-inferiority margin of 15%. 174 CD patients on adalimumab maintenance therapy in long-term (>9 months) clinical and biochemical remission will be included (C-reactive protein (CRP) <10 mg/L, faecal calprotectin (FC) <150 µg/g, Harvey-Bradshaw Index (HBI) <5). Patients will be randomised 2:1 into the intervention (adalimumab interval lengthening) or control group (adalimumab EOW). The intervention group will lengthen the adalimumab administration interval to every 3 weeks, and after 24 weeks to every 4 weeks. Clinical and biochemical disease activity will be monitored every 12 weeks by physician global assessment, HBI, CRP and FC. In case of disease flare, dosing will be increased. A flare is defined as two of three of the following criteria; FC>250 µg/g, CRP≥10 mg/l, HBI≥5. Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost-effectiveness. ETHICS AND DISSEMINATION: The study is approved by the Medical Ethics Committee Arnhem-Nijmegen, the Netherlands (registration number NL58948.091.16). Results will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBERS: EudraCT registry (2016-003321-42); Clinicaltrials.gov registry (NCT03172377); Dutch trial registry (NTRID6417).

Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation.

The aim of this study was to investigate whether dendritic cells (DCs) can induce sensitization to aeroallergen in a mouse model of allergic asthma. Ovalbumin-pulsed (OVA-pulsed) or unpulsed myeloid DCs that were injected into the airways of naive mice migrated into the mediastinal lymph nodes. When challenged 2 weeks later with an aerosol of OVA, activated CD4 and CD8 lymphocytes, eosinophils, and neutrophils were recruited to the lungs of actively immunized mice. These CD4(+) lymphocytes produced predominantly IL-4 and IL-5 but also IFN-gamma, whereas CD8(+) lymphocytes produced predominantly IFN-gamma. Histological analysis revealed perivascular and peribronchial eosinophilic infiltrates and goblet cell hyperplasia. Studies in IL-4(-/-) and CD28(-/-) mice revealed that production of IL-4 by host cells and provision of costimulation to T cells by DCs were critical for inducing the response. Lung CD4(+) T cells strongly expressed the Th2 marker T1/ST2, and signaling through this molecule via a ligand expressed on DCs was essential for the establishment of airway eosinophilia. These data demonstrate that DCs in the airways induce sensitization to inhaled antigen and that molecules expressed on the surface of these cells are critical for the development of Th2-dependent airway eosinophilia.

Predictors of lung function and its decline in mild to moderate COPD in association with gender: results from the Euroscop study.

BACKGROUND: There is increasing appreciation of gender differences in COPD but scant data whether risk factors for low lung function differ in men and women. We analysed data from 3 years follow-up in 178 women and 464 men with COPD, participants in the Euroscop Study who were smokers unexposed to inhaled corticosteroids. METHODS: Explanatory variables of gender, age, starting age and pack-years smoking, respiratory symptoms, FEV(1)%FVC and FEV(1)%IVC (clinically important measures of airway obstruction), body mass index (BMI), and change in smoking were included in multiple linear regression models with baseline and change in post-bronchodilator FEV(1) as dependent variables. RESULTS: Reduced baseline FEV(1) was associated with respiratory symptoms in men only. Annual decline in FEV(1) was not associated with respiratory symptoms in either men or women, and was 55 ml less in obese men (BMI 30 kg/m(2)) than men having normal BMI, an effect not seen in women. It was 32 ml faster in women with FEV(1)%FVC

Numerical chromosome 1, 7, 9, and 11 aberrations in bladder cancer detected by in situ hybridization.

Forty transitional cell carcinomas of the human urinary bladder (TCCs) were examined for numerical aberrations of chromosomes 1, 7, 9, and 11 by in situ hybridization using chromosome-specific probes. Our interphase cytogenetic study of 24 low-grade, noninvasive TCCs, which were near-diploid by flow cytometry, showed a numerical aberration for at least 1 of these chromosomes in 14 of these cases. Most strikingly, a monosomy for chromosome 9 was found in 9 of 24 low-grade TCCs. A trisomy for chromosomes 1, 7, and 11 was detected in 5, 2, and 1 case(s), respectively. In 1 case a monosomy for chromosome 1 was detected by in situ hybridization. Monosomy for chromosome 9 was the only detected numerical change in 5 low-grade TCC cases. Examination of 16 invasive TCCs showed extra copies for chromosomes 1 and 7 in 7 flow cytometrically diploid cases with numerical chromosome aberrations; also, loss of chromosome 9 was detected. In 5 invasive and 2 noninvasive aneuploid/tetraploid TCCs a profound imbalance between the different chromosomes was found. In 5 of these cases an evident underrepresentation of chromosome 9 in comparison to chromosomes 1, 7, and 11 was detected. This underrepresentation of chromosome 9 in diploid, as well as aneuploid, TCCs, and in some cases the constant ratio between this chromosome and the other chromosomes, may be explained by a process of tetraploidization. Therefore, loss of chromosome 9 may be one of the primary genetic events in TCC oncogenesis, with secondary events, such as tetraploidization, correlated to tumor progression. Our results show that in situ hybridization can be routinely used to study important cytogenetic changes which occur during the development of a malignant disease.

Preparation and characterization of conjugates of (modified) human serum albumin and liposomes: drug carriers with an intrinsic anti-HIV activity.

Human serum albumin (HSA) derivatized with cis-aconitic anhydride (Aco-HSA) that was earlier shown to inhibit replication of human immunodeficiency virus type 1 (HIV-1), was covalently coupled to conventional liposomes, consisting of phosphatidylcholine, cholesterol and maleimido-4-(p-phenylbutyryl)phosphatidylethanolamine, using the heterobifunctional reagent N-succinimidyl-S-acetylthioacetate (SATA). The amount of HSA that could be coupled to the liposomes depended on derivatization of the HSA and ranged from 64.2 +/- microgram HSA/micromol total lipid for native HSA to 29.5 +/- 2.7 microgram HSA/micromol total lipid for HSA in which 53 of the epsilon amino groups of lysine were derivatized with cis-aconitic anhydride (Aco53-HSA). Incorporation of 3.8 mol% of total lipid of a poly(ethylene glycol) derivative of phosphatidylethanolamine (PEG-PE) in the liposomes resulted in a lower coupling efficiency of Aco-HSA. The elimination and distribution of the liposomal conjugates in rats in vivo was largely dependent on the modification of the HSA coupled to the liposomes. With native HSA-liposomes, more than 70% of the conjugate was still found in the blood plasma 30 min after i.v. injection in rats, while at this time Aco-HSA-liposomes were completely cleared from the circulation. The rapid clearance of conventional Aco-HSA-liposomes was due to a rapid uptake into the liver and could be considerably decreased by incorporating PEG-PE in the liposomal bilayer. After 3 h 60% of Aco-HSA-PEG-liposome conjugates were found in the blood. In an in vitro anti-HIV-1 assay, the 50% inhibitory concentrations (IC50) for Aco39-HSA-liposomes and Aco53-HSA-liposomes expressed as protein weight, were 2.87 microgram/ml and 0.154 microgram/ml, respectively. When PEG-PE was incorporated, the Aco53-HSA-liposomes retained anti HIV-1 activity (IC50:3.13 microgram/ml). The possibility to modulate the residence time in the bloodstream of Aco-HSA-liposomes and the potent anti-HIV-1 activity of these conjugates, may allow the development of an intrinsically active drug carrier system. By incorporating anti HIV-1 drugs such as AZT into such liposomes a drug delivery system can be designed that might act simultaneously on the virus/cell binding by virtue of the coupled Aco-HSA and on the RNA/DNA transcription of the HIV-1 replication cycle through the nucleoside analogue.

Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance.

The locations of HIV-1 RT nucleoside and non-nucleoside inhibitor-binding sites and inhibitor-resistance mutations are analyzed in the context of the three-dimensional structure of the enzyme and implications for mechanisms of drug inhibition and resistance are discussed. In order to help identify residues that may play a role in inhibitor binding, solvent accessibilities of amino acids that comprise the inhibitor-binding sites in the structure of HIV-1 RT complexed with a dsDNA template-primer are analyzed. While some mutations that cause resistance to nucleoside analogs, such as AZT, ddI, and ddC, are located near enough to the dNTP-binding site to directly interfere with binding of nucleoside analogs, many are located away from the dNTP-binding site and more likely confer resistance by other mechanisms. Many of the latter mutations are located on the surface of the DNA-binding cleft and may lead to altered template-primer positioning or conformation, causing a distortion of the geometry of the polymerase active site and consequent discrimination between normal and altered dNTP substrates. Other nucleoside analog-resistance mutations located on the periphery of the dNTP-binding site may exert their effects via altered interactions with dNTP-binding site residues. The structure of the hydrophobic region in HIV-1 RT that binds non-nucleoside inhibitors, for example, nevirapine and TIBO, has been analyzed in the absence of bound ligand. The pocket that is present when non-nucleoside inhibitors are bound is not observed in the inhibitor-free structure of HIV-1 RT with dsDNA. In particular it is filled by Tyr181 and Tyr188, suggesting that the pocket is formed primarily by rotation of these large aromatic side-chains. Existing biochemical data, taken together with the three-dimensional structure of HIV-1 RT, makes it possible to propose potential mechanisms of inhibition by non-nucleoside inhibitors. One such mechanism is local distortion of HIV-1 RT structural elements thought to participate in catalysis: the beta 9-beta 10 hairpin (which contains polymerase active site residues) and the beta 12-beta 13 hairpin ("primer grip"). An alternative possibility is restricted mobility of the p66 thumb subdomain, which is supported by the observation that structural elements of the non-nucleoside inhibitor-binding pocket may act as a "hinge" for the thumb.(ABSTRACT TRUNCATED AT 400 WORDS)

Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant.

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is an important target for chemotherapeutic agents used in the treatment of AIDS; the TIBO compounds are potent non-nucleoside inhibitors of HIV-1 RT (NNRTIs). Crystal structures of HIV-1 RT complexed with 8-Cl TIBO (R86183, IC50 = 4.6 nM) and 9-Cl TIBO (R82913, IC50 = 33 nM) have been determined at 3.0 A resolution. Mutant HIV-1 RT, containing Cys in place of Tyr at position 181 (Tyrl81Cys), is highly resistant to many NNRTIs and HIV-1 variants containing this mutation have been selected in both cell culture and clinical trials. We also report the crystal structure of Tyrl81Cys HIV-1 RT in complex with 8-Cl TIBO (IC50 = 130 nM) determined at 3.2 A resolution. Averaging of the electron density maps computed for different HIV-1 RT/NNRTI complexes and from diffraction datasets obtained using a synchrotron source from frozen (-165 degrees C) and cooled (-10 degrees C) crystals of the same complex was employed to improve the quality of electron density maps and to reduce model bias. The overall locations and conformations of the bound inhibitors in the complexes containing wild-type HIV-1 RT and the two TIBO inhibitors are very similar, as are the overall shapes and volumes of the non-nucleoside inhibitor-binding pocket (NNIBP). The major differences between the two wild-type HIV-1 RT/TIBO complexes occur in the vicinity of the TIBO chlorine substituents and involve the polypeptide segments around the beta5-beta6 connecting loop (residues 95 to 105) and the beta13-beta14 hairpin (residues 235 and 236). In all known structures of HIV-1 RT/NNRTI complexes, including these two, the position of the beta12-beta13 hairpin or the "primer grip" is significantly displaced relative to the position in the structure of HIV-1 RT complexed with a double-stranded DNA and in unliganded HIV-1 RT structures. Since the primer grip helps to position the template-primer, this displacement suggests that binding of NNRTIs would affect the relative positions of the primer terminus and the polymerase active site. This could explain biochemical data showing that NNRTI binding to HIV-1 RT reduces efficiency of the chemical step of DNA polymerization, but does not prevent binding of either dNTPs or DNA. When the structure of the Tyr181Cys mutant HIV-1 RT in complex with 8-Cl TIBO is compared with the corresponding structure containing wild-type HIV-1 RT, the overall conformations of Tyr181Cys and wild-type HIV-1 RT and of the 8-Cl TIBO inhibitors are very similar. Some positional changes in the polypeptide backbone of the beta6-beta10-beta9 sheet containing residue 181 are observed when the Tyr181Cys and wild-type complexes are compared, particularlty near residue Val179 of beta9. In the p51 subunit, the Cys181 side-chain is oriented in a similar direction to the Tyr181 side-chain in the wild-type complex. However, the electron density corresponding to the sulfur of the Cys181 side-chain in the p66 subunit is very weak, indicating that the thiol group is disordered, presumably because there is no significant interaction with either 8-Cl TIBO or nearby amino acid residues. In the mutant complex, there are slight rearrangements of the side-chains of other amino acid residues in the NNIBP and of the flexible dimethylallyl group of 8-Cl TIBO; these conformational changes could potentially compensate for the interactions that were lost when the relatively large tyrosine at position 181 was replaced by a less bulky cysteine residue. In the corresponding wild-type complex, Tyr181 iin the p66 subunit has significant interactions with the bound inhibitor and the position of the Tyr181 side-chain is well defined in both subunits. Apparently the Tyr181 --> Cys mutation eliminates favorable contacts of the aromatic ring of the tyrosine and the bou

Tachykinin receptor antagonists: potential in airways diseases.

Several lines of evidence indicate a role for the tachykinin peptides in airways diseases. For instance, elevated levels of tachykinins have been recovered from the airways of patients with asthma and chronic obstructive pulmonary disease (COPD), and airway inflammation leads to an upregulation of the tachykinin NK1 and NK2 receptors. Recent advances in tachykinin receptor pharmacology have allowed a more detailed analysis of this system and preclinical animal studies have indicated a role for the NK1 and NK2 receptors in bronchoconstriction, airway hyperresponsiveness and airway inflammation caused by allergic and nonallergic stimuli. In the past three years, work has entered the clinic and selective or dual-selective NK1/NK2 receptor antagonists appear to have the potential to affect the different aspects of asthma and COPD.

Technical aspects of dental CBCT: state of the art.

As CBCT is widely used in dental and maxillofacial imaging, it is important for users as well as referring practitioners to understand the basic concepts of this imaging modality. This review covers the technical aspects of each part of the CBCT imaging chain. First, an overview is given of the hardware of a CBCT device. The principles of cone beam image acquisition and image reconstruction are described. Optimization of imaging protocols in CBCT is briefly discussed. Finally, basic and advanced visualization methods are illustrated. Certain topics in these review are applicable to all types of radiographic imaging (e.g. the principle and properties of an X-ray tube), others are specific for dental CBCT imaging (e.g. advanced visualization techniques).

Comparison of mandibular bone microarchitecture between micro-CT and CBCT images.

OBJECTIVES: To compare microarchitecture parameters of bone samples scanned using micro-CT (µCT) to those obtained by using CBCT. METHODS: A bone biopsy trephine bur (3 × 10 mm) was used to remove 20 cylindrical bone samples from 20 dry hemimandibles. Samples were scanned using µCT (µCT 35; SCANCO Medical, Brüttisellen, Switzerland) with a voxel size of 20 µm and CBCT (3D Accuitomo 170; J. Morita, Kyoto, Japan) with a voxel size of 80 µm. All corresponding sample scans were aligned and cropped. Image analysis was carried out using BoneJ, including the following parameters: skeleton analysis, bone surface per total volume (BS/TV), bone volume per total volume (BV/TV), connectivity density, anisotropy, trabecular thickness and spacing, structure model index, plateness and fractal dimension. Pearson and Spearman correlation coefficients (R) were calculated. CBCT values were then calibrated using the slope of the linear fit with the µCT values. The mean error after calibration was calculated and normalized to the standard deviation of the µCT values. RESULTS: R-values ranged between 0.05 (plateness) and 0.83 (BS/TV). Correlation was significant for both Spearman and Pearson's R for 8 out of 16 parameters. After calibration, the smallest normalized error was found for BV/TV (0.48). For other parameters, the error range was 0.58-2.10. CONCLUSIONS: Despite the overall correlation, this study demonstrates the uncertainty associated with using bone microarchitecture parameters on CBCT images. Although clinically relevant parameter ranges are not available, the errors found in this study may be too high for some parameters to be considered for clinical application.

CBCT-based bone quality assessment: are Hounsfield units applicable?

CBCT is a widely applied imaging modality in dentistry. It enables the visualization of high-contrast structures of the oral region (bone, teeth, air cavities) at a high resolution. CBCT is now commonly used for the assessment of bone quality, primarily for pre-operative implant planning. Traditionally, bone quality parameters and classifications were primarily based on bone density, which could be estimated through the use of Hounsfield units derived from multidetector CT (MDCT) data sets. However, there are crucial differences between MDCT and CBCT, which complicates the use of quantitative gray values (GVs) for the latter. From experimental as well as clinical research, it can be seen that great variability of GVs can exist on CBCT images owing to various reasons that are inherently associated with this technique (i.e. the limited field size, relatively high amount of scattered radiation and limitations of currently applied reconstruction algorithms). Although attempts have been made to correct for GV variability, it can be postulated that the quantitative use of GVs in CBCT should be generally avoided at this time. In addition, recent research and clinical findings have shifted the paradigm of bone quality from a density-based analysis to a structural evaluation of the bone. The ever-improving image quality of CBCT allows it to display trabecular bone patterns, indicating that it may be possible to apply structural analysis methods that are commonly used in micro-CT and histology.

Effect of exposure parameters and voxel size on bone structure analysis in CBCT.

OBJECTIVE: To evaluate the effect of exposure parameters and voxel size on bone structure analysis in dental CBCT. METHODS: 20 cylindrical bone samples underwent CBCT scanning (3D Accuitomo 170; J. Morita, Kyoto, Japan) using three combinations of tube voltage (kV) and tube current-exposure time product (mAs), corresponding with a CT dose index of 3.4 mGy: 90 kV and 62 mAs, 73 kV and 108.5 mAs, and 64 kV and 155 mAs. Images were reconstructed with a voxel size of 0.080 mm. In addition, the 90 kV scan was reconstructed at voxel sizes of 0.125, 0.160, 0.200, 0.250 and 0.300 mm. The following parameters were measured: bone surface (BS) and bone volume (BV) per total volume (TV), fractal dimension, connectivity density, anisotropy, trabecular thickness (Tb. Th.) and trabecular spacing (Tb. Sp.), structure model index (SMI), plateness, branches, junctions, branch length and triple points. RESULTS: For most parameters, there was no significant effect of the kV value. For BV/TV, "90 kV" differed significantly from the other kV settings; for SMI, "64 vs 73 kV" was significant. For BS/TV, fractal dimension, connectivity density, branches, junctions and triple points values incrementally decreased at larger voxel sizes, whereas an increase was seen for Tb. Th., Tb. Sp., SMI and branch length. For anisotropy and plateness, no (or little) effect of voxel size was seen; for BV/TV, the effect was inconsistent. CONCLUSIONS: Most bone structure parameters are not affected by the kV if the radiation dose is constant. Parameters dealing with the trabecular structure are heavily affected by the voxel size.

Radiological Protection in Cone Beam Computed Tomography (CBCT). ICRP Publication 129.

The objective of this publication is to provide guidance on radiological protection in the new technology of cone beam computed tomography (CBCT). Publications 87 and 102 dealt with patient dose management in computed tomography (CT) and multi-detector CT. The new applications of CBCT and the associated radiological protection issues are substantially different from those of conventional CT. The perception that CBCT involves lower doses was only true in initial applications. CBCT is now used widely by specialists who have little or no training in radiological protection. This publication provides recommendations on radiation dose management directed at different stakeholders, and covers principles of radiological protection, training, and quality assurance aspects. Advice on appropriate use of CBCT needs to be made widely available. Advice on optimisation of protection when using CBCT equipment needs to be strengthened, particularly with respect to the use of newer features of the equipment. Manufacturers should standardise radiation dose displays on CBCT equipment to assist users in optimisation of protection and comparisons of performance. Additional challenges to radiological protection are introduced when CBCT-capable equipment is used for both fluoroscopy and tomography during the same procedure. Standardised methods need to be established for tracking and reporting of patient radiation doses from these procedures. The recommendations provided in this publication may evolve in the future as CBCT equipment and applications evolve. As with previous ICRP publications, the Commission hopes that imaging professionals, medical physicists, and manufacturers will use the guidelines and recommendations provided in this publication for implementation of the Commission's principle of optimisation of protection of patients and medical workers, with the objective of keeping exposures as low as reasonably achievable, taking into account economic and societal factors, and consistent with achieving the necessary medical outcomes.

Optimization of dental CBCT exposures through mAs reduction.

OBJECTIVES: To investigate the effect of tube current-exposure time (mAs) reduction on clinical and technical image quality for different CBCT scanners, and to determine preliminary minimally acceptable values for the mAs and contrast-to-noise ratio (CNR) in CBCT. METHODS: A polymethyl methacrylate (PMMA) phantom and an anthropomorphic skull phantom, containing a human skeleton embedded in polyurethane, were scanned using four CBCT devices, including seven exposure protocols. For all protocols, the mAs was varied within the selectable range. Using the PMMA phantom, the CNRAIR was measured and corrected for voxel size. Eight axial slices and one coronal slice showing various anatomical landmarks were selected for each CBCT scan of the skull phantom. The slices were presented to six dentomaxillofacial radiologists, providing scores for various anatomical and diagnostic parameters. RESULTS: A hyperbolic relationship was seen between CNRAIR and mAs. Similarly, a gradual reduction in clinical image quality was seen at lower mAs values; however, for several protocols, image quality remained acceptable for a moderate or large mAs reduction compared with the standard exposure setting, depending on the clinical application. The relationship between mAs, CNRAIR and observer scores was different for each CBCT device. Minimally acceptable values for mAs were between 9 and 70, depending on the criterion and clinical application. CONCLUSIONS: Although noise increased at a lower mAs, clinical image quality often remained acceptable at exposure levels below the manufacturer's recommended setting, for certain patient groups. Currently, it is not possible to determine minimally acceptable values for image quality that are applicable to multiple CBCT models.

Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6000 samples.

OBJECTIVE: To evaluate in HIV-1 the extent of phenotypic and genotypic antiretroviral drug resistance and cross-resistance towards the protease inhibitors (PIs) saquinavir, ritonavir, indinavir and nelfinavir among a set of patient samples originating from European and US routine clinical practice and submitted for phenotypic drug resistance testing and/or genotypic analysis. The mutational pattern(s) underlying both resistance and cross-resistance to PIs was investigated. METHOD: Over 6000 patient isolates with plasma viral load greater than 1000 copies/ml plasma were analysed. Phenotypic resistance was evaluated by a recombinant virus assay. Phenotypic resistance is expressed as the fold-increase of the 50% inhibitory concentration (IC50) value of a compound for a patient-derived recombinant virus isolate compared with that for a wild-type laboratory virus. Genotypic analysis is reported as amino acid changes at positions in the HIV-1 protease compared to a wild-type reference. RESULTS: Phenotypic resistance to any single PI was observed in 17 to 25% of the clinical isolates investigated. Phenotypic cross-resistance among PIs (> 10-fold increase in IC50 value) was detected in 59 to 80% of the samples resistant (> 10-fold increase in IC50 value) to at least one PI. The prevalent mutations in PI-resistant isolates involved substitutions at codons 10, 36, 46, 54, 71, 77, 82 and 90. The most frequent mutational pattern in samples with PI cross-resistance involved combined substitutions at positions 10 and 90, extended with substitutions at positions 54, 71, 77, 82 or 84. CONCLUSIONS: Extensive use of first-generation PIs leads to the emergence of HIV-1 isolates possessing cross-resistance to all members of this class. Identification of particular mutational profiles among these isolates may assist in the design of new generation inhibitors with specific activity against protease-mutant HIV strains.

Baseline HIV drug resistance profile predicts response to ritonavir-saquinavir protease inhibitor therapy in a community setting.

OBJECTIVE: To determine whether baseline drug resistance assays could help to predict treatment failure with the protease inhibitor combination ritonavir-saquinavir. METHODS: Baseline HIV-1 drug resistance was determined for 76 consecutive patients who started treatment with the dual protease inhibitor combination ritonavir-saquinavir between September 1996 and June 1997 either alone or in combination with other antiviral agents. Resistance to 10 different antiviral agents was assessed by both phenotype (Virco Antivirogram) and genotype (Vircogen). RESULTS: Resistance inferred from viral genotype was similar to measured phenotypic resistance for both ritonavir and saquinavir (P<0.01). Baseline drug resistance phenotype was predictive of poor virological response to this dual protease inhibitor combination, despite the confounding effects of other antivirals. Patients were at least four times less likely to achieve a 0.5 log10 decrease in plasma HIV RNA viral load if their viral isolates were resistant to ritonavir or saquinavir. Patients classified as resistant to either drug using either method had median decreases in plasma viral load of 0.05 log10 HIV RNA copies/ml or less, compared to >0.8 log10 for those with sensitive virus. Patients resistant to both drugs never achieved plasma viral loads <100000 copies/ml. As little as fourfold increases in baseline resistance appeared to be sufficient to compromise even dual protease inhibitor therapy. CONCLUSION: Baseline resistance to ritonavir or saquinavir or both was associated with a poor antiviral response. Our data suggest that the measurement of drug resistance may assist in optimizing antiretroviral therapy in the clinic.