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PubMed2002

Normalized quantification of human cytomegalovirus DNA by competitive real-time PCR on the LightCycler instrument.

The development of a novel normalized quantitative competitive real-time PCR on the LightCycler instrument (NQC-LC-PCR) and its application to the quantification of cytomegalovirus (CMV) DNA in clinical samples are described. A heterologous competitor DNA was spiked into test samples and served as an internal amplification control. The internal control (IC) DNA in the test samples was coamplified with the CMV DNA and was tested against a calibrator sample that contained equal amounts of IC DNA and CMV reference standard DNA. An algorithm was developed to normalize possible varying amplification efficiencies between the standard and the samples. After normalization, CMV DNA copy numbers were determined in absolute terms. In a routine clinical setting, normalized quantification by NQC-LC-PCR using a single IC concentration led to results ranging from 500 to 50,000 CMV DNA copies/ml. The results obtained with conventional real-time quantification on the LightCycler instrument were almost identical to those obtained with the NQC-LC-PCR-based quantification. This was the case only for samples in which the PCR was not inhibited. With partially inhibited samples, NQC-LC-PCR was still able to correctly quantify CMV DNA copy numbers even when the PCR was inhibited by about 70%. By analyzing 80 undefined clinical samples, we found that NQC-LC-PCR was suitable for the routine assessment of CMV DNA in clinical plasma samples. Since the ICs were already added to the samples during the DNA purification, almost the entire assay was controlled for sample adequacy. Thus, false negative results were precluded. The NQC-LC-PCR approach developed should be adaptable for additional microbiological applications.

Cytomegalovirus↗

PubMedDate not supplied

A preliminary phantom study on a proposed model for quantification of renal planar scintigraphy.

A method for estimation of the absolute renal activity within background activity in renal planar scintigraphy will be presented. This method corrects for oversubtraction of background activity with consideration of background activity of the kidney volume, and employs the depth-independent buildup factor (DIBF) method for the correction of attenuation and scatter of photons. This method requires the depth and thickness of the organ and the thickness of background for a background activity correction. The transmission factor (TF) for a volume source is derived from integrating TF for a thin source over the thickness of the organ for the DIBF method. To validate this method, phantom studies with various uniform background activity concentrations were performed and the data were compared with conventional background subtraction that do not consider the organ's volume. The results showed that with the conventional background subtraction method at all depth activity was underestimated with errors of 5%-30% for organ/background concentration ratios of 5-40, while this method estimated the true count rate with errors of less than 5%. More accurate quantifications of renal functions such as renal uptake, glomerular filtration rate (GFR) and renogram may be obtained by this proposed method on the planar images.

Biophysical Phenomena↗

PubMed2004

Multiple spin-echo spectroscopic imaging for rapid quantitative assessment of N-acetylaspartate and lactate in acute stroke.

Monitoring the signal levels of lactate (Lac) and N-acetylaspartate (NAA) by chemical shift imaging can provide additional knowledge about tissue damage in acute stroke. Despite the need for this metabolic information, spectroscopic imaging (SI) has not been used routinely for acute stroke patients, mainly due to the long acquisition time required. The presented data demonstrate that the application of a fast multiple spin-echo (MSE) SI sequence can reduce the measurement time to 6 min (four spin echoes per echo train, 32 x 32 matrix). Quantification of Lac and NAA in terms of absolute concentrations (i.e., mmol/l) can be achieved by means of the phantom replacement approach, with correction terms for the longitudinal and transversal relaxation adapted to the multiple spin-echo sequence. In this pilot study of 10 stroke patients (symptom onset < 24 hr), metabolite concentrations obtained from MSE-SI add important information regarding tissue viability that is not provided by other sequences (e.g., diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI)). Metabolic changes extended beyond the borders of the apparent diffusion coefficient (ADC) lesion in nine of the 10 patients, showing a rise in Lac concentrations up to 18 mmol/l, while NAA levels sometimes dropped below the detection level. Considerable differences among the patients in terms of the Lac concentrations and the size of the SI-ADC mismatch were observed.

Acute Disease↗

PubMed2004

Analysis of force profile during a maximum voluntary isometric contraction task.

This study analyses maximum voluntary isometric contraction (MVIC) and its measurement by recording the force profile during maximal-effort, 7-s hand-grip contractions. Six healthy subjects each performed three trials repeated at short intervals to study variation from fatigue. These three trials were performed during three separate sessions at daily intervals to look at random variation. A pattern of force development during a trial was identified. An initiation phase, with or without an initiation peak, was followed by a maintenance phase, sometimes with secondary pulses and an underlying decline in force. Of these three MVIC parameters, maximum force during the maintenance phase showed less random variability compared to intertrial fatigue variability than did maximum force during the initiation phase or absolute maximum force. Analysis of MVIC as a task, rather than a single, maximal value reveals deeper levels of motor control in its generation. Thus, force parameters other than the absolute maximum force may be better suited to quantification of muscle performance in health and disease.

Adult↗

PubMed1995

A synthetic standard DNA construct for use in quantification of murine cytokine mRNA molecules.

A synthetic DNA construct has been developed as a standard molecule whereby murine cytokine mRNA molecules can be quantified by the reverse transcription-polymerase chain reaction (RT-PCR). The construct, designated Cytoquant 1, allows the quantification of murine IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IFN-gamma, TNF-alpha, TGF-beta, GM-CSF, CD4, CD8, HPRT and beta-actin mRNA levels. This technique is based on the amplification of a transcribed RNA molecule from Cytoquant 1 as an internal standard control in both the RT and PCR reactions. The quantification data from these analyses are expressed in absolute values, i.e. molecules/cell, which allows the data derived from separate experiments to be compared. In this study, mRNAs encoding beta-actin, IL-10, IFN-gamma and GM-CSF have been quantitated in both Th1 and Th2 cell clones with, and without, stimulation. The quantitative analysis data are highly reproducible and cytokine mRNA concentrations are reflective of restricted cytokine secretion patterns. Furthermore, constitutive cytokine mRNA levels are detectable in resting cells, eliminating the need for exogenous stimulation. The high degree of sensitivity and accuracy make this methodology uniquely suited for the study of T-cell subset cytokine expression in both in vivo and in vitro biological models.

Animals↗

PubMed1997

Determination of propiomazine in rat plasma by direct injection on coupled liquid chromatography columns with electrochemical detection.

This method describes the determination of propiomazine by direct injection of rat plasma into a chromatography system based on coupled reversed-phase columns. An extraction column, packed with porous silica particles with covalent-bound alpha1-acid glycoprotein (AGP), was used to separate the plasma proteins from the analyte. After isolation the analyte was transferred to the analytical column for separation and detection. Propiomazine was detected by an electrochemical detector and the limit of quantification was 2.0 ng/ml (100 pg injected). The absolute recovery was 80.9+/-2.4% at 9.0 ng/ml level. The inter-day and intra-day precision was 10.9% (5.6 ng/ml) and 2.8% (9.0 ng/ml), respectively.

Animals↗

PubMed1998

High-performance liquid chromatographic determination of the insulin sensitizing agent DRF-2189 in rat plasma.

A high-performance liquid chromatographic method for the determination of DRF-2189, using troglitazone as internal standard, is described. A dichloromethane-ethyl acetate solvent mixture (6:4, v/v) was used as the extraction solvent. A Kromasil C18 column with a mobile phase consisting of 0.05 M phosphate buffer-acetonitrile-methanol (22.5:37.5:40) (pH 5.0) was used at a flow-rate of 1.0 ml/min. The eluate was monitored by using fluorescence detection with excitation and emission wavelengths at 292 nm and 325 nm, respectively. Ratio of peak area of analyte to internal standard was used for quantification of plasma samples. Using this method, the absolute recovery of DRF-2189 from rat plasma was >95% and the limit of quantitation was 50 ng/ml. The intra-day relative standard deviation (R.S.D.) ranged from 1.74 to 7.24% at 1 microg/ml and 1.86 to 3.83% at 10 microg/ml. The inter-day R.S.D.s were 8.34 and 4.91% at 1 and 10 microg/ml, respectively. The method was applied to measure plasma concentrations of DRF-2189 in pharmacokinetic studies in Wistar rats.

Animals↗

PubMed2006

Relative sensitivity factors of inorganic cations in frozen-hydrated standards in secondary ion MS analysis.

We describe the measurement, at 100 K, of the SIMS relative sensitivity factors (RSFs) of the main physiological cations Na+, K+, Mg2+, and Ca2+ in frozen-hydrated (F-H) ionic solutions. Freezing was performed by either plunge freezing or high-pressure freezing. We also report the measurement of the RSFs in flax fibers, which are a model for ions in the plant cell wall, and in F-H ionic samples, which are a model for ions in the vacuole. RSFs were determined under bombardment with neutral oxygen (FAB) for both the fibers and the F-H samples. We show that referencing to ice-characteristic secondary ions is of little value in determining RSFs and that referencing to K is preferable. The RSFs of Na relative to K and of Ca relative to Mg in F-H samples are similar to their respective values in fiber samples, whereas the RSFs of both Ca and Mg relative to K are lower in fibers than in F-H samples. Our data show that the physical factors important for the determination of the RSFs are not the same in F-H samples and in homogeneous matrixes. Our data show that it is possible to perform a SIMS relative quantification of the cations in frozen-hydrated samples with an accuracy on the order of 15%. Referencing to K permits the quantification of the ionic ratios, even when the absolute concentration of the referencing ion is unknown. This is essential for physiological studies of F-H biological samples.

Journal Article↗

PubMed2003

Role of ADME characteristics in drug discovery and their in silico evaluation: in silico screening of chemicals for their metabolic stability.

Drug discovery is a long, arduous process broadly grouped into disease target identification, target validation, high-throughput identification of "hits" and "leads", lead optimization, and pre-clinical and clinical evaluation. Each area is a vast discipline in itself. However, all but the first two stages involve, to varying degrees, the characterization of absorption, distribution, metabolism, excretion, (ADME), and toxicity (T) of the molecules being pursued as potential drug candidates. Clinical failures of about 50% of the Investigational New Drug (IND) filings are attributed to their inadequate ADMET attributes. It is, therefore, no surprise that, in the current climate of social and regulatory pressure on healthcare costs, the pharmaceutical industry is searching for any means to minimize this attrition. Building mathematical models, called in silico screens, to reliably predict ADMET attributes solely from molecular structure is at the heart of this effort in reducing costs as well as development cycle times. This article reviews the emerging field of in silico evaluation of ADME characteristics. For different approaches that have been employed in this area, a critique of the scope and limitations of their descriptors, statistical methods, and reliability are presented. For instance, are geometry-based descriptors absolutely essential or is lower-level structure quantification equally good? What advantages, if any, do we have for methods like artificial neural networks over the least squares optimization methods with rigorous statistical diagnostics? Is any in silico screen worth application, let alone interpretation, if it is not adequately validated? Once deemed acceptable, what good is an in silico screen if it cannot be made available at the workbench of drug discovery teams distributed across the globe throughout multi-national pharmaceutical companies? These are not mere discussion points, rather this article embarks on the stepwise mechanics of developing a successful in silico screen. The process is exemplified by our efforts in developing one such screen for predicting metabolic stability of chemicals in a human S9 liver homogenate assay. A real-life use of this in silico screen in a variety of discovery projects at GlaxoSmithKline is presented, highlighting successes and limitations of such applications. Finally, we project some capabilities of in silico ADME tools for greater impact and contribution to successful, efficient drug discovery.

Computer-Aided Design↗

PubMed1975

Liquid chromatography in pharmaceutical analysis IV: determination of antispasmodic mixtures.

Parameters associated with the separation of antianxiety-antispasmodic agents were investigated using high-pressure liquid chromatography. Eight widely prescribed drugs were studied. The compounds were chromatographed on reversed-phase octadecyltrichlorosilane (C18) or diphenyldichlorosilane (phenyl) columns, using mixtures of absolute methanol and distilled water buffered with ammonium dihydrogen phosphate, ammonium acid phosphate, or ammonium carbonate. A mixture of phenobarbital-propantheline bromide was selected to demonstrate the utility of the separation and quantification method. The mixture was chromatographed on a phenyl column, using absolute methanol-aqueous 1 percent ammonium dihydrogen phosphate (60:40) (pH 5.85) at a flow rate of 1.4 ml/min. Each determination can be achieved in approximately 15 min with an accuracy of 1-2 percent.

Atropine↗

PubMed2006

Determining 234Th and 238U in rocks, soils, and sediments via the doublet gamma at 92.5 keV.

Efficient and accurate measurements of uranium (U) and U-series radionuclides in earth's materials are needed to assess its environmental impact, reconstruct geochemical histories, and quantify heat production in the crust. To date, measurements of 234Th and 238U by gamma spectrometry have relied on the quantification of 234Th gamma emissions at approximately 63 keV (absolute intensity = 3.7%) and the (234m)Pa gamma at 1001 keV (absolute intensity = 0.84%). However, use of the 63 keV emissions can be hampered by 232Th interferences and self absorption, and the 1001 keV photon has a very low yield. Here we describe the effective use of the 234Th doublet gamma emission at approximately 92.5 keV (total absolute intensity = 4.8%) for 234Th and 238U measurements. This doublet has been largely ignored because of its proximity to the Th K(alpha1) (93.3 keV) and thus its vulnerability to a Th self-fluorescence interference. We demonstrate that additions of U and 40K to a Th ore sample do not increase the count rate at 92-93 keV above that which would be expected from the associated additions of U and 234Th. We also show that the Th self-fluorescence interference appears to be an anomaly associated only with the analysis of relatively thick (>1 mm) Th minerals, and suggest that fluorescence will not complicate the 92-93 keV region in most environmental samples. A review of decay data reveals that Th K(alpha1) X-rays associated with the decay of 235U and 228Ac can significantly interfere with quantification of the 92.5 keV 234Th doublet. We show that simple experimentally-derived correction factors for these X-rays can be used to accurately determine 234Th using its strongest gammas, resulting in higher count rates and smaller self-absorption corrections relative to the traditional analytical lines. Total 1 sigma analytical error associated with U measurements at 92.5 keV ranged from 1 to 9% and is dominated by the relative size of the 228Ac interference. Detection limits for U in environmental samples using this technique are on the order of 50 ppb.

Journal Article↗

PubMed1991

[Quantification of T-lymphocyte subpopulations. Immunological marker in human immunodeficiency virus infections].

The absolute number of CD4+ and CD8+ T cells was counted directly in the blood of 75 healthy controls and 223 individuals infected with human immunodeficiency virus (HIV). The HIV-seropositive individuals were also classified clinically according to the system recommended by the Centers for Disease Control. We observed a pattern of changes in the T cell subset counts of the patient group. This pattern could be defined by five T cell stages ranging from normal T cell subset values to values representing severe T cell immunodeficiency. A close correlation was observed between the immunological and clinical classification of the patients. Quantification of T cell subsets may provide useful information in the follow-up of individuals infected with HIV, particularly in assessing the indications for antiviral therapy, and its effects.

HIV Infections↗

PubMed1991

Quantification of glutamate, glutamine, and other metabolites in in vivo proton NMR spectroscopy.

A reliable quantification of in vivo 1H MRS spectra is hampered by extensive line overlap, by intensity distortions due to the water suppressing pulse sequence and complex modulation patterns of J-coupled spins, and by deviations between the experimental and model lineshapes in computer fitting programs. By correcting the experimental lineshape, using a suitable pulse sequence, and incorporating prior knowledge about the spin systems and the intensity distortions, a sufficient quantification is possible. If reliable T2 values are available absolute concentrations can be determined.

Animals↗

PubMed2006

High-performance liquid chromatographic method for the determination of moclobemide and its two major metabolites in human plasma.

A selective, sensitive, and simple high-performance liquid chromatographic (HPLC) method was developed for the determination of moclobemide and its two major metabolites, Ro 12-5637 and Ro 12-8095, in human plasma. Sample preparation (0.5 ml of plasma) involved solid-phase extraction (SPE) using Speedisk H(2)O-Philic DVB columns. Separations were performed on a Waters XTerra RP18 column (5 microm, 150 mm x 4.6 mm). The mobile phase consisted of 10 mM KH(2)PO(4) with 1% triethylamine (pH 3.9) and acetonitrile (83:17, v/v), and a flow-rate was 1.2 ml/min. The total run time was 13 min. UV detection was performed at 240 nm. Mean absolute recoveries were > or =90% and the limit of quantification (LOQ) for all analytes was 0.02 mg/l. Calibration curves were linear (r>0.995) over a wide range of the analyte concentrations in plasma; thus, the method is suitable for different clinical studies when large variations in the drug/metabolites concentrations are observed. During a 5-day assay validation procedure the accuracy and precision were tested and proven (relative errors (RE)< or =13%; intra-day coefficient of variation (CV)< or =7%; inter-day CV< or =13%). Many drugs frequently used in the target patient population were evaluated for potential interference in order method selectivity to be ensured. The assay has been used in a clinical pharmacokinetic study to assess steady-state pharmacokinetics of moclobemide and two metabolites in depressive patients on mono- and combined therapy.

Benzamides↗

PubMed2001

Lymphatic transport of proteins after s.c. injection: implications of animal model selection.

Subcutaneous (s.c.) administration continues to be the main route for the delivery of protein drugs due to their poor bioavailability by most non-parenteral routes. While small drug molecules are rapidly and extensively absorbed after s.c. injection, the systemic bioavailability of protein drugs is often incomplete and variable. Given the widespread use of the s.c. route for protein drugs, surprisingly little is known about the factors that govern the rate and extent of protein absorption from the interstitial space and the role of the lymphatic system in the transport of these molecules to the systemic circulation. The few studies that have directly addressed the role of lymphatic transport in protein bioavailability are complicated by the use of methods and models that vary widely. In this review we will evaluate the available literature describing the lymphatic transport of proteins after s.c. injection and more specifically, address the impact of experimental variation (e.g. site of cannulation, animal model, anesthesia) on the interpretation of the data obtained. We will also describe in some detail the sheep model currently in use in our laboratory, which allows both estimation of the extent of uptake of protein drugs into the lymphatics draining the injection site, and quantification of the contribution of lymphatic transport to the absolute bioavailability.

Animals↗

PubMed1997

The variability of the centre of pressure pattern.

INTRODUCTION:: The centre of pressure pattern (COPP), or force line, has been used to describe abnormal foot movement during gait and as a method to assess foot orthoses effectiveness. The purpose, therefore, of this study was to measure the between-trial variability of the COPP as well as explore possible differences between shoe-floor and within-shoe measurements. METHODS:: Ten healthy individuals from a pool of 110 volunteers were selected for this study based upon their willingness to participate and the presence of a forefoot and/or rearfoot valgus or varus deformity. An EMED-SF pressure platform was used to collect COPP data at the shoe-floor interface. The EMED PEDAR insole pressure system was used to collect COPP data within-the-shoe. Ten trials of COPP were recorded simultaneously using the two systems as the subjects walked over ground in standardized footwear and two different types of foot orthoses. The footwear used consisted of the Reebok Boston Road running shoe. The two types of orthoses studied were a rigid orthotic with forefoot and/or rearfoot posts and soft orthotic without any posts. Quantification of the COPP was achieved by calculating its absolute integral. RESULTS:: The result of a one-way repeated measuresANOVA and subsequent post-hoc analysis showed that the rigid orthoses condition was significantly different from the soft orthoses or no orthosis conditions. Analysis of the between-trial reliability for COPP integral calculation, however, indicated that there was 43.4 to 48.6% variability. The intraclass correlation coefficients were found to be less than 0.504. DISCUSSION:: While the results showed that the within-shoe shoe only condition and the soft orthoses condition caused the greatest decrease in the COPP integral, the COPP integral was extremely inconsistent, whether measured at the shoe-floor interface or within-the-shoe. CONCLUSION:: The results of this investigation indicate that COPP is highly variable when measured either at the shoe-floor interface or within-the-shoe over multiple trials. Based upon these findings, the COPP, as measured by its absolute integral, would be a poor representation of foot movement and, as such, would not be an acceptable method for the assessment of foot orthoses effectiveness.

Journal Article↗

PubMed2004

Direct gene expression analysis.

The direct analysis of single biological molecules is getting increasingly important in basic as well as pharmaceutical research (e.g. for gene expression analysis). In particular single-molecule fluorescence detection provides exciting new opportunities to probe biochemical processes in unprecedented detail. Currently several academic and industrial research groups work on the development of single molecule detection based technologies in order to directly detect and analyze RNA and DNA molecules. As these developed methods are characterized as homogenous assays and obviate any amplification of the target or the signal, they provide clear advantages compared to methods like real-time PCR or DNA- arrays. In the following we describe a recently developed approach based on fluorescence correlation spectroscopy (FCS). This expression assay is based on gene-specific hybridization of two dye-labeled DNA probes to a selected target molecule (either DNA or RNA) in solution. The subsequent dual color cross-correlation analysis allows the quantification of the bio-molecule of interest in absolute numbers. Target concentrations of less than 10(-12) M can be easily monitored, covering the direct analysis of the expression levels of high, medium and low abundant genes.

Animals↗

PubMedDate not supplied

Spiral CT evaluation of pulmonary emphysema using a low-dose technique.

PURPOSE: To evaluate the diagnostic accuracy and clinical acceptability of low-dose spiral CT for determining pulmonary volumes and emphysema extension in patients with pulmonary emphysema, in comparison with studies based on spiral CT at conventional dose. MATERIALS AND METHODS: We prospectively evaluated eighteen patients, current or former smokers, with a clinical diagnosis of chronic obstructive pulmonary disease. All the patients underwent: HRCT with three scans at predetermined levels; quantitative spiral CT, with two inspiratory scans, one conventional scan at 240 mA, and the second one a low-dose scan at 80 mA. We used the following parameters: 120 kV, rotation time 0.8", scan time less than 20" (single inspiratory breath-hold), layer thickness 7.5 mm, pitch 6 (high speed), interpolation algorithm at 180 degrees. A 3D reconstruction was performed, with segmentation of the lungs and automatic quantification of pulmonary volumes. We compared the volumes of absolute and percent emphysema and the ratings of the dose delivered to the patient (CTDIw and DLP) obtained with the two spiral CT scans with each other and with the respiratory function tests. RESULTS: The average total lung capacity (TLC) obtained by conventional-dose spiral CT (CTs1) was 6889.4 cc (SD +/-1813.2), and the capacity with low-dose spiral CT (CTs2) was 6929.4 cc (SD +/-1811.6). The percentage of emphysema was 39.7% (range: 2.2-63.5%; SD: +/-19.9) for the CTs1 and 41.1% (range: 2.1-66.4%; SD: +/-20). The CTDIw corresponding to CTs1 was 12.2 mGy (range: 11.9-16.4; SD: +/-1), the one corresponding to CTs2, 3.6 mGy (range: 3.6-4.9; SD: +/-0.3). The DLP corresponding to CTs1 was 391.7 mGy x cm (range: 333.3-518.9; SD: +/-46.7), the one corresponding to CTs2 was 117.8 mGy x cm (range: 100.3-156; SD: +/-14). As for the respiratory function tests, the total lung capacity (TLC) obtained by body plethysmography was 7061 cc (SD: +/-2029.7); the percent TLC was 115.9 (range: 66-165; SD: +/-27.6), the forced expiratory volume at one second (FEV1%, percentage of predicted value) was 46.7% (range: 17-123; SD: +/-27.3), residual volume (RV%) as a percentage of predicted value was 186.3 (range: 84-359; SD: +/-80.7), the Tiffeneau index (TI) was 46% (range: 25-71; SD: +/-15.7). We observed a very significant correlation between radiological and functional TLC for both CT methods. The percentage scores for emphysema obtained with the two methods correlated significantly with the functional indexes. The pixel index of CTs1 correlated with TLC% (r=0.87; p<0.0001), FEV1% (r=-0.53; p<0.02), RV% (r=0.76; p=0.004), TI (r=-0.79; p=0.0001). The pixel index of CTs2 correlated with TLC% (r=0.87; p<0.0001), FEV1% (r=-0.56; p=0.01), RV% (r=0.78; p=0.003), TI (r=-0.8; p=0.0001). The adoption of the method with low tube current entailed a highly significant reduction in the estimated dose delivered to patients (CTDIw and DLP) with r=0.9 and p < 0.0001. DISCUSSION AND CONCLUSIONS: Quantitative low-dose spiral CT is a very good method to quantify pulmonary volumes and calculate the extension of the anatomic emphysema. The reduction of mA from 240 to 80 lowers the estimated dose by 30%, without compromising the accuracy of the results. Our study achieved a highly significant correlation between the results obtained with the two spiral CT techniques and between these results and the respiratory function tests. In clinical practice, the easiest way to reduce the dose in spiral CT of the lung is to reduce the tube current. The low-dose method allows a significant reduction in radiation exposure. Further studies are required to establish to what extent the dose can be reduced without increasing in quantum noise and thereby compromising the quality of the study.

Adult↗