Image intensity normalisation by maximising the Siddon line integral in the joint intensity distribution space.

This paper presents a novel data-driven method for image intensity normalisation, which is a prerequisite step for any kind of image comparison. The method involves a novel application of the Siddon algorithm that was developed initially for fast reconstruction of tomographic images and is based on a linear normalisation model with either one or two parameters. The latter are estimated by maximising the line integral, computed using the Siddon algorithm, in the 2D joint intensity distribution space of image pairs. The proposed normalisation method, referred to as Siddon Line Integral Maximisation (SLIM), was compared with three other methodologies, namely background ratio (BAR) scaling, linear fitting and proportional scaling, using a large number of synthesised datasets. SLIM was also compared with BAR normalisation when applied to phantom data and two clinical examples. The new method was found to be more accurate and less biased than its counterparts for the range of characteristics selected for the synthesised data. These findings were in agreement with the results from the analysis of the experimental and clinical data.

An investigation into the use of CMOS active pixel technology in image-guided radiotherapy.

The increased intelligence, read-out speed, radiation hardness and potential large size of CMOS active pixel sensors (APS) gives them a potential advantage over systems currently used for verification of complex treatments such as IMRT and the tracking of moving tumours. The aim of this work is to investigate the feasibility of using an APS-based system to image the megavoltage treatment beam produced by a linear accelerator (Linac), and to demonstrate the logic which may ultimately be incorporated into future sensor and FPGA design to evaluate treatment and track motion. A CMOS APS was developed by the MI(3) consortium and incorporated into a megavoltage imaging system using the standard lens and mirror configuration employed in camera-based EPIDs. The ability to resolve anatomical structure was evaluated using an Alderson RANDO head phantom, resolution evaluated using a quality control (QC3) phantom and contrast using an in-house developed phantom. A complex intensity-modulated radiotherapy (IMRT) treatment was imaged and two algorithms were used to determine the field-area and delivered dose, and the position of multi-leaf collimator (MLC) leaves off-line. Results were compared with prediction from the prescription and found to agree within a single image frame time for dose delivery and 0.02-0.03 cm for the position of collimator leaves. Such a system therefore shows potential as the basis for an on-line verification system capable of treatment verification and monitoring patient motion.

The application of polymer gel dosimeters to dosimetry for targeted radionuclide therapy.

There is a lack of standardized methodology to perform dose calculations for targeted radionuclide therapy and at present no method exists to objectively evaluate the various approaches employed. The aim of the work described here was to investigate the practicality and accuracy of calibrating polymer gel dosimeters such that dose measurements resulting from complex activity distributions can be verified. Twelve vials of the polymer gel dosimeter, 'MAGIC', were uniformly mixed with varying concentrations of P-32 such that absorbed doses ranged from 0 to 30 Gy after a period of 360 h before being imaged on a magnetic resonance scanner. In addition, nine vials were prepared and irradiated using an external 6 MV x-ray beam. Magnetic resonance transverse relaxation time, T2, maps were obtained using a multi-echo spin echo sequence and converted to R2 maps (where T2 = 1/R2). Absorbed doses for P-32 irradiated gel were calculated according to the medical internal radiation dose schema using EGSnrc Monte Carlo simulations. Here the energy deposited in cylinders representing the irradiated vials was scored. A relationship between dose and R(2) was determined. Effects from oxygen contamination were present in the internally irradiated vials. An increase in O2 sensitivity over those gels irradiated externally was thought to be a result of the longer irradiation period. However, below the region of contamination dose response appeared homogenous. Due do a drop-off of dose at the periphery of the internally irradiated vials, magnetic resonance ringing artefacts were observed. The ringing did not greatly affect the accuracy of calibration, which was comparable for both methods. The largest errors in calculated dose originated from the initial activity measurements, and were approximately 10%. Measured R2 values ranged from 5-35 s(-1) with an average standard deviation of 1%. A clear relationship between R2 and dose was observed, with up to 40% increased sensitivity for internally irradiated gels. Curve fits to the calibration data followed a single exponential function. The correlation coefficients for internally and externally irradiated gels were 0.991 and 0.985, respectively. With the ability to accurately calibrate internally dosed polymer gels, this technology shows promise as a means to evaluate dosimetry methods, particularly in cases of non-uniform uptake of a radionuclide.

The PETRRA positron camera: design, characterization and results of a physical evaluation.

The PETRRA positron camera is a large-area (600 mm x 400 mm sensitive area) prototype system that has been developed through a collaboration between the Rutherford Appleton Laboratory and the Institute of Cancer Research/Royal Marsden Hospital. The camera uses novel technology involving the coupling of 10 mm thick barium fluoride scintillating crystals to multi-wire proportional chambers filled with a photosensitive gas. The performance of the camera is reported here and shows that the present system has a 3D spatial resolution of approximately 7.5 mm full-width-half-maximum (FWHM), a timing resolution of approximately 3.5 ns (FWHM), a total coincidence count-rate performance of at least 80-90 kcps and a randoms-corrected sensitivity of approximately 8-10 kcps kBq(-1) ml. For an average concentration of 3 kBq ml(-1) as expected in a patient it is shown that, for the present prototype, approximately 20% of the data would be true events. The count-rate performance is presently limited by the obsolete off-camera read-out electronics and computer system and the sensitivity by the use of thin (10 mm thick) crystals. The prototype camera has limited scatter rejection and no intrinsic shielding and is, therefore, susceptible to high levels of scatter and out-of-field activity when imaging patients. All these factors are being addressed to improve the performance of the camera. The large axial field-of-view of 400 mm makes the camera ideally suited to whole-body PET imaging. We present examples of preliminary clinical images taken with the prototype camera. Overall, the results show the potential for this alternative technology justifying further development.

Statistical pixelwise inference models for planar data analysis: an application to gamma-camera uniformity monitoring.

In this paper two tests based on statistical models are presented and used to assess, quantify and provide positional information of the existence of bias and/or variations between planar images acquired at different times but under similar conditions. In the first test a linear regression model is fitted to the data in a pixelwise fashion, using three mathematical operators. In the second test a comparison using z-scoring is used based on the assumption that Poisson statistics are valid. For both tests the underlying assumptions are as simple and few as possible. The results are presented as parametric maps of either the three operators or the z-score. The z-score maps can then be thresholded to show the parts of the images which demonstrate change. Three different thresholding methods (naive, adaptive and multiple) are presented: together they cover almost all the needs for separating the signal from the background in the z-score maps. Where the expected size of the signal is known or can be estimated, a spatial correction technique (referred to as the reef correction) can be applied. These tests were applied to flood images used for the quality control of gamma camera uniformity. Simulated data were used to check the validity of the methods. Real data were acquired from four different cameras from two different institutions using a variety of acquisition parameters. The regression model found the bias in all five simulated cases and it also found patterns of unstable regions in real data where visual inspection of the flood images did not show any problems. In comparison the z-map revealed the differences in the simulated images from as low as 1.8 standard deviations from the mean, corresponding to a differential uniformity of 2.2% over the central field of view. In all cases studied, the reef correction increased significantly the sensitivity of the method and in most cases the specificity as well. The two proposed tests can be used either separately or in combination and are capable of showing trends and/or the magnitude of difference between images acquired under similar conditions with high positional and statistical precision. In addition to gamma camera quality control, they could be applied to any pair (or set) of registered planar images to detect subtle changes, e.g. a set of scintigrams or conventional radiographs of a patient before, during and after treatment.

Multicellular dosimetry in voxel geometry for targeted radionuclide therapy.

A software package to investigate absorbed doses and dose-rates at the cellular and multicellular scale has been developed that considers two- and three-dimensional activity distributions and makes use of analytical representations of the point-dose kernels for (131)I, (32)P, and (90)Y. This software allows cell assemblies to be simulated by definition of the number, size, and geometry of cells and their nuclei, and radionuclide uptake can be specified to occur within the nucleus, the cytoplasm, at the membrane, or within the extracellular space. The software has been validated at a cellular scale by comparison with results obtained using spherical geometry, as found in the literature. At a multicellular scale, comparisons were made with a Monte Carlo simulation in voxel geometry. The software has been designed to work within a user-defined voxel geometry. This geometry is useful not only to simulate complex cell assemblies and realistic heterogeneous radionuclide distributions, but will also allow the use of histological and autoradiographic data. Absorbed dose distributions for a single cell calculated using this code varied significantly with activity localization within the cell, and to a lesser extent, with the cellular geometry. At a multicellular level, a two-dimensional heterogeneous activity distribution inferred from a two-dimensional image of a slice throughout a spheroid was used to calculate a dose-rate distribution. This resulted in a heterogeneous dose-rate delivery even for longer-range radionuclides such as (90)Y and (32)P.

Scaling images using their background ratio. An application in statistical comparisons of images.

Comparison of two medical images often requires image scaling as a pre-processing step. This is usually done with the scaling-to-the-mean or scaling-to-the-maximum techniques which, under certain circumstances, in quantitative applications may contribute a significant amount of bias. In this paper, we present a simple scaling method which assumes only that the most predominant values in the corresponding images belong to their background structure. The ratio of the two images to be compared is calculated and its frequency histogram is plotted. The scaling factor is given by the position of the peak in this histogram which belongs to the background structure. The method was tested against the traditional scaling-to-the-mean technique on simulated planar gamma-camera images which were compared using pixelwise statistical parametric tests. Both sensitivity and specificity for each condition were measured over a range of different contrasts and sizes of inhomogeneity for the two scaling techniques. The new method was found to preserve sensitivity in all cases while the traditional technique resulted in significant degradation of sensitivity in certain cases.

Continuous angiotensin II infusion increases tumour: normal blood flow ratio in colo-rectal liver metastases.

Insufficient blood flow within colo-rectal hepatic metastases is a factor which may limit drug delivery to, and thus the response of, these tumours to regional chemotherapy. Loco-regional flow may be manipulated pharmacologically to enhance the tumour blood flow relative to that of the normal liver. However, as yet, only transient effects have been studied. Patients receiving regional chemotherapy for unresectable hepatic disease were given a 45 min regional infusion of the vasoconstrictor Angiotensin II. Intrahepatic blood flow distribution was assessed serially by Positron Emission Tomography (PET) imaging together with the trapping tracer copper(II) pyruvaldehyde bis(N-4-methylthiosemicarbazone) (Cu-PTSM) labelled using copper-62. Eleven lesions in nine patients were studied, with no adverse effects. Prior to Angiotensin II administration tumour blood flow was generally found to be greater than that of liver (10/11 lesions; 8/9 patients; median TNR 1.3, iqr 0.9-2.5). A significant increase in relative flow to tumour was seen in response to 10 min Angiotensin II infusion in most cases (7/11 lesions; 7/9 patients; median TNR 2.1, iqr 1.4-4.1; P = 0.008), which appeared to be sustained throughout the 45 min infusion period (median TNR 1.85, iqr 1.3-3.8; P = 0.03). These effects were accompanied by transient elevation of mean arterial pressure, but no change in pulse rate. These observations suggest that prolonged regional vasoconstrictor administration could prove useful in the management of unresectable colo-rectal hepatic metastases, and that further development of vascular manipulation to enhance tumour targeting and drug delivery is warranted.

Identification of a series of PPAR gamma/delta dual agonists via solid-phase parallel synthesis.

We have developed a general solid-phase synthesis for identification of PPAR ligands. Synthesis of a 480-member library led to the identification of a potent PPAR gamma/delta dual agonist 23. Compound 23 showed good plasma exposure in rats and demonstrated antihyperglycemic and antihyperlipidemic efficacy in diabetic fatty Zucker rats.

Effects of fenofibrate on lipid parameters in obese rhesus monkeys.

Fenofibrate is a member of the fibrate class of hypolipidemic agents used clinically to treat hypertriglyceridemia and mixed hyperlipidemia. The fibrates were developed primarily on the basis of their cholesterol and triglyceride lowering in rodents. Fibrates have historically been ineffective at lowering triglycerides in experimentally-induced dyslipidemia in nonhuman primate models. The spontaneously obese rhesus monkey is a well-recognized animal model for the study of human obesity and type 2 diabetes, and many of these monkeys exhibit naturally occurring lipid abnormalities, including elevated triglycerides and low HDL cholesterol (HDL-C), similar to patients with type 2 diabetes. To explore whether the obese rhesus model was predictive of the lipid lowering effects of fibrates, we evaluated fenofibrate in six hypertriglyceridemic, hyperinsulinemic, nondiabetic animals in a 20-week, dose-escalating study. The study consisted of a 4-week baseline period, two treatment periods of 10 mg/kg twice daily (b.i.d) for 4 weeks and 30 mg/kg b.i.d. for 8 weeks, and a 4-week washout period. Fenofibrate (30 mg/kg b.i.d) decreased serum triglycerides 55% and LDL-C 27%, whereas HDL-C increased 35%. Apolipoproteins B-100 and C-III levels were also reduced 70% and 29%, respectively. Food intake, body weight, and plasma glucose were not affected throughout the study. Interestingly, plasma insulin levels decreased 40% during the 30 mg/kg treatment period, suggesting improvement in insulin sensitivity. These results support the use of obese rhesus monkey as an excellent animal model for studying the effects of novel hypolipidemic agents, particularly agents that impact serum triglycerides and HDL-C.

2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1.

A series of 2-amino-5-arylthiobenzonitriles (1) was found to be active against HIV-1. Structural modifications led to the sulfoxides (2) and sulfones (3). The sulfoxides generally showed antiviral activity against HIV-1 similar to that of 1. The sulfones, however, were the most potent series of analogues, a number having activity against HIV-1 in the nanomolar range. Structural-activity relationship (SAR) studies suggested that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral activities. However, optimal antiviral activities were manifested by compounds where both meta groups in the arylsulfonyl moiety were substituted and one of the substituents was a methyl group. Such a disubstitution led to compounds 3v, 3w, 3x, and 3y having IC50 values against HIV-1 in the low nanomolar range. When gauged for their broad-spectrum antiviral activity against key non-nucleoside reverse transcriptase inhibitor (NNRTI) related mutants, all the di-meta-substituted sulfones 3u-z and the 2-naphthyl analogue 3ee generally showed single-digit nanomolar activity against the V106A and P236L strains and submicromolar to low nanomolar activity against strains E138K, V108I, and Y188C. However, they showed a lack of activity against the K103N and Y181C mutant viruses. The elucidation of the X-ray crystal structure of the complex of 3v (739W94) in HIV-1 reverse transcriptase showed an overlap in the binding domain when compared with the complex of nevirapine in HIV-1 reverse transcriptase. The X-ray structure allowed for the rationalization of SAR data and potencies of the compounds against the mutants.

62Cu-PTSM and PET used for the assessment of angiotensin II-induced blood flow changes in patients with colorectal liver metastases.

The aim of this study was to establish a quantitative positron emission tomography (PET) method for investigating angiotensin II (AII)-induced changes in blood flow distribution in the liver. This was in order to evaluate the role of vascular manipulation applied to locoregional chemotherapy treatment in patients with colorectal liver metastases. The tracer selected was copper-62 (II) pyruvaldehyde bis-(N4-methyl)thiosemicarbazone (62Cu-PTSM), which exhibits high first-pass extraction and tissue retention following intra-arterial administration. The short half-life of the tracer and its availability from a 62Zn/62Cu generator enabled short-interval repeat PET scans on patients in a single imaging session. Distribution of tracer within the liver was imaged in a single view using a PET camera with rotating large-area detectors. By optimisation of the acquisition protocol, it was possible to acquire sufficient data to produce good-quality images and to quantify tracer uptake with an accuracy of <10%. Reproducibility of the imaging method was assessed in a single patient in whom three consecutive 62Cu-PTSM PET scans were obtained, and in whom no vascular manipulation was performed. Sets of scans (before, during and immediately after a 45-min AII infusion) were obtained in nine patients to assess blood flow changes associated with prolonged vascular manipulation. Significant individual responses, varying in both the magnitude and the duration of flow change, were observed in the majority of cases (7/11 lesions; 7/9 patients). These findings illustrate the potential of 62Cu-PTSM and PET for pharmacological studies. The wide range of individual patient responses to AII infusion suggests that PET blood flow assessment would be of value for selecting patients in whom this procedure may be effective.

Classification of reflectance spectra from pigmented skin lesions, a comparison of multivariate discriminant analysis and artificial neural networks.

Successful treatment of skin cancer, especially melanoma, depends on early detection, but diagnostic accuracy, even by experts, can be as low as 56% so there is an urgent need for a simple, accurate, non-invasive diagnostic tool. In this paper we have compared the performance of an artificial neural network (ANN) and multivariate discriminant analysis (MDA) for the classification of optical reflectance spectra (320 to 1100 nm) from malignant melanoma and benign naevi. The ANN was significantly better than MDA, especially when a larger data set was used, where the classification accuracy was 86.7% for ANN and 72.0% for MDA (p < 0.001). ANN was better at learning new cases than MDA for this particular classification task. This study has confirmed that the convenience of ANNs could lead to the medical community and patients benefiting from the improved diagnostic performance which can be achieved by objective measurement of pigmented skin lesions using spectrophotometry.

FDG-PET in the prediction of survival of patients with cancer of the pancreas: a pilot study.

Carcinoma of the pancreas is an aggressive tumour with an extremely poor prognosis. Recent studies have shown that chemotherapy can improve survival as well as quality of life. Since the prognosis is generally poor, the identification of early responders to chemotherapy is important to avoid unnecessary toxicity in patients who are not responding. Response assessment by conventional radiographic methods is problematical because treatment induces fibrosis and makes tumour measurements difficult. The aim of this pilot study was to assess 18-fluoro-deoxy-glucose positron emission tomography (FDG-PET) as an early marker of the benefit of chemotherapy. Eleven patients with histologically proven adenocarcinoma of the pancreas were treated with protracted venous infusional 5-fluorouracil (PVI 5-FU) alone or PVI 5-FU and mitomycin C (MMC). FDG-PET scans were performed prior to and at 1 month following the commencement of chemotherapy. FDG uptake was compared with the tumour dimensions measured on a computer tomographic (CT) scan. Patients were followed up for relapse, death and symptomatic response. Three of the 11 patients had no measurable FDG uptake prior to chemotherapy. Of the eight patients who had measurable uptake prior to treatment, seven had a reduction in uptake at 1 month. Six out of the 11 patients had no measurable FDG uptake at 1 month. The overall survival (OS) in these patients ranged from 124 to 1460 days, with a median of 318.5 days. This was superior in comparison to patients who had residual FDG uptake at 1 month (median survival 318.5 days vs 139 days; P = 0.034) and there was a trend to improved symptoms (84% [5/6] vs 20% [1/5]; P = 0.13). There was no statistically significant correlation between best CT response and FDG uptake at 1 month. These results suggest that the absence of FDG uptake at 1 month following chemotherapy for carcinoma of the pancreas is an indicator of improved overall survival. This suggests that FDG-PET may be superior to response assessment by conventional radiographic methods and FDG-PET may have the potential to help make difficult treatment decisions in the management of pancreatic cancer. Larger prospective studies are required to confirm this finding.

The performance of a CCD digital autoradiography imaging system.

Autoradiography is a widely used technique for imaging trace quantities of radioactivity within biological samples, conventionally using photographic film. This method produces images with high spatial resolution, but it suffers from very low sensitivity and poor dynamic range. Digital autoradiography systems with greatly improved sensitivity and linearity are commercially available, but the spatial resolution is usually much less than that achieved using film. We report here the design, construction and characterization of a novel digital autoradiography system based on scientific-grade charged coupled devices (CCDs). Images of x-ray and beta emissions from radionuclides commonly used in autoradiography show that the system can perform high-speed quantitative imaging with a spatial resolution of approximately 30, microm. Using a frame by frame acquisition method the dynamic range is shown to be at least three orders of magnitude. The absolute detection efficiency is comparable to the best of the currently available digital systems. CCD images of 125I and 14C radioisotope distributions in tissue samples are superior to the equivalent film images and have been acquired in 1-10% of the time.

Spectrophotometric assessment of pigmented skin lesions: methods and feature selection for evaluation of diagnostic performance.

This study documents the optical reflectance characteristics of pigmented skin lesions and evaluates their potential for improving the differential diagnosis of malignant melanoma from benign pigmented skin lesions. Optical reflectance spectra in the wavelength range 320-1100 nm were obtained from 121 lesions already selected by expert dermatologists as suspicious of malignancy. Characteristic differences in spectra from benign and malignant lesions were studied. Feature extraction showed significant differences between lesion groups classified by histology. Seven of the most relevant features were used in the discriminant analysis of reflectance spectra from 15 melanoma and 32 compound naevi which resulted in a sensitivity of 100% and specificity of 84.4% when compared with histology. This simple objective technique appears to perform as well as the expert dermatologist and may improve the diagnostic accuracy of non-specialists such as trainees and GPs. Further prospective clinical study of reflectance spectrophotometry in a larger patient group is now required.

Are 18fluorodeoxyglucose positron emission tomography and magnetic resonance imaging useful in the prediction of relapse in lymphoma residual masses?

Treatment of both Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) frequently results in a residual mass visible radiologically. Such patients may receive radiotherapy unnecessarily because the residual mass may represent benign fibrotic tissue rather than residual active lymphoma. Radiotherapy has been shown to have significant short and more worrying long-term toxicity. Refining the criteria for its use would be a major advance. A number of clinical investigations have been evaluated to more accurately determine the nature of such lesions, including erythrocyte sedimentation rate (ESR), magnetic resonance imaging (MRI) and high-dose gallium-67 scanning (HDGS) but none has proven utility. 18[F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is an imaging technique that has been shown to be useful in distinguishing fibrosis from residual active disease in solid tumours. The aim of this study was to compare FDG PET and MRI in the assessment of residual masses following treatment for lymphoma. Patients with NHL/HD who had a residual mass following chemotherapy were eligible for this study. Patients had a combination of MRI and/or PET. All scans were completed within 5 months of the end of treatment. Patients were followed-up for relapse. 56 patients had an MRI scan, 24 had a PET scan and 22 patients had both investigations. Overall sensitivity and specificity, respectively, were for MRI 45% and 74%, PET 50% and 69%, and PET/MRI concurring 50% and 67%. There was a trend for improved relapse-free survival (RFS) with a negative result of both MRI and PET, but this was not statistically significant. The predictive value for both tests failed to reach statistical significance. Subgroup analysis suggests that PET may be better at predicting relapse in patients with NHL, especially those with masses above the diaphragm. There is no convincing evidence that either MRI or PET or the combination can reliably predict relapse within residual masses after treatment for lymphoma. A negative PET scan however appears to be more informative than a positive result and may well aid clinical decision making. There are a number of factors that may produce false-positive results, including post-treatment inflammatory changes, the sensitivity of the test in the setting of minimal residual disease and the heterogeneity of the histological subtypes studied. A negative PET (or MRI) result in lymphoma residual masses following therapy may negate the necessity for further therapy such as chemotherapy or radiotherapy and their concomitant toxicities.

A CCD-based system for the detection of DNA in electrophoresis gels by UV absorption.

A method and apparatus for the detection and quantification of large fragments of unlabelled nucleic acids in agarose gels is presented. The technique is based on ultraviolet (UV) absorption by nucleotides. A deuterium source illuminates individual sample lanes of an electrophoresis gel via an array of optical fibres. As DNA bands pass through the illuminated region of the gel the amount of UV light transmitted is reduced because of absorption by the DNA. During electrophoresis the regions of DNA are detected on-line using a UV-sensitive charge coupled device (CCD). As the absorption coefficient is proportional to the mass of DNA the technique is inherently quantitative. The mass of DNA in a region of the gel is approximately proportional to the integrated signal in the corresponding section of the CCD image. This system currently has a detection limit of less than 1.25 ng compared with 2-10 ng for the most popular conventional technique, ethidium bromide (EtBr) staining. In addition the DNA sample remains in its native state. The removal of the carcinogenic dye from the detection procedure greatly reduces associated biological hazards.

The role of red blood cell polymorphisms in resistance and susceptibility to malaria.

In regions highly endemic for Plasmodium falciparum malaria, red cell polymorphisms that confer resistance to severe disease are widespread. Sickle cell trait, alpha-thalassemia, glucose-6-phosphate dehydrogenase deficiency, and blood groups were determined in 100 children from Gabon with severe malaria who were matched with 100 children with mild malaria and followed up for evaluation of reinfections. The sickle cell trait was significantly associated with mild malaria and blood group A with severe malaria. During follow-up, the original severe cases had significantly higher rates of reinfection than the original mild cases, with higher parasitemia and lower hematocrit values. Incidence rates did not differ in the context of erythrocyte polymorphisms, but patients with sickle cell trait presented with markedly lower levels of parasitemia than those without. Thus, the severity of malaria is partly determined by the presence of blood group A and the sickle cell trait. The different presentation of reinfections in severe versus mild cases probably reflects different susceptibility to malaria.