GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Genetic determinants of micronucleus formation in vivo.

Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.

MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

A distinctive epigenetic ageing profile in human granulosa cells.

STUDY QUESTION: Does women's age affect the DNA methylation (DNAm) profile differently in mural granulosa cells (MGCs) from other somatic cells? SUMMARY ANSWER: Accumulation of epimutations by age and a higher number of age-related differentially methylated regions (DMR) in MGCs were found compared to leukocytes from the same woman, suggesting that the MGCs have a distinctive epigenetic profile. WHAT IS KNOWN ALREADY: The mechanisms underlying the decline in women's fertility from the mid-30s remain to be fully elucidated. The DNAm age of many healthy tissues changes predictably with and follows chronological age, but DNAm age in some reproductive tissues has been shown to depart from chronological age (older: endometrium; younger: cumulus cells, spermatozoa). STUDY DESIGN, SIZE, DURATION: This study is a multicenter cohort study based on retrospective analysis of prospectively collected data and material derived from healthy women undergoing IVF or ICSI treatment following ovarian stimulation with antagonist protocol. One hundred and nineteen women were included from September 2016 to June 2018 from four clinics in Denmark and Sweden. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were obtained from 118 healthy women with varying ovarian reserve status. MGCs were collected from 63 of the 119 women by isolation from pooled follicles immediately after oocyte retrieval. DNA from leukocytes and MGCs was extracted and analysed with a genome-wide methylation array. Data from the methylation array were processed using the ENmix package. Subsequently, DNAm age was calculated using established and tailored age predictors and DMRs were analysed with the DMRcate package. MAIN RESULTS AND ROLE OF CHANCE: Using established age predictors, DNAm age in MGCs was found to be considerable younger and constant (average: 2.7 years) compared to chronological age (average: 33.9 years). A Granulosa Cell clock able to predict the age of both MGCs (average: 32.4 years) and leukocytes (average: 38.8 years) was successfully developed. MGCs differed from leukocytes in having a higher number of epimutations (P = 0.003) but predicted telomere lengths unaffected by age (Pearson's correlation coefficient = -0.1, P = 0.47). DMRs associated with age (age-DMRs) were identified in MGCs (n = 335) and in leukocytes (n = 1) with a significant enrichment in MGCs for genes involved in RNA processing (45 genes, P = 3.96 × 10-08) and gene expression (152 genes, P = 2.3 × 10-06). The top age-DMRs included the metastable epiallele VTRNA2-1, the DNAm regulator ZFP57 and the anti-Müllerian hormone (AMH) gene. The apparent discordance between different epigenetic measures of age in MGCs suggests that they reflect difference stages in the MGC life cycle. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: No gene expression data were available to associate with the epigenetic findings. The MGCs are collected during ovarian stimulation, which may influence DNAm; however, no correlation between FSH dose and number of epimutations was found. WIDER IMPLICATIONS OF THE FINDINGS: Our findings underline that the somatic compartment of the follicle follows a different methylation trajectory with age than other somatic cells. The higher number of epimutations and age-DMRs in MGCs suggest that their function is affected by age. STUDY FUNDING/COMPETING INTEREST(S): This project is part of ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS, the Danish National Research Foundation and the European Research Council. The authors declare no conflict of interest.

Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI.

STUDY QUESTION: How is timing of voice break related to other male pubertal milestones as well as to BMI? SUMMARY ANSWER: We provide a comprehensive temporal analysis of male pubertal milestones, including reproductive hormone dynamics, confirm voice break as a late milestone of male puberty and report a likely causal relationship between higher BMI and earlier age at voice break in men. WHAT IS KNOWN ALREADY: Voice break represents a late pubertal milestone and recalled age at voice break is frequently used in epidemiological studies as a measure of puberty. In contrast, clinical studies use mainly testicular enlargement and/or genital tanner stage as the marker of pubertal onset. However, neither correlation of pubertal milestones nor reproductive hormone dynamics have been assessed in detail previously. Further, although BMI and puberty timing are known to be closely linked, cause and effect between these traits are not known. STUDY DESIGN, SIZE, DURATION: The study included a population-based mixed cross-sectional and longitudinal cohort (2006-2014, COPENHAGEN Puberty Study) of 730 healthy Danish boys. Data for 55 871 male research participants from the 23andMe study were obtained, including genome-wide single nucleotide polymorphism data and age at voice break. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a detailed evaluation of pubertal milestones and reproductive hormone levels (study population 1). A Mendelian randomization (MR) approach was used to determine the likely causal link between BMI and timing of voice break (study population 2). MAIN RESULTS AND THE ROLE OF CHANCE: Voice break occurred at mean age 13.6 (95% CI: 13.5-13.8) years. At voice break, mean (95% CI) testosterone levels, LH levels and bi-testicular volume were 10.9 (10.0-11.7) nmol/L, 2.4 (2.2-2.5) IU/L and 24 (23-25) mL, respectively. Voice break correlated moderately strongly with timing of male pubertal milestones, including testicular enlargement, gonadarche, pubarche, sweat odor, axillary hair growth and testosterone above limit of detection (r2 range: 0.43-0.61). Timing of all milestones was negatively associated with age-specific BMI (all P ≤ 0.001). MR analyses inferred likely causal effects of higher BMI on earlier voice break in males (-0.35 years/approximate SD, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Participation rate of the population-based cohort was 25%. Further, boys that were followed longitudinally were examined approximately every 6 months limiting the time resolution of pubertal milestones. Using adult BMI as exposure instead of prepubertal BMI in the MR analysis and the known inaccuracies of the testosterone immunoassay at low testosterone levels may be further limitations. WIDER IMPLICATIONS OF THE FINDINGS: We provide valuable normative data on the temporal relation of male pubertal milestones. Further, the likely causal relationship between BMI and puberty timing highlights the importance of preventing obesity in childhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Danish Agency for Science, Technology and Innovation (09-067 180); Danish Ministry of the Environment, CeHoS (MST-621-00 065); Capital Region of Denmark (R129-A3966); Ministry of Higher Education and Science (DFF-1331-00 113); Innovation Fund Denmark (InnovationsFonden, 14-2013-4); The International Center for Research and Research Training in Endocrine Disrupting Effects of Male Reproduction and Child Health. B.H., F.R.D., J.R.B.P. and K.K.O. are supported by the Medical Research Council (MC_UU_12015/2). The 23andMe study is supported by the National Human Genome Research Institute of the National Institutes of Health (R44HG006981). Members of the 23andMe Research Team are employees of 23andMe, Inc. and hold stock or stock options in 23andMe. TRIAL REGISTRATION NUMBER: NCT01411527.

Circulating beta-carotene levels and type 2 diabetes-cause or effect?

AIMS/HYPOTHESIS: Circulating beta-carotene levels are inversely associated with risk of type 2 diabetes, but the causal direction of this association is not certain. In this study we used a Mendelian randomisation approach to provide evidence for or against the causal role of the antioxidant vitamin beta-carotene in type 2 diabetes. METHODS: We used a common polymorphism (rs6564851) near the BCMO1 gene, which is strongly associated with circulating beta-carotene levels (p = 2 x 10(-24)), with each G allele associated with a 0.27 standard deviation increase in levels. We used data from the InCHIANTI and Uppsala Longitudinal Study of Adult Men (ULSAM) studies to estimate the association between beta-carotene levels and type 2 diabetes. We next used a triangulation approach to estimate the expected effect of rs6564851 on type 2 diabetes risk and compared this with the observed effect using data from 4549 type 2 diabetes patients and 5579 controls from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium. RESULTS: A 0.27 standard deviation increase in beta-carotene levels was associated with an OR of 0.90 (95% CI 0.86-0.95) for type 2 diabetes in the InCHIANTI study. This association was similar to that of the ULSAM study (OR 0.90 [0.84-0.97]). In contrast, there was no association between rs6564851 and type 2 diabetes (OR 0.98 [0.93-1.04], p = 0.58); this effect size was also smaller than that expected, given the known associations between rs6564851 and beta-carotene levels, and the associations between beta-carotene levels and type 2 diabetes. CONCLUSIONS/INTERPRETATION: Our findings in this Mendelian randomisation study are in keeping with randomised controlled trials suggesting that beta-carotene is not causally protective against type 2 diabetes.

Impact of a novel prioritization framework on clinician-led oncology drug submissions.

Background: In Canada, requests for public reimbursement of cancer drugs are predominately initiated by pharmaceutical manufacturers. Clinician-led submissions provide a mechanism to initiate the drug funding process when industry does not submit a request for funding consideration. Although such requests are resource-intensive to produce, Cancer Care Ontario (cco) has the capacity to facilitate clinician-led submissions. In 2014, cco began developing a cancer drug prioritization framework that allocates resources to systematically address a growing number of clinician-identified funding gaps with clinician-led submissions. Methods: Cancer site-specific drug advisory committees established by cco consist of health care practitioners whose roles include identifying and prioritizing funding gaps. The committees submit their identified gaps to a cross-cancer-site prioritization exercise in which the requests are ranked based on a set of guiding principles derived from health technology assessment. The requests are then sequentially allocated the resources needed to meet submission requirements. Whether the funding gap is of provincial or pan-Canadian relevance determines where the submission is filed for assessment. Results: Since its inception, the cco framework has identified 17 funding gaps in 9 cancer sites. In 4 prioritizations, the framework supported 6 submissions. As of June 2018, the framework had contributed to the eventual funding of more than 9 new drug-indication pairs, with more awaiting funding consideration. Conclusions: The cco prioritization framework has enabled clinicians to effectively and systematically identify, prioritize, and fill funding gaps not addressed by industry. Ultimately, the framework helps to ensure that patients can access evidence-informed and cost-effective therapies. The framework will continue to evolve as it encounters new challenges, including funding requests for rare indications.

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.

PURPOSE: Mesenchymal epithelial transition factor ( MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancer (NSCLC) and can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant-positive NSCLC. PATIENTS AND METHODS: MET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naïve EGFR-mutant-positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant-positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG. RESULTS: Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to 15.0 months) for MET-high and -low, respectively ( P = .566), with no significant difference in response rate regardless of copy number thresholds. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, which is consistent with marked intratumoral heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response (TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET amplification (five [3.2%] of 154). CONCLUSION: Although up to 26% of TKI-naïve EGFR-mutant-positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to TKI, except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant-positive NSCLC.

Isolation and characterization of a Saccharomyces cerevisiae peptide transport gene.

We have cloned and characterized a Saccharomyces cerevisiae peptide transport gene (PTR2) isolated from a genomic DNA library by directly selecting for functional complementation of a peptide transport-deficient mutant. Deletion and frameshift mutageneses were used to localize the complementing activity to a 3.1-kbp region on the transforming plasmid. DNA sequencing of the complementing region identified an open reading frame spanning 1,803 bp. The deduced amino acid sequence predicts a hydrophobic peptide consisting of 601 amino acids, having a molecular mass of 68.1 kDa, composed in part of 12 hydrophobic segments, and sharing significant similarities with a nitrate transport protein encoded by the CHL1 gene of Arabidopsis thaliana. Northern (RNA) hybridization experiments demonstrated a single transcript that was 1.8 kb in length and that was transiently induced by the addition of L-leucine to the growth medium. The PTR2 gene was localized to the right arm of chromosome XI by contour-clamped homogeneous electric field gel chromosome blotting and by hybridization to known chromosome XI lambda phage clones of S. cerevisiae DNA. PTR2 was tightly linked to the UBI2 gene, with the coding sequences being separated by a 466-bp region and oriented so that the genes were transcribed convergently. A chromosomal disruption of the PTR2 gene in a haploid strain was not lethal under standard growth conditions. The cloning of PTR2 represents the first example of the molecular genetic characterization of a eucaryotic peptide transport gene.

Survival outcomes in elderly patients with glioblastoma.

AIMS: Many elderly glioblastoma patients are excluded from randomised trials due to age, comorbidity or poor functional status. The purpose of this study was to describe the survival outcomes in all elderly patients with glioblastoma managed at a tertiary cancer centre. MATERIALS AND METHODS: A retrospective chart review identified 235 elderly patients (age 65 years or over) with a histological diagnosis of glioblastoma between 1 December 2006 and 31 December 2013. The primary outcome of this study was overall survival by treatment type. Univariate and multivariate Cox proportional hazard models were used to explore significant prognostic variables associated with overall survival. RESULTS: The median survival for all patients was 6.5 months (95% confidence interval 5.3-7.7), with 1 year overall survival of 23.7% (95% confidence interval 18.8-30.0). The median survival for patients treated with radiation and chemotherapy was 11.1 months (95% confidence interval 8.1-13.7). Patients treated with radiation alone had a median survival of 6.8 months (95% confidence interval 5.6-7.9). For patients managed with comfort measures only, the median survival was 1.9 months (95% confidence interval 1.6-2.6). Univariate analysis revealed age, performance status, surgery type (biopsy, subtotal resection, gross total resection) and type of treatment received (comfort measures only, radiotherapy alone, radiotherapy and chemotherapy) to be statistically associated with overall survival. In the multivariate analysis, only two predictive factors (treatment received and surgery type) were significant. CONCLUSIONS: Elderly patients with glioblastoma selected for treatment (surgery followed by radiation alone or radiation and chemotherapy) survive longer than patients managed with comfort measures. Prospective randomised trials will help guide management for patients eligible for therapy. Elderly patients with glioblastoma who are deemed not eligible for active therapy have very short survival.

Consensus against both endarterectomy and routine screening for asymptomatic carotid artery stenosis. Canadian Stroke Consortium.

BACKGROUND: Despite several randomized controlled trials, the role of carotid endarterectomy for asymptomatic patients is controversial. Validated evidence-based guidelines are needed. METHODS: Thirty-five members of the Canadian Stroke Consortium, an independent body of cerebrovascular disease experts, reviewed evidence-based guidelines developed by the Canadian Task Force on the Periodic Health Examination. We held 3 rounds of Delphi consensus to solicit opinion and agreement. RESULTS: We found a high level of interrater agreement for all guidelines using multiple statistical measures. Members agreed that evidence is insufficient to endorse carotid endarterectomy for asymptomatic patients with angiographically proven stenosis of more than 60% (kappa = 0.70, P < .01). Reasons cited included concern over the reproducibility of low surgical morbidity rates in the community at large, the questionable clinical benefit conferred by surgery, and the lack of proven reduction in the risk of major disabling stroke. Screening the general population for asymptomatic stenosis was unanimously rejected. Also, screening even patients with risk factors or proven atherosclerosis at other sites was not endorsed (kappa = 0.91 and kappa = 0.79, respectively, both P < .01). CONCLUSIONS: There is insufficient evidence to recommend carotid endarterectomy for asymptomatic patients. Evidence is also insufficient to endorse a screening strategy even for patients with risk factors for carotid disease. While stroke prevention remains a critical goal, we do not recommend that it be accomplished by screening or by performing carotid surgery in asymptomatic patients.

Transient encephalopathy after paclitaxel (Taxol) infusion.

Paclitaxel (Taxol) is a novel antineoplastic agent that acts by promoting microtubule polymerization. Although myelosuppression and peripheral neurotoxicity are well known and dose limiting, there have been no reports of CNS toxicity apart from two patients with seizures. This may reflect that paclitaxel has little or no blood-brain barrier penetration. We report two women treated with paclitaxel who developed a clinical state characterized by confusion, word-finding difficulty, and behavioral changes. One had bilateral extensor plantar responses. These symptoms appeared 1 week after paclitaxel infusion and resolved spontaneously. Subsequent infusions were associated with a similar self-resolving encephalopathy in one patient and recurrent headache and ataxia in the other. Neuroimaging (including enhanced MRI), LP, and laboratory investigations did not reveal other causes. Electroencephalography showed diffuse nonspecific slowing. One MRI had prominent but nonspecific high signal intensity abnormalities in the deep white matter of the cerebral hemispheres. Based on temporal association, diagnostic exclusion, and repeated episodes with subsequent challenges, we believe these patients may have experienced CNS toxicity from paclitaxel. The mechanism for this self-resolving encephalopathic process is unclear.

The role of noninvasive tests versus pulmonary angiography in the diagnosis of pulmonary embolism.

We studied 243 patients in whom 248 pulmonary angiograms were performed because of suspected pulmonary embolism. Ventilation and perfusion lung scanning in 140 of them revealed 38 to be in low and high probability groups. Of 19 patients with subsegmental and nonsegmental perfusion defects that were matched with ventilation defects, none had pulmonary embolism. Conversely, angiography was positive in 17 of 19 patients with multiple segmental or lobar perfusion defects in areas of normal ventilation. Doppler flow examinations of the veins of the legs showed normal flow in 61 of 79 (77 percent) patients with pulmonary emboli and, therefore, were insensitive indicators of embolism. There was no mortality from angiography, and serious complications occurred in 2 percent of the patients. Anticoagulation in 83 patients was associated with bleeding in 25, two of whom died. The data indicate that ventilation-perfusion lung scanning can be used to separate many of the patients suspected of having pulmonary embolism who need anticoagulant treatment from those who do not. However, there is a considerable number of patients with nonspecific abnormalities on lung scan. For this group of patients with nonspecific abnormalities, the risk of complications from empiric treatment with anticoagulant drugs is probably greater than the risk of complications from pulmonary angiography. Further, our data show that patients with negative angiography have a very low risk of subsequent pulmonary embolism. In this group of patients, therefore, pulmonary embolism should be demonstrated by angiography before long-term anticoagulant therapy is prescribed.

Simultaneous acquisition of emission and transmission data for improved thallium-201 cardiac SPECT imaging using a technetium-99m transmission source.

Transmission computed tomography (TCT) data provides useful complementary information to single-photon emission computed tomography (SPECT) reconstructions, especially for cardiac studies. In particular, TCT data has been used to correct for nonuniform attenuation in the chest. Typically the transmission data are acquired in a separate acquisition, but simultaneous acquisition is preferable both to save time and to avoid difficulties involved with registration. In this work, we present a technique for simultaneously acquiring 201Tl SPECT and TCT data using a 99mTc sheet source that requires only minor equipment modifications. The use of these isotopes results in cross-contamination of the emission and transmission data. We present a practical technique to compensate for this contamination using post-acquisition image processing. This technique was evaluated by performing phantom and patient studies. The resulting images compare well with data obtained from separate emission and transmission studies.

Determination of the optimum filter function for SPECT imaging.

An observer study was performed in order to evaluate several filters used in SPECT imaging. The filters were applied to the simulated projection data of a uniform activity density cylinder which contained a cold, spherical lesion, 2 cm in diameter. The data incorporated the effects of the detector and scatter response functions, photon attenuation, and noise. Reconstructed transaxial images were used in 2AFC and ROC observer studies testing lesion detectability. In the 2AFC experiment, the Hanning filter scored lowest and did not show a optimum cutoff frequency. The Butterworth filter performed better and showed a well-defined optimum cutoff frequency at 0.15 cycles/pixel. The Metz filter performed as well as the optimum Butterworth but did not show an optimum power factor. In the ROC study, a high power Metz filter demonstrated an ROC curve of lower Az index and different shape from a lower power Metz filter and the optimum Butterworth filter.

An evaluation of maximum likelihood-expectation maximization reconstruction for SPECT by ROC analysis.

A ROC study was performed in order to evaluate whether the maximum likelihood expectation maximization (ML-EM) reconstruction algorithm improves diagnostic performance compared to the conventional filtered backprojection method in SPECT. Several implementations of the algorithm were tested including 25 and 50 iteration stopping points, with and without nonuniform attenuation compensation, and with and without Metz filtering. Filtered backprojection was with Metz filter and without attenuation compensation. The test data were computer simulated to model cardiac 201Tl SPECT. The data incorporated the effects of nonuniform attenuation, distance-dependent collimator response, and scatter. Patient CT images provided realistic anatomy and attenuation information for the data simulation. Four observers each viewed 120 images for each of the reconstruction methods. Lesion detectability with ML-EM increased with Metz filtering and decreased with nonuniform attenuation compensation. The best MIL-EM implementation, 50 iterations with Metz filtering and without attenuation compensation, was not statistically better than filtered backprojection.

Design and clinical utility of a fan beam collimator for SPECT imaging of the head.

A long bore fan beam collimator for imaging the head was designed and constructed for a SPECT system with a rotating scintillation camera. In order to avoid the patient's shoulder during rotation of the camera with a thick camera housing, the long bore design is necessary to allow the collimator to get close to the patient's head for improved spatial resolution. Operating at the minimum radius of rotation, the prototype fan beam collimator provides about the same spatial resolution as the high resolution collimator, while the geometric efficiency is equal to approximately 85% of that of the general purpose and approximately 55% higher than the high resolution collimator. Images from a phantom study demonstrate good image quality and are void of artifacts. Comparative clinical studies on temporomandibular joints (TMJ) between the LEGP and fan beam collimators also confirm the superior image quality obtained with the fan beam collimator.

Correction of nonuniform attenuation in cardiac SPECT imaging.

Correction for photon attenuation in cardiac SPECT imaging using a measured attenuation distribution with an iterative expectation maximization (EM) algorithm and an iterative Chang algorithm were compared with the conventional filtered backprojection and an iterative EM algorithm without attenuation correction. The attenuation distribution was determined from a transmission computed tomography study that was obtained using an external collimated sheet source. The attenuation of the emitting photons was modeled in the EM algorithm by an attenuated projector-backprojector that used the estimated attenuation distribution to calculate attenuation factors for each pixel along each projection and backprojection ray. Results from a heart-lung phantom study and a 201Tl patient study demonstrated that the iterative EM algorithm with attenuation correction provided improved image quality in terms of reduced streak artifacts and noise, and more accurate quantitative information in terms of improved radioactivity distribution uniformity where uniformity existed, and better anatomic object definition.