Core Imaging Library - Part I: a versatile Python framework for tomographic imaging.

We present the Core Imaging Library (CIL), an open-source Python framework for tomographic imaging with particular emphasis on reconstruction of challenging datasets. Conventional filtered back-projection reconstruction tends to be insufficient for highly noisy, incomplete, non-standard or multi-channel data arising for example in dynamic, spectral and in situ tomography. CIL provides an extensive modular optimization framework for prototyping reconstruction methods including sparsity and total variation regularization, as well as tools for loading, preprocessing and visualizing tomographic data. The capabilities of CIL are demonstrated on a synchrotron example dataset and three challenging cases spanning golden-ratio neutron tomography, cone-beam X-ray laminography and positron emission tomography. This article is part of the theme issue 'Synergistic tomographic image reconstruction: part 2'.

Commentary on a combined approach to the problem of developing biomarkers for the prediction of spontaneous preterm labor that leads to preterm birth.

INTRODUCTION: Globally, preterm birth has replaced congenital malformation as the major cause of perinatal mortality and morbidity. The reduced rate of congenital malformation was not achieved through a single biophysical or biochemical marker at a specific gestational age, but rather through a combination of clinical, biophysical and biochemical markers at different gestational ages. Since the aetiology of spontaneous preterm birth is also multifactorial, it is unlikely that a single biomarker test, at a specific gestational age will emerge as the definitive predictive test. METHODS: The Biomarkers Group of PREBIC, comprising clinicians, basic scientists and other experts in the field, with a particular interest in preterm birth have produced this commentary with short, medium and long-term aims: i) to alert clinicians to the advances that are being made in the prediction of spontaneous preterm birth; ii) to encourage clinicians and scientists to continue their efforts in this field, and not to be disheartened or nihilistic because of a perceived lack of progress and iii) to enable development of novel interventions that can reduce the mortality and morbidity associated with preterm birth. RESULTS: Using language that we hope is clear to practising clinicians, we have identified 11 Sections in which there exists the potential, feasibility and capability of technologies for candidate biomarkers in the prediction of spontaneous preterm birth and how current limitations to this research might be circumvented. DISCUSSION: The combination of biophysical, biochemical, immunological, microbiological, fetal cell, exosomal, or cell free RNA at different gestational ages, integrated as part of a multivariable predictor model may be necessary to advance our attempts to predict sPTL and PTB. This will require systems biological data using "omics" data and artificial intelligence/machine learning to manage the data appropriately. The ultimate goal is to reduce the mortality and morbidity associated with preterm birth.

Automated angular and translational tomographic alignment and application to phase-contrast imaging.

X-ray computerized tomography (CT) is a 3D imaging technique that makes use of x-ray illumination and image reconstruction techniques to reproduce the internal cross-sections of a sample. Tomographic projection data usually require an initial relative alignment or knowledge of the exact object position and orientation with respect to the detector. As tomographic imaging reaches increasingly better resolution, thermal drifts, mechanical instabilities, and equipment limitations are becoming the main dominant factors contributing to sample positioning uncertainties that will further introduce reconstruction artifacts and limit the attained resolution in the final tomographic reconstruction. Alignment algorithms that require manual interaction impede data analysis with ever-increasing data acquisition rates, supplied by more brilliant sources. We present in this paper an iterative reconstruction algorithm for wrapped phase projection data and an alignment algorithm that automatically takes 5 degrees of freedom, including the possible linear and angular motion errors, into consideration. The presented concepts are applied to simulated and real measured phase-contrast data, exhibiting a possible improvement in the reconstruction resolution. A MATLAB implementation is made publicly available and will allow robust analysis of large volumes of phase-contrast tomography data.

The association between angiogenic markers and fetal sex: Implications for preeclampsia research.

OBJECTIVE: Current research suggests sexual dimorphism between the male and female fetoplacental units, but with unknown relevance for preeclampsia. We investigated the association between fetal sex and concentrations of the angiogenic markers soluble Fms-like kinase 1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in first and second-third trimester in women with/without preeclampsia, and the impact of fetal sex on the prognostic value of angiogenic markers for preeclampsia. STUDY DESIGN: Observational study in a prospective, population-based cohort of 2110 singleton pregnancies with 150 preeclampsia cases. RESULTS: Higher sFlt-1 concentrations were observed for women carrying female fetuses in first trimester (all, 1107.65 vs. 992.27pg/ml; preeclampsia cases, 1118.79 vs. 934.49pg/ml, p<0.05) and in second-third trimester (all, 1130.03 vs. 1043.15pg/ml; preeclampsia, 1480.30 vs. 1152.86pg/ml, p<0.05), with similar findings for the sFlt-1/PlGF ratio concentrations in first (29.67 vs. 27.39 p<0.05) and second-third trimester (3.56 vs. 3.22, p<0.05). In first trimester, log transformed concentrations of PlGF, sFlt-1 and sFlt-1/PlGF (all participants) and sFlt-1 (preeclampsia cases) associated with fetal sex in adjusted analyses (p<0.05). In second-third trimester, only log(sFlt-1) associated with fetal sex (all, p=0.028; preeclampsia, p=0.067) In receiver operating curve analysis, prediction of early-onset preeclampsia by sFlt-1/PlGF tended to be superior in pregnancies with female vs. male fetuses (p=0.06). CONCLUSION: Sexual dimorphism was observed for concentrations of angiogenic markers. Female fetal sex was associated to higher sFlt-1 and sFlt-1/PlGF ratio concentrations in both healthy pregnancies and women developing preeclampsia. Fetal sex should be considered in research and clinical use of angiogenic markers.

How little data is enough? Phase-diagram analysis of sparsity-regularized X-ray computed tomography.

We introduce phase-diagram analysis, a standard tool in compressed sensing (CS), to the X-ray computed tomography (CT) community as a systematic method for determining how few projections suffice for accurate sparsity-regularized reconstruction. In CS, a phase diagram is a convenient way to study and express certain theoretical relations between sparsity and sufficient sampling. We adapt phase-diagram analysis for empirical use in X-ray CT for which the same theoretical results do not hold. We demonstrate in three case studies the potential of phase-diagram analysis for providing quantitative answers to questions of undersampling. First, we demonstrate that there are cases where X-ray CT empirically performs comparably with a near-optimal CS strategy, namely taking measurements with Gaussian sensing matrices. Second, we show that, in contrast to what might have been anticipated, taking randomized CT measurements does not lead to improved performance compared with standard structured sampling patterns. Finally, we show preliminary results of how well phase-diagram analysis can predict the sufficient number of projections for accurately reconstructing a large-scale image of a given sparsity by means of total-variation regularization.

Metabolic effects of lifestyle intervention in obese pregnant women. Results from the randomized controlled trial 'Lifestyle in Pregnancy' (LiP).

AIMS: The Lifestyle in Pregnancy intervention in obese pregnant women resulted in significantly lower gestational weight gain compared with the control group, but without improvement in rates of clinical pregnancy complications. The impact of the lifestyle intervention on metabolic measurements in the study participants is now reported. METHODS: The Lifestyle in Pregnancy study was a randomized controlled trial among 360 obese women (BMI 30-45 kg/m²) who were allocated in early pregnancy to lifestyle interventions with diet counselling and physical activities or to the control group. Fasting blood samples, including plasma glucose, insulin, lipid profile and capillary blood glucose during a 2-h oral glucose tolerance test were carried out three times throughout pregnancy. Insulin resistance was estimated with the homeostasis model assessment of insulin resistance. RESULTS: Three hundred and four women (84%) were followed until delivery. Women in the intervention group had a significantly lower change in insulin resistance (HOMA-IR) from randomization to 28-30 weeks' gestation compared with control subjects (mean ± SD: 0.7 ± 1.3 vs. 1.0 ± 1.3, P = 0.02). Despite a significantly lower gestational weight gain in the intervention group, there was no difference between the groups with respect to total cholesterol, HDL, LDL or triglycerides. CONCLUSIONS: Lifestyle intervention in obese pregnant women resulted in attenuation of the physiologic pregnancy-induced insulin resistance. Despite restricted gestational weight gain, there were no changes in glucose or lipid metabolism between the groups.

Increasing use of antibiotics in pregnancy during the period 2000-2010: prevalence, timing, category, and demographics.

OBJECTIVE: The aim of this study was to describe the use of antibiotics in a national population-based cohort of pregnant Danish women between 2000 and 2010. DESIGN: Register-based, population-wide, cohort study. SETTING: Denmark, from 2000 to 2010. POPULATION: All pregnancies among Danish residents during the period 2000-2010 were included for analysis. METHODS: Data were obtained from the Danish Medical Birth Registry, the Danish National Patient Registry, and the Registry of Medicinal Product Statistics. The filled prescriptions for systemic antibacterial, antimycotic, and antiviral drugs, as well as intravaginally applied antibiotics, were analysed. Associations with demographic variables were assessed using multivariate analysis. MAIN OUTCOME MEASURES: Filled prescriptions for antibiotic drugs during pregnancy. RESULTS: We included 987 973 pregnancies in Denmark from 2000 to 2010; 38.9% of women with a delivery and 14.8% of women with a miscarriage or termination of pregnancy had one or more antibiotic treatments during pregnancy. Systemic antibacterial drugs were the most frequently used drug group, with filled prescriptions for 33.4% of all deliveries and 12.6% of all abortions. This proportion increased from 28.4% in 2000 to 37.0% in 2010 among deliveries. The biggest change was seen for pivmecillinam, which increased among deliveries from 6.3% in 2000 to 19.5% in 2010. Obese (odds ratio 1.51; 95% CI 1.47-1.56), young (odds ratio 1.35; 95% CI 1.30-1.39), and low-educated women (odds ratio 1.37; 95% CI 1.35-1.1.39) tended to fill more prescriptions of antibiotics during pregnancy. CONCLUSIONS: Overall, the number of women who filled prescriptions of antibiotics increased during the 11-year study period. In 2010, at least 41.5% of all deliveries were exposed to antibiotic therapy during pregnancy.

Elective caesarean section at 38 weeks versus 39 weeks: neonatal and maternal outcomes in a randomised controlled trial.

OBJECTIVES: To investigate whether elective caesarean section before 39 completed weeks of gestation increases the risk of adverse neonatal or maternal outcomes. DESIGN: Randomised controlled multicentre open-label trial. SETTING: Seven Danish tertiary hospitals from March 2009 to June 2011. POPULATION: Women with uncomplicated pregnancies, a single fetus, and a date of delivery estimated by ultrasound scheduled for delivery by elective caesarean section. METHODS: Perinatal outcomes after elective caesarean section scheduled at a gestational age of 38 weeks and 3 days versus 39 weeks and 3 days (in both groups ±2 days). MAIN OUTCOME MEASURES: The primary outcome was neonatal intensive care unit (NICU) admission within 48 hours of birth. Secondary outcomes were neonatal depression, NICU admission within 7 days, NICU length of stay, neonatal treatment, and maternal surgical or postpartum adverse events. RESULTS: Among women scheduled for elective caesarean section at 38⁺³ weeks 88/635 neonates (13.9%) were admitted to the NICU, whereas in the 39⁺³ weeks group 76/637 neonates (11.9%) were admitted (relative risk [RR] 0.86, 95% confidence interval [95% CI] 0.65-1.15). Neonatal treatment with continuous oxygen for more than 1 day (RR 0.31; 95% CI 0.10-0.94) and maternal bleeding of more than 500 ml (RR 0.79; 95% CI 0.63-0.99) were less frequent in the 39 weeks group, but these findings were insignificant after adjustment for multiple comparisons. The risk of adverse neonatal or maternal outcomes, or a maternal composite outcome (RR 1.1; 95% CI 0.79-1.53) was similar in the two intervention groups. CONCLUSIONS: This study found no significant reduction in neonatal admission rate after ECS scheduled at 39 weeks compared with 38 weeks of gestation.

Parity and tanned white skin as novel predictors of vitamin D status in early pregnancy: a population-based cohort study.

CONTEXT: In pregnancy, vitamin D insufficiency and deficiency, defined as serum 25-hydroxyvitamin D (25(OH)D) <50 nM, and <25 nM, respectively, may have adverse effects for both mother and child. Prevalence estimates, and identification of subgroups at special risk, may be useful for the planning of preventive strategies. OBJECTIVE: To study the prevalence and risk factors of hypovitaminosis D in early pregnancy. DESIGN AND METHODS: In a cross-sectional study of 1348 women in early pregnancy from the Odense Child Cohort, Denmark, 25(OH)D was determined and correlated to demographic and lifestyle variables (age, nationality, skin tone, parity, prepregnancy body mass index (BMI), smoking and sun exposure), using multiple linear and logistic regression analyses for all year, or stratified for summer and winter. The risk of vitamin D insufficiency was expressed as odds ratios (OR) with 95% confidence intervals in brackets. RESULTS: The prevalence of vitamin D insufficiency and deficiency was estimated to 27·8% and 3·5% respectively. In adjusted analyses, vitamin D insufficiency was directly associated with winter season, OR = 1·89 (1·35-2·63); increasing prepregnancy BMI, OR = 1·06 (1·03-1·10); and smoking, OR = 2·7 (1·34-5·41); but was less frequent in nulliparous, OR = 0·47 (0·33-0·68) and tanned Caucasians, OR = 0·63 (0·41-0·97). Season-specific associations having parental origin from outside Europe in summer, OR = 4·13 (1·41-12·13); in winter smoking, OR = 3·15 (1·19-8·36); and prepregnancy BMI, OR = 1·12 (1·06-1·18). CONCLUSIONS: Vitamin D insufficiency was widespread in early pregnancy. Associations to smoking, prepregnancy BMI and origin outside Europe varied with season. Multiparity and not being tanned in Caucasians represent new risk factors of vitamin D insufficiency.

Mechanisms of renal NaCl retention in proteinuric disease.

In diseases with proteinuria, for example nephrotic syndrome and pre-eclampsia, there often are suppression of plasma renin-angiotensin-aldosterone system components, expansion of extracellular volume and avid renal sodium retention. Mechanisms of sodium retention in proteinuria are reviewed. In animal models of nephrotic syndrome, the amiloride-sensitive epithelial sodium channel ENaC is activated while more proximal renal Na(+) transporters are down-regulated. With suppressed plasma aldosterone concentration and little change in ENaC abundance in nephrotic syndrome, the alternative modality of proteolytic activation of ENaC has been explored. Proteolysis leads to putative release of an inhibitory peptide from the extracellular domain of the γ ENaC subunit. This leads to full activation of the channel. Plasminogen has been demonstrated in urine from patients with nephrotic syndrome and pre-eclampsia. Urine plasminogen correlates with urine albumin and is activated to plasmin within the urinary space by urokinase-type plasminogen activator. This agrees with aberrant filtration across an injured glomerular barrier independent of the primary disease. Pure plasmin and urine samples containing plasmin activate inward current in single murine collecting duct cells. In this study, it is shown that human lymphocytes may be used to uncover the effect of urine plasmin on amiloride- and aprotinin-sensitive inward currents. Data from hypertensive rat models show that protease inhibitors may attenuate blood pressure. Aberrant filtration of plasminogen and conversion within the urinary space to plasmin may activate γ ENaC proteolytically and contribute to inappropriate NaCl retention and oedema in acute proteinuric conditions and to hypertension in diseases with chronic microalbuminuria/proteinuria.

Intrauterine extremity gangrene and cerebral infarction at term: a case report.

Intrauterine extremity gangrene in combination with cerebral infarction is a serious and rare event. We present a case with a healthy mother who gave birth to a child with this condition. At term, the mother presented at the antenatal clinic with decreased fetal movements. Cardiotocography (CTG) showed signs of fetal distress and a caesarean section was performed. The left arm of the newborn was found gangrenous. Amputation of the arm was necessary and the child was subsequently treated with anticoagulant therapy due to thrombosis and cerebral infarction in the left hemisphere found by magnetic resonance imaging (MRI). At one year of age the boy was doing well and had prosthesis as a left arm. He had no signs of further complications. Despite thorough examination of the parents and the child, the reason for the thrombosis is still unknown.

AR suppresses transcription of the alpha glycoprotein hormone subunit gene through protein-protein interactions with cJun and activation transcription factor 2.

Previously, we reported that the AR directly suppressed transcription of the alpha glycoprotein hormone subunit (alphaGSU) gene in a ligand-dependent fashion while ER had no effect. Mutagenesis studies of the alphaGSU promoter indicated that two elements were required for AR-mediated suppression: the alpha basal element and tandem cAMP response elements (CREs). Because several members of the bZip family of transcriptional proteins can bind the CREs, we used several functional assays to determine whether AR interacts selectively with cJun, activation transcription factor 2 (ATF2), or CRE binding protein (CREB). When tested by cotransfection with AR, cJun and ATF2 specifically rescued androgen-mediated suppression of the alphaGSU-reporter construct in a gonadotrope-derived cell line. In contrast, cotransfected CREB displayed no activity in this rescue assay. In fact, overexpression of CREB alone diminished activity of the alphaGSU promoter, suggesting that the transcriptional activity normally conferred by the tandem CREs in gonadotropes requires their occupancy by cJun/ATF2 heterodimers. Binding assays carried out with a glutathione-S-transferase-AR fusion protein indicated that the receptor itself also displayed a clear preference for binding cJun and ATF2. Furthermore, we ruled out the possibility that AR suppressed activity of the alphaGSU promoter by reducing synthesis of these bZip proteins. Additional experiments suggested that phosphorylation of AR or histone acetylation are unlikely requirements for AR suppression of alphaGSU promoter activity. Thus, our data suggest that AR suppresses activity of the alphaGSU promoter through direct protein-protein interactions with cJun and ATF2.

AR suppresses transcription of the LHbeta subunit by interacting with steroidogenic factor-1.

Synthesis of LH is suppressed by feedback from gonadal steroids. Previously, we demonstrated that 779 bp of the bovine LHbeta promoter was sufficient to target expression of a chloramphenicol acetyltransferase reporter gene specifically to the pituitary in transgenic mice, and found that it was appropriately suppressed after administration of T or E2. In this study, we report that ligand-bound AR, but not ligand-bound ER, directly suppressed activity of the bovine LHbeta promoter when examined in a gonadotrope-derived cell line. Additional studies with mutated bovine LHbeta promoter constructs focused on the proximal 5'-flanking region because of the presence of several cis-acting elements that are highly conserved across all mammals. These include regulatory elements that bind steroidogenic factor 1 (SF-1), Egr-1, and Pitx1. When tested by cotransfection with AR, overexpression of Egr-1, Pitx1, and constitutively active steroidogenic factor 1 (SF-1DeltaLBD) each individually rescued androgen-mediated suppression of the bovine LHbeta promoter. This suggested a functional interaction between each of these transcription proteins and AR. In contrast, overexpression of full-length SF-1 was incapable of relieving the bovine LHbeta promoter from the suppressive effect imposed by AR. This suggested that the ligand-binding domain of SF-1 plays an important role in functional interactions that occur between this protein and AR. This notion was further supported by binding assays performed with glutathione-S-transferase-AR: these identified SF-1 as a key interactive partner and localized this interaction to the ligand-binding domain of the protein. Additional binding studies indicated that protein interactions between SF-1, Pitx1, and Egr-1 interfere with formation of a binary complex that contains AR and SF-1. Thus, we conclude that AR suppresses activity of the bovine LHbeta promoter through protein-protein interactions with SF-1 and that the degree of this interaction can be modified by the presence of Egr-1 and Pitx1.

Imaging basilar skull fractures in the horse: a review.

Due to the complex nature of the anatomy of the equine head, superimposition of numerous structures, and poor soft tissue differentiation, radiography may be of limited value in the diagnosis of basilar skull fractures. However, in many horses radiographic changes such as soft tissue opacification of the guttural pouch region, irregular bone margination at the sphenooccipital line, attenuation of the nasopharynx, ventral displacement of the dorsal pharyngeal wall and the presence of irregularly shaped bone fragments in the region of the guttural pouches are suggestive of a fracture of the skull base. These findings in conjunction with physical examination findings and historical information may lead to a presumptive diagnosis of a fracture. When available and when the patient will accommodate the equipment, computed tomography may give a definitive diagnosis owing to its superior resolution and differentiation of soft tissue structures.

Calibration of a reflectance pulse oximeter in fetal lambs for arterial oxygen saturations below 70%.

OBJECTIVE: To calibrate a reflectance pulse oximeter developed at the Division of Perinatal Physiology, University Hospital of Zurich, for monitoring of oxygen saturations below 70%. METHODS: Oxygen saturation measured noninvasively with the reflectance pulse oximeter in fetal sheep was compared with oxygen saturation of arterial blood samples measured by a conventional two-wavelength oximeter. Oxygen saturation was varied by stepwise reduction of the inspired oxygen concentration of the ewe. RESULTS: A total of 58 data pairs was obtained from five fetuses, with a range of 10.9-73.5% for the reference method and 6.8-69.2% for the pulse oximetry oxygen saturation values. There was good correlation between the results obtained by the two methods (r2 = .89, P < .0001), with a 95% confidence interval of +/- 12.5%. The pulse oximeter showed a precision of 6.2% oxygen saturation. CONCLUSION: The Zurich reflectance pulse oximeter offers valid measurements of oxygen saturation levels down to 10% oxygen saturation, and is therefore suitable for monitoring the fetus during delivery.

Lameness and pleural effusion associated with an aggressive fibrosarcoma in a horse.

An 8-year-old Thoroughbred gelding was admitted for evaluation of chronic lameness of the left scapulohumeral joint of 3 months' duration. Radiography revealed a radiolucent lesion with the proximal portion of the humerus in the area of the metaphysis. Scintigraphy confirmed radiographic findings, with an increased uptake of technetium Tc 99m medronate in the proximal portion of the left humerus. A preliminary diagnosis of humeral fracture was made. Two weeks later, the horse was readmitted for clinical signs of respiratory distress. Radiographic and ultrasonographic evaluation revealed masses within the thoracic and abdominal cavities. The diagnosis was changed to neoplasm with multiple metastases. Because of the unfavorable prognosis, the horse was euthanatized. Necropsy findings confirmed an aggressive neoplasm. Special histochemical stains, immunohistochemistry, and electron microscopy were required to characterize the neoplasm as an anaplastic fibrosarcoma. Findings in this horse illustrate the importance of considering neoplasia, resulting in bone lesions, as a possible cause of chronic lameness in horses.