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Introduction: Responses to first-line programmed cell death protein 1 inhibition vary among patients with metastatic NSCLC and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. We previously reported improved clinical outcomes to first-line programmed cell death protein 1 inhibition in patients with metastatic NSCLC with a PD-L1 TPS of greater than or equal to 90% versus 50% to 89% in a pilot study. Here, we report the three-year survival with first-line pembrolizumab and cemiplimab in two large independent cohorts of patients with PD-L1 TPS greater than or equal to 90% versus 50% to 89% and characterize genomic and immunophenotypic differences between these PD-L1 expression groups, which were largely unknown. Methods: We analyzed three-year outcomes of the following two independent cohorts: (1) a multicenter cohort of patients from four academic centers in the United States treated with pembrolizumab and (2) EMPOWER-Lung 1, randomized, phase III trial comparing first-line cemiplimab with chemotherapy. Tumor genomic profiling and multiplexed immunofluorescence were performed to evaluate genomic and immunophenotypic correlates of very high PD-L1 expression. Results: At three years of follow-up, progression-free survival (hazard ratio [HR], 0.69; p < 0.001) and overall survival (HR, 0.70; p < 0.01) to first-line commercial pembrolizumab were significantly improved in patients with a PD-L1 TPS greater than or equal to 90% versus 50% to 89%. In the EMPOWER-Lung 1, patients assigned to the cemiplimab arm with a PD-L1 TPS greater than or equal to 90% also had significant improvements in progression-free survival (HR, 0.53; p < 0.0001) and overall survival (HR, 0.63; p = 0.007) compared with those with a PD-L1 of 50% to 89%. Tumor genomic profiling of 553 NSCLC samples revealed that mutations in STK11 and SMARCA4 were significantly more frequent in tumors with a PD-L1 TPS of 50% to 89% compared with those with a PD-L1 TPS greater than or equal to 90% (Q < 0.15), whereas BRCA2 was enriched in NSCLC samples with a PD-L1 TPS greater than or equal to 90% (Q < 0.15). Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8+PD1+ T cells (p = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%. Conclusion: Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%.

Introduction: The fetal haemodynamic response to acute episodes of hypoxaemia are well characterised. However, how these responses change when the hypoxaemia becomes more chronic in nature such as that associated with fetal growth restriction (FGR), is less well understood. Herein, we utilised a combination of clinically relevant MRI techniques to comprehensively characterize and differentiate the haemodynamic responses occurring during acute and chronic periods of fetal hypoxaemia., Methods: Prior to conception, carunclectomy surgery was performed on non-pregnant ewes to induce FGR. At 108-110 days (d) gestational age (GA), pregnant ewes bearing control ( n  = 12) and FGR ( n  = 9) fetuses underwent fetal catheterisation surgery. At 117-119 days GA, ewes underwent MRI sessions where phase-contrast (PC) and T 2 oximetry were used to measure blood flow and oxygenation, respectively, throughout the fetal circulation during a normoxia and then an acute hypoxia state., Results: Fetal oxygen delivery (DO 2 ) was lower in FGR fetuses than controls during the normoxia state but cerebral DO 2 remained similar between fetal groups. Acute hypoxia reduced both overall fetal and cerebral DO 2 . FGR increased ductus venosus (DV) and foramen ovale (FO) blood flow during both the normoxia and acute hypoxia states. Pulmonary blood flow (PBF) was lower in FGR fetuses during the normoxia state but similar to controls during the acute hypoxia state when PBF in controls was decreased., Conclusion: Despite a prevailing level of chronic hypoxaemia, the FGR fetus upregulates the preferential streaming of oxygen-rich blood via the DV-FO pathway to maintain cerebral DO 2 . However, this upregulation is unable to maintain cerebral DO 2 during further exposure to an acute episode of hypoxaemia. The haemodynamic alterations required at the level of the liver and lung to allow the DV-FO pathway to maintain cerebral DO 2 , may have lasting consequences on hepatic function and pulmonary vascular regulation after birth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Darby, Saini, Holman, Hammond, Perumal, Macgowan, Seed and Morrison.)

Objectives: We evaluated fetal cardiovascular physiology and mode of cardiac failure in premature miniature piglets on a pumped artificial placenta (AP) circuit., Methods: Fetal pigs were cannulated via the umbilical vessels and transitioned to an AP circuit composed of a centrifugal pump and neonatal oxygenator and maintained in a fluid-filled biobag. Echocardiographic studies were conducted to measure ventricular function, umbilical blood flow, and fluid status. In utero scans were used as control data., Results: AP fetuses (n = 13; 102±4d gestational age [term 115d]; 616 ± 139 g [g]; survival 46.4 ± 46.8 h) were tachycardic and hypertensive with initially supraphysiologic circuit flows. Increased myocardial wall thickness was observed. Signs of fetal hydrops were present in all piglets. Global longitudinal strain (GLS) measurements increased in the left ventricle (LV) after transition to the circuit. Right ventricle (RV) and LV strain rate decreased early during AP support compared with in utero measurements but recovered toward the end of the experiment. Fetuses supported for >24 h had similar RV GLS to in utero controls and significantly higher GLS compared to piglets surviving only up to 24 h., Conclusions: Fetuses on a pump-supported AP circuit experienced an increase in afterload, and redistribution of blood flow between the AP and systemic circulations, associated with elevated end-diastolic filling pressures. This resulted in heart failure and hydrops. These preterm fetuses were unable to tolerate the hemodynamic changes associated with connection to the current AP circuit. To better mimic the physiology of the native placenta and preserve normal fetal cardiovascular physiology, further optimization of the circuit will be required., (© 2024 The Author(s). Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Competing Interests: Conflict of InterestNikita Aggarwal, Barjinder Singh Saini, and Savita Gupta declare that they have no conflict of interest.

Medical imaging plays a critical role in diagnosing and treating various medical conditions. However, interpreting medical images can be challenging even for expert clinicians, as they are often degraded by noise and artifacts that can hinder the accurate identification and analysis of diseases, leading to severe consequences such as patient misdiagnosis or mortality. Various types of noise, including Gaussian, Rician, and Salt-pepper noise, can corrupt the area of interest, limiting the precision and accuracy of algorithms. Denoising algorithms have shown the potential in improving the quality of medical images by removing noise and other artifacts that obscure essential information. Deep learning has emerged as a powerful tool for image analysis and has demonstrated promising results in denoising different medical images such as MRIs, CT scans, PET scans, etc. This review paper provides a comprehensive overview of state-of-the-art deep learning algorithms used for denoising medical images. A total of 120 relevant papers were reviewed, and after screening with specific inclusion and exclusion criteria, 104 papers were selected for analysis. This study aims to provide a thorough understanding for researchers in the field of intelligent denoising by presenting an extensive survey of current techniques and highlighting significant challenges that remain to be addressed. The findings of this review are expected to contribute to the development of intelligent models that enable timely and accurate diagnoses of medical disorders. It was found that 40% of the researchers used models based on Deep convolutional neural networks to denoise the images, followed by encoder-decoder (18%) and other artificial intelligence-based techniques (15%) (Like DIP, etc.). Generative adversarial network was used by 12%, transformer-based approaches (13%) and multilayer perceptron was used by 2% of the researchers. Moreover, Gaussian noise was present in 35% of the images, followed by speckle noise (16%), poisson noise (14%), artifacts (10%), rician noise (7%), Salt-pepper noise (6%), Impulse noise (3%) and other types of noise (9%). While the progress in developing novel models for the denoising of medical images is evident, significant work remains to be done in creating standardized denoising models that perform well across a wide spectrum of medical images. Overall, this review highlights the importance of denoising medical images and provides a comprehensive understanding of the current state-of-the-art deep learning algorithms in this field., Competing Interests: Declaration of Competing Interest I Abid Sarwar, and my co-authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Fetal lungs have fewer and smaller arteries with higher pulmonary vascular resistance (PVR) than a newborn. As gestation advances, the pulmonary circulation becomes more sensitive to changes in pulmonary arterial oxygen tension, which prepares them for the dramatic drop in PVR and increase in pulmonary blood flow (PBF) that occur when the baby takes its first few breaths of air, thus driving the transition from fetal to postnatal circulation. Dynamic and intricate regulatory mechanisms control PBF throughout development and are essential in supporting gas exchange after birth. Understanding these concepts is crucial given the role the pulmonary vasculature plays in the development of complications with transition, such as in the setting of persistent pulmonary hypertension of the newborn and congenital heart disease. An improved understanding of pulmonary vascular regulation may reveal opportunities for better clinical management., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Late gestational supine positioning reduces maternal cardiac output due to inferior vena caval (IVC) compression, despite increased collateral venous return. However, little is known about the impact of maternal position on oxygen (O 2 ) delivery and consumption of the gravid uterus, fetus, placenta and lower limbs. We studied the effects of maternal positioning on these parameters in 20 healthy pregnant subjects at 36 ± 2 weeks using magnetic resonance imaging (MRI); a follow-up MRI was performed 6-months postpartum (n = 16/20). MRI techniques included phase-contrast and T1/T2 relaxometry for blood flow and oximetry imaging, respectively. O 2 transport was measured in the following vessels (bilateral where appropriate): maternal abdominal descending aorta (DAo abdo ), IVC, ovarian, paraspinal veins (PSV), uterine artery (UtA) and external iliacs, and umbilical. Maternal cardiac output was measured by summing DAo thoracic and superior vena cava flows. Supine mothers (n = 6) had lower cardiac output and O 2 delivery in the DAo abdo , UtA and external iliac arteries, and higher PSV flow than those in either the left (n = 8) or right (n = 6) lateral positions during MRI. However, O 2 consumption in the gravid uterus, fetus, placenta and lower limbs was unaffected by maternal positioning. The ratio of IVC/PSV flow decreased in supine mothers while ovarian venous flow and O 2 saturation were unaltered, suggesting a major route of pelvic venous return unaffected by maternal position. Placental-fetal O 2 transport and consumption were similar between left and right lateral maternal positions. In comparison to non-pregnant findings, DAo abdo and UtA O 2 delivery and pelvic O 2 consumption increased, while lower-limb consumption remained constant , despite reduced external iliac artery O 2 delivery in late gestation. KEY POINTS: Though sleeping supine during the third trimester is associated with an increased risk of antepartum stillbirth, the underlying biological mechanisms are not fully understood. Maternal cardiac output and uteroplacental flow are reduced in supine mothers due to inferior vena caval compression from the weight of the gravid uterus. This MRI study provides a comprehensive circulatory assessment, demonstrating reduced maternal cardiac output and O 2 delivery (uteroplacental, lower body) in supine compared to lateral positioning; however, O 2 consumption (gravid uterus, fetus, placenta, lower limbs) was preserved. Unlike other mammalian species, the ovarian veins conduct substantial venous return from the human pregnant uterus that is unaffected by maternal positioning. Lumbar paraspinal venous flow increased in supine mothers. These observations may have important considerations during major pelvic surgery in pregnancy (i.e. placenta percreta). Future studies should address the importance of maternal positioning as a potential tool to deliver improved perinatal outcomes in pregnancies with compromised uteroplacental O 2 delivery., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

Babies born with fetal growth restriction (FGR) are at higher risk of developing cardiometabolic diseases across the life course. The reduction in substrate supply to the developing fetus that causes FGR not only alters cardiac growth and structure but may have deleterious effects on metabolism and function. Using a sheep model of placental restriction to induce FGR, we investigated key cardiac metabolic and functional markers that may be altered in FGR. We also employed phase-contrast magnetic resonance imaging MRI to assess left ventricular cardiac output (LVCO) as a measure of cardiac function. We hypothesized that signalling molecules involved in cardiac fatty acid utilisation and contractility would be impaired by FGR and that this would have a negative impact on LVCO in the late gestation fetus. Key glucose (GLUT4 protein) and fatty acid (FATP, CD36 gene expression) substrate transporters were significantly reduced in the hearts of FGR fetuses. We also found reduced mitochondrial numbers as well as abundance of electron transport chain complexes (complexes II and IV). These data suggest that FGR diminishes metabolic and mitochondrial capacity in the fetal heart; however, alterations were not correlated with fetal LVCO. Overall, these data show that FGR alters fetal cardiac metabolism in late gestation. If sustained ex utero, this altered metabolic profile may contribute to poor cardiac outcomes in FGR-born individuals after birth. KEY POINTS: Around the time of birth, substrate utilisation in the fetal heart switches from carbohydrates to fatty acids. However, the effect of fetal growth restriction (FGR) on this switch, and thus the ability of the fetal heart to effectively metabolise fatty acids, is not fully understood. Using a sheep model of early onset FGR, we observed significant downregulation in mRNA expression of fatty acid receptors CD36 and FABP in the fetal heart. FGR fetuses also had significantly lower cardiac mitochondrial abundance than controls. There was a reduction in abundance of complexes II and IV within the electron transport chain of the FGR fetal heart, suggesting altered ATP production. This indicates reduced fatty acid metabolism and mitochondrial function in the heart of the FGR fetus, which may have detrimental long-term implications and contribute to increased risk of cardiovascular disease later in life., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The recent demonstration of normal development of preterm sheep in an artificial extrauterine environment has renewed interest in artificial placenta (AP) systems as a potential treatment strategy for extremely preterm human infants. However, the feasibility of translating this technology to the human preterm infant remains unknown. Here we report the support of 13 preterm fetal pigs delivered at 102 ± 4 days (d) gestation, weighing 616 ± 139 g with a circuit consisting of an oxygenator and a centrifugal pump, comparing these results with our previously reported pumpless circuit ( n = 12; 98 ± 4 days; 743 ± 350 g). The umbilical vessels were cannulated, and fetuses were supported for 46.4 ± 46.8 h using the pumped AP versus 11 ± 13 h on the pumpless AP circuit. Upon initiation of AP support on the pumped system, we observed supraphysiologic circuit flows, tachycardia, and hypertension, while animals maintained on a pumpless AP circuit exhibited subphysiologic flows. On the pumped AP circuit, there was a progressive decline in umbilical vein (UV) flow and oxygen delivery. We conclude that the addition of a centrifugal pump to the AP circuit improves survival of preterm pigs by augmenting UV flow through the reduction of right ventricular afterload. However, we continued to observe the development of heart failure within a matter of days., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Charest-Pekeski, Cho, Aujla, Sun, Floh, McVey, Sheta, Estrada, Crawford-Lean, Foreman, Mroczek, Belik, Saini, Lim, Moir, Lee, Quinn, Darby, Seed, Morrison and Haller.)

Introduction: Newborns exposed to sildenafil citrate (SC) in utero have increased rates of persistent pulmonary hypertension. The mechanism behind this has not yet been fully elucidated. We aimed to utilize a combination of clinically relevant MRI techniques to comprehensively characterize the haemodynamics of the fetal sheep whilst under the influence of SC. We hypothesized that these MRI techniques would detect SC-induced increases in pulmonary blood flow and oxygen delivery prior to birth., Methods: At 116-117 days gestational age (term, 150 days), pregnant Merino ewes (n = 9) underwent fetal catheterization surgery. MRI scans were performed during a basal state and then repeated during a constant umbilical vein infusion of SC to measure blood flow and oxygenation within the major vessels of the fetal circulation using phase-contrast-MRI and T2 oximetry., Results: Right and left ventricular cardiac outputs were not different between states. Pulmonary blood flow increased during the SC state resulting in elevated pulmonary oxygen delivery. Right to left heart shunting through the foramen ovale was reduced without reducing cerebral oxygen delivery., Conclusion: SC induces alterations to pulmonary haemodynamics in utero; a characteristic that if maintained may underlie or act as a precursor towards the elevated rates of poor pulmonary outcomes after birth. These MRI techniques are the first to comprehensively characterize sildenafil's direct impact on the pulmonary vasculature and its indirect detriment to the flow of oxygen-rich blood through the foramen ovale., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Intrauterine growth restriction (IUGR) is a result of limited substrate supply to the developing fetus in utero, and can be caused by either placental, genetic or environmental factors. Babies born IUGR can have poor long-term health outcomes, including being at higher risk of developing cardiovascular disease. Limited substrate supply in the IUGR fetus not only changes the structure of the heart but may also affect metabolism and function of the developing heart. We have utilised two imaging modalities, two-photon microscopy and phase-contrast MRI (PC-MRI), to assess alterations in cardiac metabolism and function using a sheep model of IUGR. Two-photon imaging revealed that the left ventricle of IUGR fetuses (at 140-141 d GA) had a reduced optical redox ratio, suggesting a reliance on glycolysis for ATP production. Concurrently, the use of PC-MRI to measure foetal left ventricular cardiac output (LVCO) revealed a positive correlation between LVCO and redox ratio in IUGR, but not control fetuses. These data suggest that altered heart metabolism in IUGR fetuses is indicative of reduced cardiac output, which may contribute to poor cardiac outcomes in adulthood., (© 2021 Wiley-VCH GmbH.)

Objectives: To characterize, using magnetic resonance imaging (MRI), the distribution of blood flow and oxygen transport in human fetuses with subtypes of congenital heart disease (CHD) that present with neonatal cyanosis., Methods: Blood flow was measured in the major vessels of 152 late-gestation human fetuses with CHD and 40 gestational-age-matched normal fetuses, using cine phase-contrast MRI. Oxygen saturation (SaO 2 ) was measured in the major vessels of 57 fetuses with CHD and 40 controls., Results: Compared with controls, we found lower combined ventricular output in fetuses with single-ventricle physiology, with the lowest being observed in fetuses with severe forms of Ebstein's anomaly. Obstructive lesions of the left or right heart were associated with increased flow across the contralateral side. Pulmonary blood flow was reduced in fetuses with Ebstein's anomaly, while those with Ebstein's anomaly and tricuspid atresia had reduced umbilical flow. Flow in the superior vena cava was elevated in fetuses with transposition of the great arteries, normal in fetuses with hypoplastic left heart, tetralogy of Fallot or tricuspid atresia and reduced in fetuses with Ebstein's anomaly. Umbilical vein SaO 2 was reduced in fetuses with hypoplastic left heart or tetralogy of Fallot. Ascending aorta and superior vena cava SaO 2 were reduced in nearly all CHD subtypes., Conclusions: Fetuses with cyanotic CHD exhibit profound changes in the distribution of blood flow and oxygen transport, which result in changes in cerebral, pulmonary and placental blood flow and oxygenation. These alterations of fetal circulatory physiology may influence the neonatal course and help account for abnormalities of prenatal growth and development that have been described in newborns with cyanotic CHD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Background: Although insufficient maternal cardiac output (CO) has been implicated in poor outcomes in mothers with heart disease (HD), maternal-fetal interactions remain incompletely understood. We sought to quantify maternal-fetal hemodynamics with the use of magnetic resonance imaging (MRI) and explore their relationship with adverse events., Methods: Pregnant women with moderate or severe HD (n = 22; mean age 32 ± 5 years) were compared with healthy control women (n = 21; 34 ± 3 years). An MRI was performed during the third trimester at peak output (maternal-fetal) and 6 months postpartum with return of maternal hemodynamics to baseline (reference). Phase-contrast MRI was used for flow quantification and was combined with T1/T2 relaxometry for derivation of fetal oxygen delivery/consumption., Results: Third-trimester CO and cardiac index (CI) measurements were similar in HD and control groups (CO 7.2 ± 1.5 vs 7.3 ± 1.6 L/min, P = 0.79; CI 4.0 ± 0.7 vs 4.3 ± 0.7 L/min/m, 2 P = 0.28). However, the magnitude of CO/CI increase (Δ, peak pregnancy - reference) in the HD group exceeded that in the control group (CO 46 ± 24% vs 27 ± 16% [P = 0.007]; CI 51 ± 28% vs 28 ± 17% [P = 0.005]). Fetal growth and oxygen delivery/consumption were similar between groups. Adverse cardiovascular outcomes (nonmutually exclusive) in 6 HD women included arrhythmia (n = 4), heart failure (n = 2), and hypertensive disorder of pregnancy (n = 1); premature delivery was observed in 2 of these women. The odds of a maternal cardiovascular event were inversely associated with peak CI (odds ratio 0.10, 95% confidence interval 0.001-0.86; P = 0.04) and Δ,CI (0.02, 0.001-0.71; P = 0.03)., Conclusions: Maternal-fetal hemodynamics can be well characterised in pregnancy with the use of MRI. Impaired adaptation to pregnancy in women with HD appears to be associated with development of adverse outcomes of pregnancy., (Copyright © 2021 Canadian Cardiovascular Society. All rights reserved.)

Purpose: Ten percent of pregnancies are affected by intrauterine growth restriction (IUGR), and evidence suggests that affected neonates have reduced activity of hepatic cytochrome P450 (CYP) drug metabolising enzymes. Given that almost all pregnant individuals take medications and additional medications are often required during an IUGR pregnancy, we aimed to determine the impact of IUGR on hepatic CYP activity in sheep fetuses and pregnant ewes., Methods: Specific probes were used to determine the impact of IUGR on the activity of several CYP isoenzymes (CYP1A2, CYP2C19, CYP2D6 and CYP3A) in sheep fetuses and pregnant ewes. Probes were administered intravenously to the ewe at 132 days (d) gestation (term 150 d), followed by blood sampling from the maternal and fetal circulation over 24 h. Maternal and fetal liver tissue was collected at 139-140 d gestation, from which microsomes were isolated and incubated with probes. Metabolite and maternal plasma cortisol concentrations were measured using Liquid Chromatography - tandem mass spectrometry (LC-MS/MS)., Results: Maternal plasma cortisol concentration and maternal hepatic CYP1A2 and CYP3A activity was significantly higher in IUGR pregnancies. Maternal hepatic CYP activity was higher than fetal hepatic CYP activity for all CYPs tested, and there was minimal CYP1A2 or CYP3A activity in the late gestation fetus when assessed using in vitro methods., Conclusions: The physiological changes to the maternal-placental-fetal unit in an IUGR pregnancy have significant effects on maternal drug metabolism, suggesting changes in medications and/or doses may be required to optimise maternal and fetal health., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Restriction of fetal substrate supply has an adverse effect on surfactant maturation in the lung and thus affects the transition from in utero placental oxygenation to pulmonary ventilation ex utero. The effects on surfactant maturation are mediated by alteration in mechanisms regulating surfactant protein and phospholipid synthesis. This study aimed to determine the effects of late gestation maternal undernutrition (LGUN) and LGUN plus fetal glucose infusion (LGUN+G) compared to Control on surfactant maturation and lung development, and the relationship with pulmonary blood flow and oxygen delivery ( D O 2 ) measured by magnetic resonance imaging (MRI) with molecules that regulate lung development. LGUN from 115 to 140 days' gestation significantly decreased fetal body weight, which was normalized by glucose infusion. LGUN and LGUN+G resulted in decreased fetal plasma glucose concentration, with no change in fetal arterial P O 2 compared to control. There was no effect of LGUN and LGUN+G on the mRNA expression of surfactant proteins (SFTP) and genes regulating surfactant maturation in the fetal lung. However, blood flow in the main pulmonary artery was significantly increased in LGUN, despite no change in blood flow in the left or right pulmonary artery and D O 2 to the fetal lung. There was a negative relationship between left pulmonary artery flow and D O 2 to the left lung with SFTP-B and GLUT1 mRNA expression, while their relationship with VEGFR2 was positive. These results suggest that increased pulmonary blood flow measured by MRI may have an adverse effect on surfactant maturation during fetal lung development. KEY POINTS: Maternal undernutrition during gestation alters fetal lung development by impacting surfactant maturation. However, the direction of change remains controversial. We examined the effects of maternal late gestation maternal undernutrition (LGUN) on maternal and fetal outcomes, signalling pathways involved in fetal lung development, pulmonary haemodynamics and oxygen delivery in sheep using a combination of molecular and magnetic resonance imaging (MRI) techniques. LGUN decreased fetal plasma glucose concentration without affecting arterial P O 2 . Surfactant maturation was not affected; however, main pulmonary artery blood flow was significantly increased in the LGUN fetuses. This is the first study to explore the relationship between in utero MRI measures of pulmonary haemodynamics and lung development. Across all treatment groups, left pulmonary artery blood flow and oxygen delivery were negatively correlated with surfactant protein B mRNA and protein expression in late gestation., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

The ductus arteriosus (DA) functionally closes during the transition from fetal to postnatal life because of lung aeration and corresponding cardiovascular changes. The thorough and explicit measurement and visualization of the right and left heart output during this transition has not been previously accomplished. We combined 4D flow MRI (dynamic volumetric blood flow measurements) and T2 relaxometry (oxygen delivery quantification) in surgically instrumented newborn piglets to assess the DA. This was performed in Large White-Landrace-Duroc piglets (n = 34) spanning four age groups: term-9 days, term-3, term+1, and term+5. Subject's DA status was classified using 4D flow: closed DA, forward DA flow, reversed DA flow, and bidirectional DA flow. Over all states, vessel diameters and flows normalized to body weight increased with age (for example in the ascending aorta flow-term-9: 126.6 ± 45.4; term+5: 260.2 ± 80.0 ml/min per kg; p = 0.0005; ascending aorta diameter-term-9: 5.2 ± 0.8; term+5: 7.7 ± 0.4 mm; p = 0.0004). In subjects with reversed DA blood flow there was lower common carotid artery blood flow (forward: 37.5 ± 9.0; reversed: 20.0 ± 7.4 ml/min per kg; p = 0.032). Linear regression revealed that as net DA flow decreases, common carotid artery flow decreases (R 2  = 0.32, p = 0.004), and left (R 2  = 0.33, p = 0.003) and right (R 2  = 0.34, p = 0.003) pulmonary artery flow increases. Bidirectional DA blood flow changed oxygen saturation as determined by MRI between the ascending and descending aorta (ascending aorta: 90.1% ± 8.4%; descending aorta: 75.6% ± 14.2%; p < 0.05). Expanded use of these techniques in preterm animal models will aid in providing new understandings of normal versus abnormal DA transition, as well as to test the effectiveness of related clinical interventions., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Key Points: Human placental function is evaluated using non-invasive Doppler ultrasound of umbilical and uterine artery pulsatility indices as measures of resistance in placental vascular beds, while measurement of placental oxygen consumption ( V O 2 ) is only possible during Caesarean delivery. This study shows the feasibility of using magnetic resonance imaging (MRI) in utero to measure blood flow and oxygen content in uterine and umbilical vessels to calculate oxygen delivery to and V O 2 by the gravid uterus, uteroplacenta and fetus. Normal late gestational human uteroplacental V O 2 by MRI was ∼4 ml min -1  kg -1 fetal weight, which was similar to our MRI measurements in sheep and to those previously measured using invasive techniques. Our MRI approach can quantify uteroplacental V O 2 , which involves the quantification of maternal- and fetal-placental blood flows, fetal oxygen delivery and V O 2 , and the oxygen gradient between uterine- and umbilical-venous blood, providing a comprehensive assessment of placental function with clinical potential., Abstract: It has not been feasible to perform routine clinical measurement of human placental oxygen consumption ( V O 2 ) and in vitro studies do not reflect true metabolism in utero. Here we propose an MRI method to non-invasively quantify in utero placental and fetal oxygen delivery ( D O 2 ) and V O 2 in healthy humans and sheep. Women (n = 20) and Merino sheep (n = 10; 23 sets of measurements) with singleton pregnancies underwent an MRI in late gestation (36 ± 2 weeks and 128 ± 9 days, respectively; mean ± SD). Blood flow (phase-contrast) and oxygen content (T1 and T2 relaxometry) were measured in the major uterine- and umbilical-placental vessels, allowing calculation of uteroplacental and fetal D O 2 and V O 2 . Maternal D O 2 (ml min -1  kg -1 fetus) to the gravid uterus was similar in humans and sheep (human = 54 ± 15, sheep = 53 ± 21, P = 0.854), while fetal D O 2 (human = 25 ± 4, sheep = 22 ± 5, P = 0.049) was slightly lower in sheep. Uteroplacental and fetal V O 2 (ml min -1  kg -1 fetus; uteroplacental: human = 4.1 ± 1.5, sheep = 3.5 ± 1.9, P = 0.281; fetus: human = 6.8 ± 1.3, sheep = 7.2 ± 1.7, P = 0.426) were similar between species. Late gestational uteroplacental:fetal V O 2 ratio did not change with age (human, P = 0.256; sheep, P = 0.121). Human umbilical blood flow (ml min -1  kg -1 fetus) decreased with advancing age (P = 0.008), while fetal V O 2 was preserved through an increase in oxygen extraction (P = 0.046). By contrast, sheep fetal V O 2 was preserved through stable umbilical flow (ml min -1  kg -1 ; P = 0.443) and oxygen extraction (P = 0.582). MRI derived measurements of uteroplacental and fetal V O 2 between humans and sheep were similar and in keeping with prior data obtained using invasive techniques. Taken together, these data confirm the reliability of our approach, which offers a novel clinical 'placental function test'., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

New Findings: What is the central question of this study? Uterine artery blood flow helps to maintain fetal oxygen and nutrient delivery. We investigated the effects of increased uterine artery blood flow mediated by resveratrol on fetal growth, haemodynamics, blood pressure regulation and oxygenation in pregnant sheep. What is the main finding and its importance? Fetuses from resveratrol-treated ewes were significantly larger and exhibited a haemodynamic profile that might promote peripheral growth. Absolute uterine artery blood flow was positively correlated with umbilical vein oxygen saturation, absolute fetal oxygen delivery and fetal growth. Increasing uterine artery blood flow with compounds such as resveratrol might have clinical significance for pregnancy conditions in which fetal growth and oxygenation are compromised., Abstract: High placental vascular resistance hinders uterine artery (UtA) blood flow and fetal substrate delivery. In the same group of animals as the present study, we have previously shown that resveratrol (RSV) increases UtA blood flow, fetal weight and oxygenation in an ovine model of human pregnancy. However, the mechanisms behind changes in growth and the effects of increases in UtA blood flow on fetal circulatory physiology have yet to be investigated. Twin-bearing ewes received s.c. vehicle (VEH, n = 5) or RSV (n = 6) delivery systems at 113 days of gestation (term = 150 days). Magnetic resonance imaging was performed at 123-124 days to quantify fetal volume, blood flow and oxygen saturation of major fetal vessels. At 128 days, i.v. infusions of sodium nitroprusside and phenylephrine were administered to study the vascular tone of the fetal descending aorta. Maternal RSV increased fetal body volume (P = 0.0075) and weight (P = 0.0358), with no change in brain volume or brain weight. There was a positive relationship between absolute UtA blood flow and umbilical vein oxygen saturation, absolute fetal oxygen delivery and combined fetal twin volume (all P ≤ 0.05). There were no differences between groups in fetal haemodynamics or blood pressure regulation except for higher blood flow to the lower body in RSV fetuses (P = 0.0170). The observed increase in fetal weight might be helpful in pregnancy conditions in which fetal growth and oxygen delivery are compromised. Further preclinical investigations on the mechanism(s) accounting for these changes and the potential to improve growth in complicated pregnancies are warranted., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

Artificial placenta (AP) technology aims to maintain fetal circulation, while promoting the physiologic development of organs. Recent reports of experiments performed in sheep indicate the intrauterine environment can be recreated through the cannulation of umbilical vessels, replacement of the placenta with a low-resistance membrane oxygenator, and incubation of the fetus in fluid. However, it remains to be seen whether animal fetuses similar in size to the extremely preterm human infant that have been proposed as a potential target for this technology can be supported in this way. Preterm Yucatan miniature piglets are similar in size to extremely preterm human infants and share similar umbilical cord anatomy, raising the possibility to serve as a good model to investigate the AP. To characterize fetal cardiovascular physiology, the carotid artery (n = 24) was cannulated in utero and umbilical vein (UV) and umbilical artery were sampled. Fetal UV flow was measured by MRI (n = 16). Piglets were delivered at 98 ± 4 days gestation (term = 115 days), cannulated, and supported on the AP (n = 12) for 684 ± 228 min (range 195-3077 min). UV flow was subphysiologic (p = .002), while heart rate was elevated on the AP compared with in utero controls (p = .0007). We observed an inverse relationship between heart rate and UV flow (r 2  = .4527; p < .001) with progressive right ventricular enlargement that was associated with reduced contractility and ultimately hydrops and circulatory collapse. We attribute this to excessive afterload imposed by supraphysiologic circuit resistance and augmented sympathetic activity. We conclude that short-term support of the preterm piglet on the AP is feasible, although we have not been able to attain normal fetal physiology. In the future, we propose to investigate the feasibility of an AP circuit that incorporates a centrifugal pump in our miniature pig model., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Key Points: The ductus venosus (DV) is a dynamic fetal shunt that allows substrate-rich blood from the umbilical vein to bypass the hepatic circulation. In vitro studies suggest a direct role of prostaglandin I 2 (PGI 2 ) in the regulation of DV tone; however, the extent of this regulation has not been determined in utero. 4D flow and T 2 oximetry magnetic resonance imaging can be combined to determine blood flow and oxygen delivery within the fetal circulation. PGI 2 increases DV shunting of substrate-rich blood but this does not increase cerebral oxygen delivery., Abstract: During fetal development, the maintenance of adequate oxygen and nutrient supply to vital organs is regulated through specialized fetal shunts. One of these shunts, the ductus venosus (DV), allows oxygen-rich blood to preferentially stream from the placenta toward the heart and brain. Herein, we combine magnetic resonance imaging (MRI) techniques that measure blood flow (4D flow) and oxygen saturation (T 2 oximetry) in the fetal circuit to determine whether umbilical vein infusion of prostaglandin I 2 (PGI 2 , regulator of DV tone ex utero) directly dilates the DV and thus increases the preferential streaming of oxygen-rich blood toward the brain. At 114-115 days gestational age (dGA; term = 150 days), fetal sheep (n = 6) underwent surgery to implant vascular catheters in the fetal femoral artery, femoral vein, amniotic cavity and umbilical vein. Fetal MRI scans were performed at 119-124 dGA. 4D flow and T 2 oximetry were performed to measure blood flow and oxygen saturation across the fetal circulation in both a basal state and whilst the fetus was receiving a continuous infusion of PGI 2 . The proportion of oxygenated blood that passed through the DV from the umbilical vein was increased by PGI 2 . Cerebral oxygen delivery was unchanged in the PGI 2 state. This may be a result of decreased flow from the right to left side of the heart as blood flow through the foramen ovale was decreased by PGI 2 . We have shown that although PGI 2 acts on the DV to increase the proportion of oxygen-rich blood that bypasses the liver, this does not increase cerebral oxygen delivery in the fetal sheep., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: The comprehensive visualization and quantification of in vivo fetal hepatic haemodynamics, particularly the shunting of ductus venosus blood, has been elusive and is not yet fully understood. We introduce the combination of chronically instrumented fetal sheep and 4D flow MRI of the whole fetal liver, which allows retrospective blood flow measurement in all visible vessels as well as qualitative assessment. The applicability and usefulness of this technique is exhibited in normally grown fetal Merino sheep in mid- and late-gestation with detailed dynamic distribution of hepatic blood flow presented. The feasibility of this approach in clinical pathology is demonstrated in two growth-restricted fetuses at mid-gestation. Further exemplification of blood flow quantification is performed over major hepatic vessels., Abstract: Although the fetal vasculature has been demarcated and well understood for several decades, the corresponding haemodynamics permitting oxygen- and nutrient-rich blood delivery to the fetal organs has been comparatively difficult to study. We married two well-established methods: 4D flow MRI, a volumetric and dynamic blood-flow measurement technique, and chronically instrumented sheep to broadly assess fetal hepatic circulation. We performed this technique in mid- and late-gestation fetal Merino sheep under normoxemic conditions and major hepatic vasculature was segmented to quantify blood flow and related parameters. Dynamic blood flow was visualized, exhibiting an acceleration of umbilical vein blood through the ductus venosus as well as spiralling into the inferior vena cava where its stream remained separate from that of the hepatic veins and lower body. Ductus venosus changes from mid- to late-gestation included larger diameter (mid: 5.8 ± 0.9 vs. late: 7.1 ± 1.1 mm; P = 0.003) and cross-sectional area (mid: 27.1 ± 8.6 vs. late: 40.4 ± 11.8 mm 2 ; P = 0.003), and lower velocity averaged over the cardiac cycle (mid: 15.7 ± 5.4 vs. late: 9.8 ± 7.0 cm s -1 ; P = 0.020). This resulted in higher magnitude blood flow (indexed to umbilical vein input) at mid-gestation in the ductus venosus (mid: 0.73 ± 0.21; late: 0.46 ± 0.21; P = 0.008). The visualization and quantification results support the further use of this technique to better understand regional blood flow changes during normal or abnormal fetal growth, as well as to observe acute haemodynamic responses to physiological challenges or drug interventions., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: Human fetal Doppler ultrasound and invasive blood gas measurements obtained by cordocentesis or at the time of delivery reveal similarities with sheep (an extensively used model for human fetal cardiovascular physiology). Oxygen saturation (SO 2 ) measurements in human fetuses have been limited to the umbilical and scalp vessels, providing little information about normal regional SO 2 differences in the fetus. Blood T2 MRI relaxometry presents a non-invasive measure of SO 2 in the major fetal vessels. This study presents the first in vivo validation of fetal vessel T2 oximetry against the in vitro T2-SO 2 relationship using catheterized sheep fetuses and compares the normal SO 2 in the major vessels between the human and sheep fetal circulations. Human fetal vessel SO 2 by T2 MRI confirms many similarities with the sheep fetal circulation and is able to demonstrate regional differences in SO 2 ; in particular the significantly higher SO 2 in the left versus right heart., Abstract: Blood T2 magnetic resonance imaging (MRI) relaxometry non-invasively measures oxygen saturation (SO 2 ) in major vessels but has not been validated in fetuses in vivo. We compared the blood T2-SO 2 relationship in vitro (tubes) and in vivo (vessels) in sheep, and measured SO 2 across the normal human and sheep fetal circulations by T2. Singleton pregnant ewes underwent surgery to implant vascular catheters. In vitro and in vivo sheep blood T2 measurements were related to corresponding SO 2 measured using a blood gas analyser, as well as relating T2 and SO 2 of human fetal blood in vitro. MRI oximetry was performed in the major vessels of 30 human fetuses at 36 weeks (term, 40 weeks) and 10 fetal sheep (125 days; term, 150 days). The fidelity of in vivo fetal T2 oximetry was confirmed through comparison of in vitro and in vivo sheep blood T2-SO 2 relationships (P = 0.1). SO 2 was similar between human and sheep fetuses, as was the fetal oxygen extraction fraction (human, 33 ± 11%; sheep, 34 ± 7%; P = 0.798). The presence of streaming in the human fetal circulation was demonstrated by the SO 2 gradient between the ascending aorta (68 ± 10%) and the main pulmonary artery (49 ± 9%; P < 0.001). Human and sheep fetal vessel MRI oximetry based on T2 is a validated approach that confirms the presence of streaming of umbilical venous blood towards the heart and brain. Streaming is important in ensuring oxygen delivery to these organs and its disruption may have important implications for organ development, especially in conditions such as congenital heart disease and fetal growth restriction., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Key Points: The application of fetal cardiovascular magnetic resonance imaging (CMR) to assess fetal cardiovascular physiology and cardiac function through the quantification of ventricular volumes has previously been investigated, but the approach has not yet been fully validated. Ventricular output measurements calculated from heart rate and stroke volumes (SV) of the right and left ventricles measured by ventricular volumetry (VV) exhibited a high level of agreement with phase-contrast (PC) blood flow measurements in the main pulmonary artery and ascending aorta, respectively. Ejection fraction of the right ventricle, which is lower than that of the left ventricle in postnatal subjects, was similar to the left ventricular ejection fraction in the fetus; probably due to the different loading conditions present in the fetal circulation. This study provides evidence to support the reliability of VV in the sheep fetus, providing evidence for its use in animal models of human diseases affecting the fetal circulation., Abstract: The application of ventricular volumetry (VV) by cardiovascular magnetic resonance imaging (CMR) in the fetus remains challenging due to the small size of the fetal heart and high heart rate. The reliability of this technique in utero has not yet been established. The aim of this study was to assess the feasibility and reliability of VV in a fetal sheep model of human pregnancy. Right and left ventricular outputs by stroke volume (SV) measured using VV were compared with 2D phase-contrast (PC) CMR measurements of blood flow in the main pulmonary artery (MPA) and ascending aorta (AAo). At 124-140 days (d) gestation, singleton bearing Merino ewes underwent CMR under general anaesthesia using fetal femoral artery catheters, implanted at 109-117d, to trigger cine steady state free precession acquisitions of ventricular short-axis stacks. The short-axis cine stacks were segmented at end-systole and end-diastole, yielding right and left ventricular SV, ejection fraction, and cardiac outputs (SV × heart rate). PC cine acquisitions of MPA and AAo were analysed to measure blood flow, which served as comparators for the right and left cardiac outputs by VV. There was good correlation and agreement between VV and PC measures of ventricular outputs with no significant bias (r 2  = 0.926; P < 0.0001; Bias = -4.7 ± 10.5 ml min -1  kg -1 ; 95% limits of agreement: -15.9 to 25.2 ml min -1  kg -1 ). This study validates fetal VV by CMR in a large animal model of human pregnancy and provides preliminary reference values of fetal sheep right and left ventricles in late gestation., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

In the last decade, technological advances have enabled the acquisition of high spatial and temporal resolution cardiac magnetic resonance imaging (MRI) in the fetus. Fetal cardiac MRI has emerged as an alternative to ultrasound, which may be helpful to confirm a diagnosis of congenital heart disease when ultrasound assessment is hampered, for example in late gestation or in the setting of oligohydramnios. MRI also provides unique physiologic information, including vessel blood flow, oxygen saturation and hematocrit, which may be helpful to investigate cardiac and placental diseases. In this review, we summarize some of the main techniques and significant advances in the field to date. Level of Evidence: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2020;51:1030-1044., (© 2019 International Society for Magnetic Resonance in Medicine.)

Key Points: Substrate restriction during critical developmental windows of gestation programmes offspring for a predisposition towards cardiovascular disease in adult life. This study aimed to determine the effect of maternal resveratrol (RSV) treatment in an animal model in which chronic fetal catheterisation is possible and the timing of organ maturation reflects that of the human. Maternal RSV treatment increased uterine artery blood flow, fetal oxygenation and fetal weight. RSV was not detectable in the fetal circulation, indicating that it may not cross the sheep placenta. This study highlights RSV as a possible intervention to restore fetal substrate supply in pregnancies affected by placental insufficiency., Abstract: Suboptimal in utero environments with reduced substrate supply during critical developmental windows of gestation predispose offspring to non-communicable diseases such as cardiovascular disease (CVD). Improving fetal substrate supply in these pregnancies may ameliorate the predisposition these offspring have toward adult-onset CVD. This study aimed to determine the effect of maternal resveratrol (RSV) supplementation on uterine artery blood flow and the direct effects of RSV on the fetal heart in a chronically catheterised sheep model of human pregnancy. Maternal RSV treatment significantly increased uterine artery blood flow as measured by phase contrast magnetic resonance imaging, mean gestational fetal P a O 2 and S a O 2 as well as fetal weight. RSV was not detectable in the fetal circulation, and mRNA and protein expression of the histone/protein deacetylase SIRT1 did not differ between treatment groups. No effect of maternal RSV supplementation on AKT/mTOR or CAMKII signalling in the fetal left ventricle was observed. Maternal RSV supplementation is capable of increasing fetal oxygenation and growth in an animal model in which cardiac development parallels that of the human., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Objective: This study aims to noninvasively quantify blood flow in the uterine arteries (UTAs) and umbilical vein (UV) using phase-contrast magnetic resonance imaging (PC-MRI) and test whether these correlate with maternal fitness parameters., Method: Resting UTA and UV flows were measured in 23 healthy 30 ± 3-year-old women who engaged in moderate-intensity physical activity during pregnancy. Participant fitness was characterized in the second and third trimesters using the submaximal oxygen uptake (VO 2 ) test measuring heart rate (HR), VO 2 , ventilation (ventilatory equivalent [VE]/VO 2 ), and the Borg rating of perceived exertion (respiratory quotient [RQ]). Linear regression models were used to determine the associations between blood flow and maternal fitness measures., Results: Blood flows in the UTA (957 ± 241 mL/min) and UV (132 ± 38 mL/min/kg) were successfully measured in 20 (87%) participants. Neither was associated with any physical fitness parameters (HR, VO 2 , VE/VO 2 , and RQ) nor with any second-to-third trimester change in these parameters., Conclusion: PC-MRI can be used to noninvasively measure blood flow in the UTA and UV. Neither resting UTA nor UV flow is associated with maternal fitness parameters. This is the first MRI-based study to provide novel hemodynamic data suggesting decoupling between maternal moderate fitness level and the maternal-placental-fetal hemodynamic system in healthy, normal body mass index (BMI) pregnancies., (© 2019 John Wiley & Sons, Ltd.)

Background: To date it has not been possible to obtain a comprehensive 3D assessment of fetal hemodynamics because of the technical challenges inherent in imaging small cardiac structures, movement of the fetus during data acquisition, and the difficulty of fusing data from multiple cardiac cycles when a cardiac gating signal is absent. Here we propose the combination of volumetric velocity-sensitive cardiovascular magnetic resonance imaging ("4D flow" CMR) and a specialized animal preparation (catheters to monitor fetal heart rate, anesthesia to immobilize mother and fetus) to examine fetal sheep cardiac hemodynamics in utero., Methods: Ten pregnant Merino sheep underwent surgery to implant arterial catheters in the target fetuses. Anesthetized ewes underwent 4D flow CMR with acquisition at 3 T for fetal whole-heart coverage with 1.2-1.5 mm spatial resolution and 45-62 ms temporal resolution. Flow was measured in the heart and major vessels, and particle traces were used to visualize circulatory patterns in fetal cardiovascular shunts. Conservation of mass was used to test internal 4D flow consistency, and comparison to standard 2D phase contrast (PC) CMR was performed for validation., Results: Streaming of blood from the ductus venosus through the foramen ovale was visualized. Flow waveforms in the major thoracic vessels and shunts displayed normal arterial and venous patterns. Combined ventricular output (CVO) was 546 mL/min per kg, and the distribution of flows (%CVO) were comparable to values obtained using other methods. Internal 4D flow consistency across 23 measurement locations was established with differences of 14.2 ± 12.1%. Compared with 2D PC CMR, 4D flow showed a strong correlation (R 2  = 0.85) but underestimated flow (bias = - 21.88 mL/min per kg, p < 0.05)., Conclusions: The combination of fetal surgical preparation and 4D flow CMR enables characterization and quantification of complex flow patterns in utero. Visualized streaming of blood through normal physiological shunts confirms the complex mechanism of substrate delivery to the fetal heart and brain. Besides offering insight into normal physiology, this technology has the potential to qualitatively characterize complex flow patterns in congenital heart disease phenotypes in a large animal model, which can support the development of new interventions to improve outcomes in this population.

The electrocardiogram (ECG) non-invasively monitors the electrical activities of the heart. During the process of recording and transmission, ECG signals are often corrupted by various types of noises. Minimizations of these noises facilitate accurate detection of various anomalies. In the present paper, Alexander fractional differential window (AFDW) filter is proposed for ECG signal denoising. The designed filter is based on the concept of generalized Alexander polynomial and the R-L differential equation of fractional calculus. This concept is utilized to formulate a window that acts as a forward filter. Thereafter, the backward filter is constructed by reversing the coefficients of the forward filter. The proposed AFDW filter is then obtained by averaging of the forward and backward filter coefficients. The performance of the designed AFDW filter is validated by adding the various type of noise to the original ECG signal obtained from MIT-BIH arrhythmia database. The two non-diagnostic measure, i.e., SNR, MSE, and one diagnostic measure, i.e., wavelet energy based diagnostic distortion (WEDD) have been employed for the quantitative evaluation of the designed filter. Extensive experimentations on all the 48-records of MIT-BIH arrhythmia database resulted in average SNR of 22.014 ± 3.806365, 14.703 ± 3.790275, 13.3183 ± 3.748230; average MSE of 0.001458 ± 0.00028, 0.0078 ± 0.000319, 0.01061 ± 0.000472; and average WEDD value of 0.020169 ± 0.01306, 0.1207 ± 0.061272, 0.1432 ± 0.073588, for ECG signal contaminated by the power line, random, and the white Gaussian noise respectively. A new metric named as morphological power preservation measure (MPPM) is also proposed that account for the power preservance (as indicated by PSD plots) and the QRS morphology. The proposed AFDW filter retained much of the original (clean) signal power without any significant morphological distortion as validated by MPPM measure that were 0.0126, 0.08493, and 0.10336 for the ECG signal corrupted by the different type of noises. The versatility of the proposed AFDW filter is also validated by its application on the ECG signal from MIT-BIH database corrupted by the combination of the noises as well as on the real noisy ECG signals are taken from MIT-BIH ID database. Furthermore, the comparative study has also been done between the proposed AFDW filter and existing state of the art denoising algorithms. The results clearly prove the supremacy of our proposed AFDW filter.

In the present paper, a hybrid multilevel thresholding technique that combines intuitionistic fuzzy sets and tsallis entropy has been proposed for the automatic delineation of the tumor from magnetic resonance images having vague boundaries and poor contrast. This novel technique takes into account both the image histogram and the uncertainty information for the computation of multiple thresholds. The benefit of the methodology is that it provides fast and improved segmentation for the complex tumorous images with imprecise gray levels. To further boost the computational speed, the mutation based particle swarm optimization is used that selects the most optimal threshold combination. The accuracy of the proposed segmentation approach has been validated on simulated, real low-grade glioma tumor volumes taken from MICCAI brain tumor segmentation (BRATS) challenge 2012 dataset and the clinical tumor images, so as to corroborate its generality and novelty. The designed technique achieves an average Dice overlap equal to 0.82010, 0.78610 and 0.94170 for three datasets. Further, a comparative analysis has also been made between the eight existing multilevel thresholding implementations so as to show the superiority of the designed technique. In comparison, the results indicate a mean improvement in Dice by an amount equal to 4.00% (p < 0.005), 9.60% (p < 0.005) and 3.58% (p < 0.005), respectively in contrast to the fuzzy tsallis approach.

Objective: Cardiovascular diseases generate the highest mortality in the globe population, mainly due to coronary artery disease (CAD) like arrhythmia, myocardial infarction and heart failure. Therefore, an early identification of CAD and diagnosis is essential. For this, we have proposed a new approach to detect the CAD patients using heart rate variability (HRV) signals. This approach is based on subspaces decomposition of HRV signals using multiscale wavelet packet (MSWP) transform and entropy features extracted from decomposed HRV signals. The detection performance was analyzed using Fisher ranking method, generalized discriminant analysis (GDA) and binary classifier as extreme learning machine (ELM). The ranking strategies designate rank to the available features extracted by entropy methods from decomposed heart rate variability (HRV) signals and organize them according to their clinical importance. The GDA diminishes the dimension of ranked features. In addition, it can enhance the classification accuracy by picking the best discerning of ranked features. The main advantage of ELM is that the hidden layer does not require tuning and it also has a fast rate of detection., Methodology: For the detection of CAD patients, the HRV data of healthy normal sinus rhythm (NSR) and CAD patients were obtained from a standard database. Self recorded data as normal sinus rhythm (Self&#95;NSR) of healthy subjects were also used in this work. Initially, the HRV time-series was decomposed to 4 levels using MSWP transform. Sixty two features were extracted from decomposed HRV signals by non-linear methods for HRV analysis, fuzzy entropy (FZE) and Kraskov nearest neighbour entropy (K-NNE). Out of sixty-two features, 31 entropy features were extracted by FZE and 31 entropy features were extracted by K-NNE method. These features were selected since every feature has a different physical premise and in this manner concentrates and uses HRV signals information in an assorted technique. Out of 62 features, top ten features were selected, ranked by a ranking method called as Fisher score. The top ten features were applied to the proposed model, GDA with Gaussian or RBF kernal + ELM having hidden node as sigmoid or multiquadric. The GDA method transforms top ten features to only one feature and ELM has been used for classification., Results: Numerical experimentations were performed on the combination of datasets as NSR-CAD and Self&#95;NSR- CAD subjects. The proposed approach has shown better performance using top ten ranked entropy features. The GDA with RBF kernel + ELM having hidden node as multiquadric method and GDA with Gaussian kernel + ELM having hidden node as sigmoid or multiquadric method achieved an approximate detection accuracy of 100% compared to ELM and linear discriminant analysis (LDA)+ELM for both datasets. The subspaces level-4 and level-3 decomposition of HRV signals by MSWP transform can be used for detection and analysis of CAD patients.

This paper presents a patient's confidential data hiding scheme in electrocardiogram (ECG) signal and its subsequent wireless transmission. Patient's confidential data is embedded in ECG (called stego-ECG) using chaotic map and the sample value difference approach. The sample value difference approach effectually hides the patient's confidential data in ECG sample pairs at the predefined locations. The chaotic map generates these predefined locations through the use of selective control parameters. Subsequently, the wireless transmission of the stego-ECG is analyzed using the Orthogonal Frequency Division Multiplexing (OFDM) system in a Rayleigh fading scenario for telemedicine applications. Evaluation of proposed method on all 48 records of MIT-BIH arrhythmia ECG database demonstrates that the embedding does not alter the diagnostic features of cover ECG. The secret data imperceptibility in stego-ECG is evident through the statistical and clinical performance measures. Statistical measures comprise of Percentage Root-mean-square Difference (PRD), Peak Signal to Noise Ratio (PSNR), and Kulback-Leibler Divergence (KL-Div), etc. while clinical metrics includes wavelet Energy Based Diagnostic Distortion (WEDD) and Wavelet based Weighted PRD (WWPRD). The various channel Signal-to-Noise Ratio scenarios are simulated for wireless communication of stego-ECG in OFDM system. The proposed method over all the 48 records of MIT-BIH arrhythmia database resulted in average, PRD = 0.26, PSNR = 55.49, KL-Div = 3.34 × 10 -6 , WEDD = 0.02, and WWPRD = 0.10 with secret data size of 21Kb. Further, a comparative analysis of proposed method and recent existing works was also performed. The results clearly, demonstrated the superiority of proposed method.

In this paper, a joint use of the discrete cosine transform (DCT), and differential pulse code modulation (DPCM) based quantization is presented for predefined quality controlled electrocardiogram (ECG) data compression. The formulated approach exploits the energy compaction property in transformed domain. The DPCM quantization has been applied to zero-sequence grouped DCT coefficients that were optimally thresholded via Regula-Falsi method. The generated sequence is encoded using Huffman coding. This encoded series is further converted to a valid ASCII code using the standard codebook for transmission purpose. Such a coded series possesses inherent encryption capability. The proposed technique is validated on all 48 records of standard MIT-BIH database using different measures for compression and encryption. The acquisition time has been taken in accordance to that existed in literature for the fair comparison with contemporary state-of-art approaches. The chosen measures are (1) compression ratio (CR), (2) percent root mean square difference (PRD), (3) percent root mean square difference without base (PRD1), (4) percent root mean square difference normalized (PRDN), (5) root mean square (RMS) error, (6) signal to noise ratio (SNR), (7) quality score (QS), (8) entropy, (9) Entropy score (ES) and (10) correlation coefficient (r x,y ). Prominently the average values of CR, PRD and QS were equal to 18.03, 1.06, and 17.57 respectively. Similarly, the mean encryption metrics i.e. entropy, ES and r x,y were 7.9692, 0.9962 and 0.0113 respectively. The novelty in combining the approaches is well justified by the values of these metrics that are significantly higher than the comparison counterparts.

An algorithm is presented for designing a new class of wavelets matched to the Heart Rate Variability (HRV) signals of the menstrual cycle. The proposed wavelets are used to find HRV variations between phases of menstrual cycle. The method finds the signal matching characteristics by minimising the shape feature error using Least Mean Square method. The proposed filter banks are used for the decomposition of the HRV signal. For reconstructing the original signal, the tree structure method is used. In this approach, decomposed sub-bands are selected based upon their energy in each sub-band. Thus, instead of using all sub-bands for reconstruction, sub-bands having high energy content are used for the reconstruction of signal. Thus, a lower number of sub-bands are required for reconstruction of the original signal which shows the effectiveness of newly created filter coefficients. Results show that proposed wavelets are able to differentiate HRV variations between phases of the menstrual cycle accurately than standard wavelets.

Multiscale approximate entropy (MAE) is used to quantify the complexity of a time series as a function of time scale τ. Approximate entropy (ApEn) tolerance threshold selection 'r' is based on either: (1) arbitrary selection in the recommended range (0.1-0.25) times standard deviation of time series (2) or finding maximum ApEn (ApEnmax) i.e., the point where self-matches start to prevail over other matches and choosing the corresponding 'r' (rmax) as threshold (3) or computing rchon by empirically finding the relation between rmax, SD1/SD2 ratio and N using curve fitting, where, SD1 and SD2 are short-term and long-term variability of a time series respectively. None of these methods is gold standard for selection of 'r'. In our previous study [1], an adaptive procedure for selection of 'r' is proposed for approximate entropy (ApEn). In this paper, this is extended to multiple time scales using MAEbin and multiscale cross-MAEbin (XMAEbin). We applied this to simulations i.e. 50 realizations (n = 50) of random number series, fractional Brownian motion (fBm) and MIX (P) [1] series of data length of N = 300 and short term recordings of HRV and SBPV performed under postural stress from supine to standing. MAEbin and XMAEbin analysis was performed on laboratory recorded data of 50 healthy young subjects experiencing postural stress from supine to upright. The study showed that (i) ApEnbin of HRV is more than SBPV in supine position but is lower than SBPV in upright position (ii) ApEnbin of HRV decreases from supine i.e. 1.7324 ± 0.112 (mean ± SD) to upright 1.4916 ± 0.108 due to vagal inhibition (iii) ApEnbin of SBPV increases from supine i.e. 1.5535 ± 0.098 to upright i.e. 1.6241 ± 0.101 due sympathetic activation (iv) individual and cross complexities of RRi and systolic blood pressure (SBP) series depend on time scale under consideration (v) XMAEbin calculated using ApEnmax is correlated with cross-MAE calculated using ApEn (0.1-0.26) in steps of 0.02 at each time scale in supine and upright position and is concluded that ApEn0.26 has highest correlation at most scales (vi) choice of 'r' is critical in interpreting interactions between RRi and SBP and in ascertaining true complexity of the individual RRi and SBP series.

This study presents an alternative approach to approximate entropy (ApEn) threshold value (r) selection. There are two limitations of traditional ApEn algorithm: (1) the occurrence of undefined conditional probability (CPu) where no template match is found and (2) use of a crisp tolerance (radius) threshold 'r'. To overcome these limitations, CPu is substituted with optimum bias setting ɛ opt which is found by varying ɛ from (1/N - m) to 1 in the increments of 0.05, where N is the length of the series and m is the embedding dimension. Furthermore, an alternative approach for selection of r based on binning the distance values obtained by template matching to calculate ApEnbin is presented. It is observed that ApEnmax, ApEnchon and ApEnbin converge for ɛ opt = 0.6 in 50 realizations (n = 50) of random number series of N = 300. Similar analysis suggests ɛ opt = 0.65 and ɛ opt = 0.45 for 50 realizations each of fractional Brownian motion and MIX(P) series (Lu et al. in J Clin Monit Comput 22(1):23-29, 2008). ɛ opt = 0.5 is suggested for heart rate variability (HRV) and systolic blood pressure variability (SBPV) signals obtained from 50 young healthy subjects under supine and upright position. It is observed that (1) ApEnbin of HRV is lower than SBPV, (2) ApEnbin of HRV increases from supine to upright due to vagal inhibition and (3) ApEnbin of BPV decreases from supine to upright due to sympathetic activation. Moreover, merit of ApEnbin is that it provides an alternative to the cumbersome ApEnmax procedure.

This paper presents an abdomen disease diagnostic system based on the flexi-scale curvelet transform, which uses different optimal scales for extracting features from computed tomography (CT) images. To optimize the scale of the flexi-scale curvelet transform, we propose an improved genetic algorithm. The conventional genetic algorithm assumes that fit parents will likely produce the healthiest offspring that leads to the least fit parents accumulating at the bottom of the population, reducing the fitness of subsequent populations and delaying the optimal solution search. In our improved genetic algorithm, combining the chromosomes of a low-fitness and a high-fitness individual increases the probability of producing high-fitness offspring. Thereby, all of the least fit parent chromosomes are combined with high fit parent to produce offspring for the next population. In this way, the leftover weak chromosomes cannot damage the fitness of subsequent populations. To further facilitate the search for the optimal solution, our improved genetic algorithm adopts modified elitism. The proposed method was applied to 120 CT abdominal images; 30 images each of normal subjects, cysts, tumors and stones. The features extracted by the flexi-scale curvelet transform were more discriminative than conventional methods, demonstrating the potential of our method as a diagnostic tool for abdomen diseases.

Correlation dimension (CD) is used for analysing the chaotic behaviour of the nonlinear heart rate variability (HRV) time series. In CD, the autocorrelation function is used to calculate the time delay. However, it does not provide optimum values of time delays, which leads to an inaccurate estimation of the HRV between phases of the menstrual cycle. Thus, an adaptive CD method is presented here to calculate the optimum value of the time delay based upon the information content in the HRV signal. In the proposed method, the first step is to divide the HRV signal into overlapping windows. Afterwards, the time delay is calculated for each window based on the features of the signal. This procedure of finding the optimum time delay for each window is known as adaptive autocorrelation. Then, the CD for each window is calculated using optimum time delays. Finally, adaptive CD is calculated by averaging the CD of all windows. The proposed method is applied on two data sets: (i) the standard Physionet dataset and (ii) the dataset acquired using BIOPAC(®)MP150. The results show that the proposed method can accurately differentiate between normal and diseased subjects. Further, the results prove that the proposed method is more accurate in detecting HRV variations during the menstrual cycles of 74 young women in lying and standing postures. Three statistical parameters are used to find the effectiveness of adaptive autocorrelation in calculating time delays. The comparative analysis validates the superiority of the proposed method over detrended fluctuation analyses and conventional CD.

In this paper an over-complete discrete wavelet transform (OCDWT) algorithm, obtained by blending two wavelet transform implementations that is redundant wavelet transform and the Mallat's multiresolution decomposition, has been proposed to retrieve the time-varying characteristics of HRV under two different postures, supine and standing. The OCDWT algorithm is critically sub-sampled to a given level of decomposition, below which it is then fully sampled. Five subjects were included to investigate posture-related HRV. The results showed that the high frequency fluctuations are larger in supine and get significantly reduced in standing in comparison to low frequency variations. Moreover, the very low frequency heart beat fluctuations during supine were greater than during standing. Further a comparative analysis has also been made between the Mallat's and OCDWT implementation in order to show the superiority of proposed algorithm.

Objective: To investigate the in vitro antioxidant activity of different fractions (R1, R2 and R3) obtained from pet ether extract of black pepper fruits (Piper nigrum Linn.), Materials and Methods: The fractions R1, R2 and R3 were eluted from pet ether and ethyl acetate in the ratio of 6:4, 5:5 and 4:6, respectively. 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) radical, superoxide anion radical, nitric oxide radical, and hydroxyl radical scavenging assays were carried out to evaluate the antioxidant potential of the extract., Results: The free radical scavenging activity of the different fractions of pet ether extract of P. nigrum (PEPN) increased in a concentration dependent manner. The R3 and R2 fraction of PEPN in 500 microg/ml inhibited the peroxidation of a linoleic acid emulsion by 60.48+/-3.33% and 58.89+/-2.51%, respectively. In DPPH free radical scavenging assay, the activity of R3 and R2 were found to be almost similar. The R3 (100microg/ml) fraction of PEPN inhibited 55.68+/-4.48% nitric oxide radicals generated from sodium nitroprusside, whereas curcumin in the same concentration inhibited 84.27+/-4.12%. Moreover, PEPN scavenged the superoxide radical generated by the Xanthine/Xanthine oxidase system. The fraction R2 and R3 in the doses of 1000microg/ml inhibited 61.04+/-5.11% and 63.56+/-4.17%, respectively. The hydroxyl radical was generated by Fenton's reaction. The amounts of total phenolic compounds were determined and 56.98 microg pyrocatechol phenol equivalents were detected in one mg of R3., Conclusions: P. nigrum could be considered as a potential source of natural antioxidant.

Autonomic function testing forms an integral part of physiological investigations both for human and animal research. Clinically, recent times have seen them emerging as tools in settling diagnosis in several neurological, cardiovascular, endocrinal disorders where autonomic function are compromised. The reasons for such emergence have been their simplicity, noninvasiveness, and their ability to decipher the control systems. A time-varying spectrum estimation method for analyzing heart rate variability signals dynamics is presented. As a case study, the dynamics of heart rate variability during autonomic function tests is examined using wavelets. The obtained spectrum estimates have further been decomposed into separate components and, thus, the lime variation of low and high frequency components of heart rate variability can be examined separately. Thus, the present study aims to ascertain the association between heart rate changes and HRV parameters. The wavelet based HRV analysis has been found to faithfully represent the sympathovagal balance during standard autonomic battery test.