Evaluating health perceptions of soft-tissue sarcoma patients using the Wilson-Cleary Model to identify key targets for improving outcomes and quality of care.

INTRODUCTION: Soft-tissue sarcoma (STS) is a rare cancer of the connective tissues requiring invasive treatment. Due to the complexity of treatment, STS patients experience more functional impairment and disability than other oncologic populations. Given that extant literature is unclear and exclusively focused on physical function, the objectives of this study were to use the Wilson-Cleary Model of HRQL to evaluate the extent to which biological function (tumor site, depth and size), symptoms (fatigue, pain, anxiety/depression), and functional status are associated with the health perceptions of soft-tissue sarcoma patients 12 months post-op. METHODS: Data were drawn from an inception cohort study at the McGill University Health Centre. Inclusion criteria included 18 years of age and a biopsy-confirmed diagnosis of STS. Those with evidence of metastasis at diagnosis or less than 12 months of follow-up were excluded. Statistical analyses included T-tests, Pearson correlations, and multiple linear regression. RESULTS: 331 patients were included (185 males, 146 females) with mean (SD) ages of 56 (17). Significantly more females reported pain and anxiety/depression. Self-reported function was significantly higher in males. Overall, the regression model explained 53 % of the variance in health perceptions in males, and 48 % in females. Only self-reported function was significantly associated with health perceptions in males (B = 0.34) and females (B = 0.48). Further, compared to females without pain, females with pain perceived their health as significantly worse. CONCLUSION: Evaluating health perceptions with a multidimensional lens revealed new information about the STS patient experience. Findings suggest that key targets include routine psychosocial distress monitoring and addressing rectifiable disability-related barriers promptly.

Influence of maternal psychological distress during COVID-19 pandemic on placental morphometry and texture.

The Coronavirus Disease 2019 (COVID-19) pandemic has been accompanied by increased prenatal maternal distress (PMD). PMD is associated with adverse pregnancy outcomes which may be mediated by the placenta. However, the potential impact of the pandemic on in vivo placental development remains unknown. To examine the impact of the pandemic and PMD on in vivo structural placental development using advanced magnetic resonance imaging (MRI), acquired anatomic images of the placenta from 63 pregnant women without known COVID-19 exposure during the pandemic and 165 pre-pandemic controls. Measures of placental morphometry and texture were extracted. PMD was determined from validated questionnaires. Generalized estimating equations were utilized to compare differences in PMD placental features between COVID-era and pre-pandemic cohorts. Maternal stress and depression scores were significantly higher in the pandemic cohort. Placental volume, thickness, gray level kurtosis, skewness and run length non-uniformity were increased in the pandemic cohort, while placental elongation, mean gray level and long run emphasis were decreased. PMD was a mediator of the association between pandemic status and placental features. Altered in vivo placental structure during the pandemic suggests an underappreciated link between disturbances in maternal environment and perturbed placental development. The long-term impact on offspring is currently under investigation.

Virtual reality interventions for the treatment of anxiety disorders: A scoping review.

BACKGROUND: & Objectives: Virtual Reality (VR) refers to an artificial, immersive three-dimensional environment with interactive sensory stimuli. VR is typically incorporated into the psychotherapeutic process as a means of providing exposure therapy. The objectives of this scoping review were to synthesize the most up-to-date evidence on the outcomes, acceptability, and side effects of VR interventions for treating anxiety disorders in adults. METHODS: This scoping review is grounded in the methodological framework of Arksey and O'Malley (2005). The databases searched were PubMed, EMBASE, Web of Science, PsycINFO, and ProQuest Dissertations and Theses. RESULTS: The search process identified 112 unique citations. 52 (46%) of the eligible articles examined participants with specific phobias, 25 (22%) with PTSD, 21 (19%) with social anxiety disorder, 12 (10%) with panic disorder with or without agoraphobia, and 3 (3%) with generalized anxiety disorder. VR interventions often led to statistically significant and meaningful reductions in symptoms for people with anxiety disorders. Additionally, they were acceptable to clients and associated with minimal side effects for all types of anxiety disorders, except for Combat-Related PTSD in Vietnam veterans. LIMITATIONS: Limitations included the fact that the studies in this review were of varying quality, and that articles in languages other than English and French were excluded. CONCLUSION: VR interventions appeared to be a viable alternative to conventional exposure therapy. Future research should include more male participants and have a stronger emphasis on acceptability and side effects. Increased traction for VR interventions for generalized anxiety disorder and panic disorder is also important.

Robust sex differences in functional brain connectivity are present in utero.

Sex-based differences in brain structure and function are observable throughout development and are thought to contribute to differences in behavior, cognition, and the presentation of neurodevelopmental disorders. Using multiple support vector machine (SVM) models as a data-driven approach to assess sex differences, we sought to identify regions exhibiting sex-dependent differences in functional connectivity and determine whether they were robust and sufficiently reliable to classify sex even prior to birth. To accomplish this, we used a sample of 110 human fetal resting state fMRI scans from 95 fetuses, performed between 19 and 40 gestational weeks. Functional brain connectivity patterns classified fetal sex with 73% accuracy. Across SVM models, we identified features (functional connections) that reliably differentiated fetal sex. Highly consistent predictors included connections in the somatomotor and frontal areas alongside the hippocampus, cerebellum, and basal ganglia. Moreover, high consistency features also implicated a greater magnitude of cross-region connections in females, while male weighted features were predominately within anatomically bounded regions. Our findings indicate that these differences, which have been observed later in childhood, are present and reliably detectable even before birth. These results show that sex differences arise before birth in a manner that is consistent and reliable enough to be highly identifiable.

Maternal psychological distress during the COVID-19 pandemic and structural changes of the human fetal brain.

Background: Elevated maternal psychological distress during pregnancy is linked to adverse outcomes in offspring. The potential effects of intensified levels of maternal distress during the COVID-19 pandemic on the developing fetal brain are currently unknown. Methods: We prospectively enrolled 202 pregnant women: 65 without known COVID-19 exposures during the pandemic who underwent 92 fetal MRI scans, and 137 pre-pandemic controls who had 182 MRI scans. Multi-plane, multi-phase single shot fast spin echo T2-weighted images were acquired on a GE 1.5 T MRI Scanner. Volumes of six brain tissue types were calculated. Cortical folding measures, including brain surface area, local gyrification index, and sulcal depth were determined. At each MRI scan, maternal distress was assessed using validated stress, anxiety, and depression scales. Generalized estimating equations were utilized to compare maternal distress measures, brain volume and cortical folding differences between pandemic and pre-pandemic cohorts. Results: Stress and depression scores are significantly higher in the pandemic cohort, compared to the pre-pandemic cohort. Fetal white matter, hippocampal, and cerebellar volumes are decreased in the pandemic cohort. Cortical surface area and local gyrification index are also decreased in all four lobes, while sulcal depth is lower in the frontal, parietal, and occipital lobes in the pandemic cohort, indicating delayed brain gyrification. Conclusions: We report impaired fetal brain growth and delayed cerebral cortical gyrification in COVID-19 pandemic era pregnancies, in the setting of heightened maternal psychological distress. The potential long-term neurodevelopmental consequences of altered fetal brain development in COVID-era pregnancies merit further study.

Measuring intrauterine growth in healthy pregnancies using quantitative magnetic resonance imaging.

OBJECTIVE: The aim of this study was to determine in utero fetal-placental growth patterns using in vivo three-dimensional (3D) quantitative magnetic resonance imaging (qMRI). STUDY DESIGN: Healthy women with singleton pregnancies underwent fetal MRI to measure fetal body, placenta, and amniotic space volumes. The fetal-placental ratio (FPR) was derived using 3D fetal body and placental volumes (PV). Descriptive statistics were used to describe the association of each measurement with increasing gestational age (GA) at MRI. RESULTS: Fifty-eight (58) women underwent fetal MRI between 16 and 38 completed weeks gestation (mean = 28.12 ± 6.33). PV and FPR varied linearly with GA at MRI (rPV,GA = 0.83, rFPR,GA = 0.89, p value < 0.001). Fetal volume varied non-linearly with GA (p value < 0.01). CONCLUSIONS: We describe in-utero growth trajectories of fetal-placental volumes in healthy pregnancies using qMRI. Understanding healthy in utero development can establish normative benchmarks where departures from normal may identify early in utero placental failure prior to the onset of fetal harm.

Automatic brain segmentation in preterm infants with post-hemorrhagic hydrocephalus using 3D Bayesian U-Net.

Post-hemorrhagic hydrocephalus (PHH) is a severe complication of intraventricular hemorrhage (IVH) in very preterm infants. PHH monitoring and treatment decisions rely heavily on manual and subjective two-dimensional measurements of the ventricles. Automatic and reliable three-dimensional (3D) measurements of the ventricles may provide a more accurate assessment of PHH, and lead to improved monitoring and treatment decisions. To accurately and efficiently obtain these 3D measurements, automatic segmentation of the ventricles can be explored. However, this segmentation is challenging due to the large ventricular anatomical shape variability in preterm infants diagnosed with PHH. This study aims to (a) propose a Bayesian U-Net method using 3D spatial concrete dropout for automatic brain segmentation (with uncertainty assessment) of preterm infants with PHH; and (b) compare the Bayesian method to three reference methods: DenseNet, U-Net, and ensemble learning using DenseNets and U-Nets. A total of 41 T2 -weighted MRIs from 27 preterm infants were manually segmented into lateral ventricles, external CSF, white and cortical gray matter, brainstem, and cerebellum. These segmentations were used as ground truth for model evaluation. All methods were trained and evaluated using 4-fold cross-validation and segmentation endpoints, with additional uncertainty endpoints for the Bayesian method. In the lateral ventricles, segmentation endpoint values for the DenseNet, U-Net, ensemble learning, and Bayesian U-Net methods were mean Dice score = 0.814 ± 0.213, 0.944 ± 0.041, 0.942 ± 0.042, and 0.948 ± 0.034 respectively. Uncertainty endpoint values for the Bayesian U-Net were mean recall = 0.953 ± 0.037, mean  negative predictive value = 0.998 ± 0.005, mean accuracy = 0.906 ± 0.032, and mean AUC = 0.949 ± 0.031. To conclude, the Bayesian U-Net showed the best segmentation results across all methods and provided accurate uncertainty maps. This method may be used in clinical practice for automatic brain segmentation of preterm infants with PHH, and lead to better PHH monitoring and more informed treatment decisions.

Normative placental structure in pregnancy using quantitative Magnetic Resonance Imaging.

INTRODUCTION: To characterize normative morphometric, textural and microstructural placental development by applying advanced and quantitative magnetic resonance imaging (qMRI) techniques to the in-vivo placenta. METHODS: We enrolled 195 women with uncomplicated, healthy singleton pregnancies in a prospective observational study. Women underwent MRI between 16- and 40-weeks' gestation. Morphometric and textural metrics of placental growth were calculated from T2-weighted (T2W) images, while measures of microstructural development were calculated from diffusion-weighted images (DWI). Normative tables and reference curves were constructed for each measured index across gestation and according to fetal sex. RESULTS: Data from 269 MRI studies from 169 pregnant women were included in the analyses. During the study period, placentas undergo significant increases in morphometric measures of volume, thickness, and elongation. Placental texture reveals increasing variability with advancing gestation as measured by grey level non uniformity, run length non uniformity and long run high grey level emphasis. Placental microstructure did not vary with gestational age. Placental elongation was the only metric that differed significantly between male and female fetuses. DISCUSSION: We report quantitative metrics of placental morphometry, texture and microstructure in a large cohort of healthy controls during the second and third trimesters of pregnancy. These measures can serve as normative references of in-vivo placental development to better understand placental function in high-risk conditions and allow for the early detection of placental mal-development.

Image Quality Assessment of Fetal Brain MRI Using Multi-Instance Deep Learning Methods.

BACKGROUND: Due to random motion of fetuses and maternal respirations, image quality of fetal brain MRIs varies considerably. To address this issue, visual inspection of the images is performed during acquisition phase and after 3D-reconstruction, and the images are re-acquired if they are deemed to be of insufficient quality. However, this process is time-consuming and subjective. Multi-instance (MI) deep learning methods (DLMs) may perform this task automatically. PURPOSE: To propose an MI count-based DLM (MI-CB-DLM), an MI vote-based DLM (MI-VB-DLM), and an MI feature-embedding DLM (MI-FE-DLM) for automatic assessment of 3D fetal-brain MR image quality. To quantify influence of fetal gestational age (GA) on DLM performance. STUDY TYPE: Retrospective. SUBJECTS: Two hundred and seventy-one MR exams from 211 fetuses (mean GA ± SD = 30.9 ± 5.5 weeks). FIELD STRENGTH/SEQUENCE: T2 -weighted single-shot fast spin-echo acquired at 1.5 T. ASSESSMENT: The T2 -weighted images were reconstructed in 3D. Then, two fetal neuroradiologists, a clinical neuroscientist, and a fetal MRI technician independently labeled the reconstructed images as 1 or 0 based on image quality (1 = high; 0 = low). These labels were fused and served as ground truth. The proposed DLMs were trained and evaluated using three repeated 10-fold cross-validations (training and validation sets of 244 and 27 scans). To quantify GA influence, this variable was included as an input of the DLMs. STATISTICAL TESTS: DLM performance was evaluated using precision, recall, F-score, accuracy, and AUC values. RESULTS: Precision, recall, F-score, accuracy, and AUC averaged over the three cross validations were 0.85 ± 0.01, 0.85 ± 0.01, 0.85 ± 0.01, 0.85 ± 0.01, 0.93 ± 0.01, for MI-CB-DLM (without GA); 0.75 ± 0.03, 0.75 ± 0.03, 0.75 ± 0.03, 0.75 ± 0.03, 0.81 ± 0.03, for MI-VB-DLM (without GA); 0.81 ± 0.01, 0.81 ± 0.01, 0.81 ± 0.01, 0.81 ± 0.01, 0.89 ± 0.01, for MI-FE-DLM (without GA); and 0.86 ± 0.01, 0.86 ± 0.01, 0.86 ± 0.01, 0.86 ± 0.01, 0.93 ± 0.01, for MI-CB-DLM with GA. DATA CONCLUSION: MI-CB-DLM performed better than other DLMs. Including GA as an input of MI-CB-DLM improved its performance. MI-CB-DLM may potentially be used to objectively and rapidly assess fetal MR image quality. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

Association Between Socioeconomic Status and In Utero Fetal Brain Development.

Importance: Children raised in settings with lower parental socioeconomic status are at increased risk for neuropsychological disorders. However, to date, the association between socioeconomic status and fetal brain development remains poorly understood. Objective: To determine the association between parental socioeconomic status and in vivo fetal brain growth and cerebral cortical development using advanced, 3-dimensional fetal magnetic resonance imaging. Design, Setting, and Participants: This cohort study of fetal brain development enrolled 144 healthy pregnant women from 2 low-risk community obstetrical hospitals from 2012 through 2019 in the District of Columbia. Included women had a prenatal history without complications that included recommended screening laboratory and ultrasound studies. Exclusion criteria were multiple gestation pregnancy, known or suspected congenital infection, dysmorphic features of the fetus, and documented chromosomal abnormalities. T2-weighted fetal brain magnetic resonance images were acquired. Each pregnant woman was scanned at up to 2 points in the fetal period. Data were analyzed from June through November 2020. Exposures: Parental education level and occupation status were documented. Main Outcomes and Measures: Regional fetal brain tissue volume (for cortical gray matter, white matter, cerebellum, deep gray matter, and brainstem) and cerebral cortical features (ie, lobe volume, local gyrification index, and sulcal depth) in the frontal, parietal, temporal, and occipital lobes were calculated. Results: Fetal brain magnetic resonance imaging studies were performed among 144 pregnant women (median [interquartile range] age, 32.5 [27.0-36.1] years) with gestational age from 24.0 to 39.4 weeks; 75 fetuses (52.1%) were male, and 69 fetuses (47.9%) were female. Higher parental education level was associated with significantly increased volume in the fetal white matter (mothers: ß, 2.86; 95% CI, 1.26 to 4.45; P = .001; fathers: ß, 2.39; 95% CI, 0.97 to 3.81; P = .001), deep gray matter (mothers: ß, 0.16; 95% CI, 0.002 to 0.32; P = .048; fathers: ß, 0.16; 95% CI, 0.02 to 0.31; P = .02), and brainstem (mothers: ß, 0.06; 95% CI, 0.02 to 0.10; P = .01; fathers: ß, 0.04; 95% CI, 0.004 to 0.08; P = .03). Higher maternal occupation status was associated with significantly increased volume in the fetal white matter (ß, 2.07; 95% CI, 0.88 to 3.26; P = .001), cerebellum (ß, 0.17; 95% CI, 0.04 to 0.29; P = .01), and brainstem (ß, 0.03; 95% CI, 0.001 to 0.07; P = .04), and higher paternal occupation status was associated with significantly increased white matter volume (ß, 1.98; 95% CI, 0.71 to 3.25; P < .01). However, higher socioeconomic status was associated with significantly decreased fetal cortical gray matter volume (mothers: ß, -0.11; 95% CI, -0.18 to -0.03; P = .01; fathers: ß, -0.10; 95% CI, -0.18 to -0.03; P = .01). Higher parental socioeconomic status was associated with increased volumes of 3 brain lobes of white matter: frontal lobe (mothers: ß, 0.07; 95% CI, 0.02 to 0.13; P = .01; fathers: ß, 0.06; 95% CI, 0.01 to 0.11; P = .03), parietal lobe (mothers: ß, 0.07; 95% CI, 0.03 to 0.11; P < .001; fathers: ß, 0.06; 95% CI, 0.03 to 0.10; P = .001), and temporal lobe (mothers: ß, 0.04; 95% CI, 0.02 to 0.07; P < .001; fathers: ß, 0.04; 95% CI, 0.02 to 0.07; P < .001), and maternal SES score was associated with significantly decreased volume in the occipital lobe (ß, 0.02; 95% CI, 0.002 to 0.04; P = .03). Higher parental socioeconomic status was associated with decreased cortical local gyrification index (for example, for the frontal lobe, mothers: ß, -1.1; 95% CI, -1.9 to -0.3; P = .01; fathers: ß, -0.8; 95% CI, -1.6 to -0.1; P = .03) and sulcal depth, except for the frontal lobe (for example, for the parietal lobe, mothers: ß, -9.5; 95% CI, -13.8 to -5.3; P < .001; fathers: ß, -8.7; 95% CI, -13.0 to -4.4; P < .001). Conclusions and Relevance: This cohort study found an association between parental socioeconomic status and altered in vivo fetal neurodevelopment. While being born and raised in a lower socioeconomic status setting is associated with poorer neuropsychological, educational, and socioeconomic outcomes in children, these findings suggest that altered prenatal programming may be associated with these outcomes and that future targeted prenatal interventions may be needed.

Longitudinal Trajectories of Regional Cerebral Blood Flow in Very Preterm Infants during Third Trimester Ex Utero Development Assessed with MRI.

Background The third trimester of gestation is a crucial phase of rapid brain development, but little has been reported on the trajectories of cerebral blood flow (CBF) in preterm infants in this period. Purpose To quantify regional CBF in very preterm infants longitudinally across the ex utero third trimester and to determine its relationship with clinical factors associated with brain injury and premature birth. Materials and Methods In this prospective study, very preterm infants were enrolled for three longitudinal MRI scans, and 22 healthy full-term infants were enrolled for one term MRI scan between November 2016 and February 2019. Global and regional CBF in the cortical gray matter, white matter, deep gray matter, and cerebellum were measured using arterial spin labeling with postlabeling delay of 2025 msec at 1.5 T and 3.0 T. Brain injury and clinical risk factors in preterm infants were investigated to determine associations with CBF. Generalized estimating equations were used to account for correlations between repeated measures in the same individual. Results A total of 75 preterm infants (mean postmenstrual age [PMA]: 29.5 weeks ± 2.3 [standard deviation], 34.9 weeks ± 0.8, and 39.3 weeks ± 2.0 for each scan; 43 male infants) and 22 full-term infants (mean PMA, 42.1 weeks ± 2.0; 13 male infants) were evaluated. In preterm infants, global CBF was 11.9 mL/100 g/min ± 0.2 (standard error). All regional CBF increased significantly with advancing PMA (P ≤ .02); the cerebellum demonstrated the most rapid CBF increase and the highest mean CBF. Lower CBF was associated with intraventricular hemorrhage in all regions (P ≤ .05) and with medically managed patent ductus arteriosus in the white matter and deep gray matter (P = .03). Mean CBF of preterm infants at term-equivalent age was significantly higher compared with full-term infants (P ≤ .02). Conclusion Regional cerebral blood flow increased significantly in preterm infants developing in an extrauterine environment across the third trimester and was associated with intraventricular hemorrhage and patent ductus arteriosus. © RSNA, 2021 Online supplemental material is available for this article.

Global Network Organization of the Fetal Functional Connectome.

Recent advances in brain imaging have enabled non-invasive in vivo assessment of the fetal brain. Characterizing brain development in healthy fetuses provides baseline measures for identifying deviations in brain function in high-risk clinical groups. We examined 110 resting state MRI data sets from fetuses at 19 to 40 weeks' gestation. Using graph-theoretic techniques, we characterized global organizational features of the fetal functional connectome and their prenatal trajectories. Topological features related to network integration (i.e., global efficiency) and segregation (i.e., clustering) were assessed. Fetal networks exhibited small-world topology, showing high clustering and short average path length relative to reference networks. Likewise, fetal networks' quantitative small world indices met criteria for small-worldness (σ > 1, ω = [-0.5 0.5]). Along with this, fetal networks demonstrated global and local efficiency, economy, and modularity. A right-tailed degree distribution, suggesting the presence of central areas that are more highly connected to other regions, was also observed. Metrics, however, were not static during gestation; measures associated with segregation-local efficiency and modularity-decreased with advancing gestational age. Altogether, these suggest that the neural circuitry underpinning the brain's ability to segregate and integrate information exists as early as the late 2nd trimester of pregnancy and reorganizes during the prenatal period. Significance statement. Mounting evidence for the fetal origins of some neurodevelopmental disorders underscores the importance of identifying features of healthy fetal brain functional development. Alterations in prenatal brain connectomics may serve as early markers for identifying fetal-onset neurodevelopmental disorders, which in turn provide improved surveillance of at-risk fetuses and support the initiation of early interventions.

Evaluating the Use of a PRO Questionnaire in Clinical Practice.

Aalborg University Hospital in Farsø uses data from a patient-reported outcome (PRO) questionnaire in order to predict if patients diagnosed with osteoarthritis will benefit from surgery. The purpose of including PRO in the decision-making is to ensure quality and transparency, to include patients in their own treatment, and to make the patients central to both the decision-making and the dialogue. Our evaluation of the use of the PRO questionnaire is based on the observation of patients filling out the questionnaire and interviews with 7 patients and a doctor. We found that there were several usability issues especially for the patients, such as navigation problems and a lack of consistency in the layout of the measurement scales. Furthermore, some questions were difficult for the patients to interpret. The interviewed patients did not report any value from answering the questionnaire. We argue that it may take more than filling out a questionnaire for the patient to feel involved in their own treatment.

Digital Support for Self-Management in Children with Diabetes: Understanding Their Needs and Developing a Design Concept.

In this paper we present a study on the needs and requirements in a digital tool to support self-management in children and adolescents (0-18 years) with type 1 diabetes. The study was formally initiated by the Steno Diabetes Center North Jutland (SDCN), which wanted to develop a virtual universe that could support children and young people in coping with their disease. Through this study we interviewed the project manager from SDCN and the head of the family group in North Jutland. Furthermore, we observed a workshop involving health care professionals and learning specialists who were working with ideas for the virtual universe. We conducted two focus group interviews, one for children with type 1 diabetes and one for parents with diabetic children. The analysis of the data revealed very different ideas about what digital support is important for the self-management of this target group. Health care professionals focused on developing various learning materials using virtual reality or augmented reality, while the parents desired security and control and requested materials that could inform and educate people in their locale, such as school teachers, parents of their children's friends, etc. The children emphasized the importance of not being singled out and requested simple tools that could be used from their smartphones. They especially asked for tools that could help them manage their diabetes by themselves in a fast and effective way, e.g., making it easier to count carbohydrates and calculate their insulin intake. Based on the analysis, we developed suggestions for a design. The main lesson learned from this study was the importance of focusing on the actual users and their everyday lives in developing new tools, and not on technological possibilities.

Non-invasive measurement of biochemical profiles in the healthy fetal brain.

Proton magnetic resonance spectroscopy (1H-MRS) of the fetal brain can be used to study emerging metabolite profiles in the developing brain. Identifying early deviations in brain metabolic profiles in high-risk fetuses may offer important adjunct clinical information to improve surveillance and management during pregnancy. OBJECTIVE: To investigate the normative trajectory of the fetal brain metabolites during the second half of gestation, and to determine the impact of using different Cramer-Rao Lower Bounds (CRLB) threshold on metabolite measurements using magnetic resonance spectroscopy. STUDY DESIGN: We prospectively enrolled 219 pregnant women with normal fetal ultrasound and biometric measures. We performed a total of 331 fetal 1H-MRS studies with gestational age in the rage of 18-39 weeks with 112 of the enrolled participants scanned twice. All the spectra in this study were acquired on a GE 1.5 T scanner using long echo-time of 144 â€‹ms and analyzed in LCModel. RESULTS: We successfully acquired and analyzed fetal 1H-MRS with a success rate of 93%. We observed increases in total NAA, total creatine, total choline, scyllo inositol and total NAA-to-total choline ratio with advancing GA. Our results also showed faster increases in total NAA and total NAA-to-total choline ratio during the third trimester compared to the second trimester. We also observed faster increases in total choline and total NAA in female fetuses. Increasing the Cramer-Rao lower bounds threshold progressively from 100% to 40%-20% increased the mean metabolite concentrations and decreased the number of observations available for analysis. CONCLUSION: We report serial fetal brain biochemical profiles in a large cohort of health fetuses studied twice in gestation with a high success rate in the second and third trimester of pregnancy. We present normative in-vivo fetal brain metabolite trajectories over a 21-week gestational period which can be used to non-invasively measure and monitor brain biochemistry in the healthy and high-risk fetus.

Sustained plasma hepcidin suppression and iron elevation by Anticalin-derived hepcidin antagonist in cynomolgus monkey.

BACKGROUND AND PURPOSE: Anaemia of chronic disease (ACD) has been linked to iron-restricted erythropoiesis imposed by high circulating levels of hepcidin, a 25 amino acid hepatocyte-derived peptide that controls systemic iron homeostasis. Here, we report the engineering of the human lipocalin-derived, small protein-based anticalin PRS-080 hepcidin antagonist with high affinity and selectivity. EXPERIMENTAL APPROACH: Anticalin- and hepcidin-specific pharmacokinetic (PK)/pharmacodynamic modelling (PD) was used to design and select the suitable drug candidate based on t1/2 extension and duration of hepcidin suppression. The development of a novel free hepcidin assay enabled accurate analysis of bioactive hepcidin suppression and elucidation of the observed plasma iron levels after PRS-080-PEG30 administration in vivo. KEY RESULTS: PRS-080 had a hepcidin-binding affinity of 0.07 nM and, after coupling to 30 kD PEG (PRS-080-PEG30), a t1/2 of 43 h in cynomolgus monkeys. Dose-dependent iron mobilization and hepcidin suppression were observed after a single i.v. dose of PRS-080-PEG30 in cynomolgus monkeys. Importantly, in these animals, suppression of free hepcidin and subsequent plasma iron elevation were sustained during repeated s.c. dosing. After repeated dosing and followed by a treatment-free interval, all iron parameters returned to pre-dose values. CONCLUSIONS AND IMPLICATIONS: In conclusion, we developed a dose-dependent and safe approach for the direct suppression of hepcidin, resulting in prolonged iron mobilization to alleviate iron-restricted erythropoiesis that can address the root cause of ACD. PRS-080-PEG30 is currently in early clinical development.