Is sequential cranial ultrasound reliable for detection of white matter injury in very preterm infants?

Cranial ultrasound (cUS) may not be reliable for detection of diffuse white matter (WM) injury. Our aim was to assess in very preterm infants the reliability of a classification system for WM injury on sequential cUS throughout the neonatal period, using magnetic resonance imaging (MRI) as reference standard. In 110 very preterm infants (gestational age < 32 weeks), serial cUS during admission (median 8, range 4-22) and again around term equivalent age (TEA) and a single MRI around TEA were performed. cUS during admission were assessed for presence of WM changes, and contemporaneous cUS and MRI around TEA additionally for abnormality of lateral ventricles. Sequential cUS (from birth up to TEA) and MRI were classified as normal/mildly abnormal, moderately abnormal, or severely abnormal, based on a combination of findings of the WM and lateral ventricles. Predictive values of the cUS classification were calculated. Sequential cUS were classified as normal/mildly abnormal, moderately abnormal, and severely abnormal in, respectively, 22%, 65%, and 13% of infants and MRI in, respectively, 30%, 52%, and 18%. The positive predictive value of the cUS classification for the MRI classification was high for severely abnormal WM (0.79) but lower for normal/mildly abnormal (0.67) and moderately abnormal (0.64) WM. Sequential cUS during the neonatal period detects severely abnormal WM in very preterm infants but is less reliable for mildly and moderately abnormal WM. MRI around TEA seems needed to reliably detect WM injury in very preterm infants.Epidemiology in Pediatrics and Child Healt

Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect

Cancer cells adopt glycolysis as the major source of metabolic energy production for fast cell growth. The HIF-1-induced PFKFB3 plays a key role in this adaptation by elevating the concentration of Fru-2,6-BP, the most potent glycolysis stimulator. As this metabolic conversion has been suggested to be a hallmark of cancer, PFKFB3 has emerged as a novel target for cancer chemotherapy. Here, we report that a small molecular inhibitor, N4A, was identified as an initial lead compound for PFKFB3 inhibitor with therapeutic potential. In an attempt to improve its potency, we determined the crystal structure of the PFKFB3•N4A complex to 2.4 Å resolution and, exploiting the resulting molecular information, attained the more potent YN1. When tested on cultured cancer cells, both N4A and YN1 inhibited PFKFB3, suppressing the Fru-2,6-BP level, which in turn suppressed glycolysis and, ultimately, led to cell death. This study validates PFKFB3 as a target for new cancer therapies and provides a framework for future development efforts

Comprehensive Brain MRI Segmentation in High Risk Preterm Newborns

Most extremely preterm newborns exhibit cerebral atrophy/growth disturbances and white matter signal abnormalities on MRI at term-equivalent age. MRI brain volumes could serve as biomarkers for evaluating the effects of neonatal intensive care and predicting neurodevelopmental outcomes. This requires detailed, accurate, and reliable brain MRI segmentation methods. We describe our efforts to develop such methods in high risk newborns using a combination of manual and automated segmentation tools. After intensive efforts to accurately define structural boundaries, two trained raters independently performed manual segmentation of nine subcortical structures using axial T2-weighted MRI scans from 20 randomly selected extremely preterm infants. All scans were re-segmented by both raters to assess reliability. High intra-rater reliability was achieved, as assessed by repeatability and intra-class correlation coefficients (ICC range: 0.97 to 0.99) for all manually segmented regions. Inter-rater reliability was slightly lower (ICC range: 0.93 to 0.99). A semi-automated segmentation approach was developed that combined the parametric strengths of the Hidden Markov Random Field Expectation Maximization algorithm with non-parametric Parzen window classifier resulting in accurate white matter, gray matter, and CSF segmentation. Final manual correction of misclassification errors improved accuracy (similarity index range: 0.87 to 0.89) and facilitated objective quantification of white matter signal abnormalities. The semi-automated and manual methods were seamlessly integrated to generate full brain segmentation within two hours. This comprehensive approach can facilitate the evaluation of large cohorts to rigorously evaluate the utility of regional brain volumes as biomarkers of neonatal care and surrogate endpoints for neurodevelopmental outcomes

Testing the sensitivity of Tract-Based Spatial Statistics to simulated treatment effects in preterm neonates

Early neuroimaging may provide a surrogate marker for brain development and outcome after preterm birth. Tract-Based Spatial Statistics (TBSS) is an advanced Diffusion Tensor Image (DTI) analysis technique that is sensitive to the effects of prematurity and may provide a quantitative marker for neuroprotection following perinatal brain injury or preterm birth. Here, we test the sensitivity of TBSS to detect diffuse microstructural differences in the developing white matter of preterm infants at term-equivalent age by modelling a 'treatment' effect as a global increase in fractional anisotropy (FA). As proof of concept we compare these simulations to a real effect of increasing age at scan. 3-Tesla, 15-direction diffusion tensor imaging (DTI) was acquired from 90 preterm infants at term-equivalent age. Datasets were randomly assigned to 'treated' or 'untreated' groups of increasing size and voxel-wise increases in FA were used to simulate global treatment effects of increasing magnitude in all 'treated' maps. 'Treated' and 'untreated' FA maps were compared using TBSS. Predictions from simulated data were then compared to exemplar TBSS group comparisons based on increasing postmenstrual age at scan. TBSS proved sensitive to global differences in FA within a clinically relevant range, even in relatively small group sizes, and simulated data were shown to predict well a true biological effect of increasing age on white matter development. These data confirm that TBSS is a sensitive tool for detecting global group-wise differences in FA in this population

Rethinking Suicide in Rural Australia: A study Protocol for Examining and Applying Knowledge of the Social Determinants to Improve Prevention in Non-Indigenous Populations

Disproportionate rates of suicide in rural Australia in comparison to metropolitan areas pose a significant public health challenge. The dynamic interrelationship between mental and physical health, social determinants, and suicide in rural Australia is widely acknowledged. Advancement of this knowledge, however, remains hampered by a lack of adequate theory and methods to understand how these factors interact, and the translation of this knowledge into constructive strategies and solutions. This paper presents a protocol for generating a comprehensive dataset of suicide deaths and factors related to suicide in rural Australia, and for building a program of research to improve suicide prevention policy and practice to better address the social determinants of suicide in non-indigenous populations. The two-phased study will use a mixed-methods design informed by intersectionality theory. Phase One will extract, code, and analyse quantitative and qualitative data on suicide in regional and remote Australia from the National Coronial Information System (NCIS). Phase Two will analyse suicide prevention at three interrelated domains: policy, practice, and research, to examine alignment with evidence generated in Phase One. Findings from Phase One and Two will then be integrated to identify key points in suicide prevention policy and practice where action can be initiated.</jats:p

Suicide in rural Australia: A retrospective study of mental health problems, healthseeking and service utilisation

Background Suicide rates are higher in rural Australia than in major cities, although the factors contributing to this are not well understood. This study highlights trends in suicide and examines the prevalence of mental health problems and service utilisation of non-Indigenous Australians by geographic remoteness in rural Australia. Methods A retrospective study of National Coronial Information System data of intentional self-harm deaths in rural New South Wales, Queensland, South Australia and Tasmania for 2010- 2015 from the National Coronial Information System. Results There were 3163 closed cases of intentional self-harm deaths by non-Indigenous Australians for the period 2010-2015. The suicide rate of 12.7 deaths per 100,000 persons was 11% higher than the national Australian rate and increased with remoteness. Among people who died by suicide, up to 56% had a diagnosed mental illness, and a further 24% had undiagnosed symptoms. Reported diagnoses of mental illness decreased with remoteness, as did treatment for mental illness, particularly in men. The most reported diagnoses were mood disorders (70%), psychotic disorders (9%) and anxiety disorders (8%). In the six weeks before suicide, 22% of cases had visited any type of health service at least once, and 6% had visited two or more services. Medication alone accounted for 76% of all cases treated. Conclusions Higher suicide rates in rural areas, which increase with remoteness, may be attributable to decreasing diagnosis and treatment of mental disorders, particularly in men. Less availability of mental health specialists coupled with socio-demographic factors within more remote areas may contribute to lower mental health diagnoses and treatment. Despite an emphasis on improving health-seeking and service accessibility in rural Australia, research is needed to determine factors related to the under-utilisation of services and treatment by specific groups vulnerable to death by suicide

Regional specificity of magnetic resonance imaging and histopathology following cerebral ischemia in preterm fetal sheep

Early and accurate evaluation of the nature and extent of cerebral injury in the preterm infant brain is important for prognostication and decision making in the neonatal intensive care unit. The capability of magnetic resonance imaging (MRI) to define acute ischemic changes in white and gray matter in comparison to contemporaneous histopathology has not been adequately ascertained. The aim of this study is to assess whether postmortem MRI predicts the nature and extent of brain injury in a preterm fetal sheep model of cerebral hypoperfusion. MRI examinations were performed on fetal sheep brains (d99-100 gestation), perfusion fixed 72 hours after an ischemic insult (n = 7) with left-hemispheric placement of a microdialysis probe and compared with sham-occlusion (n = 3) and unoperated-control fetuses (n = 4). Cerebral ischemia was associated with MRI changes including global cerebral injury and diffuse white matter signal abnormality, which corresponded closely with histological damage. However, histological changes in deep structures, including the corona radiata, thalamus, and globus pallidus were not reliably detected on MRI. These findings confirm that in preterm fetal sheep, MRI can accurately assess cortical gray matter and subcortical and periventricular white matter abnormalities 3 days after hypoxic-ischemic injury but appears to have limited sensitivity to detect injury to deep structures

White matter volume and anisotropy in preterm children: A pilot study of neurocognitive correlates

The objectives of this study were to evaluate the differences in whole brain white matter (WM) volume and anisotropy between preterm and term children and to determine the relationships with cognitive outcome. Twenty-five low birth weight (BW), preterm, neurologically normal children between 8.8 and 11.5 y of age were recruited for volumetric and diffusion-tensor magnetic resonance imaging (DTI), together with 13 age-matched term control subjects. Subsequent intelligence quotient (IQ) testing was performed for 21 preterm children within 6 mo of imaging studies. We computed the mean volume and fractional anisotropy (FA) of the whole brain WM and compared the differences between the two groups. Mean WM volume and FA were significantly lower in the preterm group (p = 0.014 and p < 0.001, respectively). Multiple regression analysis found both WM volume and FA to be independent variables significantly affecting full scale IQ (FSIQ) (r = 0.407, p = 0.021 and r = 0.496, p = 0.005, respectively) after adjusting for BW, gestational age (GA), and gender. In the evaluation of the whole brain WM of preterm children, we found that both volume and FA remain reduced at late childhood with both parameters significantly affecting long-term cognitive outcome. © International Pediatrics Research Foundation, Inc. 2007. All Rights Reserved.link_to_subscribed_fulltex