37 research outputs found
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Community-acquired pneumonia in children: cell-free plasma sequencing for diagnosis and management.
Community-acquired pneumonia (CAP) is a common cause of pediatric hospital admission. Empiric antibiotic therapy for hospitalized children with serious CAP now targets the most likely pathogen(s), including those that may demonstrate significant antibiotic resistance. Cell-free plasma next-generation sequencing (CFPNGS) was first made available for Pediatric Infectious Diseases physicians in June 1, 2017, to supplement standard-of-care diagnostic techniques. A retrospective chart review was performed for children hospitalized with CAP between June 1, 2017, and January 22, 2018, to evaluate the impact of CFPNGS. We identified 15 hospitalized children with CAP without other underlying medical conditions for whom CFPNGS was performed. CFPNGS identified a pathogen in 13 of 15 (86%) children compared with 47% for those using standard culture and PCR-based methods alone. Changes in antibiotic management were made in 7 of 15 (47%) of children as a result of CFPNGS
Incidence and phenotypes of childhood-onset genetic epilepsies:a prospective population-based national cohort
Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy
Characterizing rat brain tissue properties during postnatal development and in experimental hydrocephalus using magnetic resonance imaging and light sheet microscopy
The research described in this thesis encompassed three studies related to the biomechanical and vascular factors in acute obstructive hydrocephalus using the rat as a model. In the first study, early postnatal longitudinal brain mechanical properties were monitored in healthy rats and magnetic resonance elastography (MRE) data was found correlating to major cellular integrity changes within the tissue, such as neuronal proliferation and myelination process. In the second study, the effect of internal mechanical impact on the adult rat brains with induced acute obstructive hydrocephalus was investigated using MRE, diffusion tensor imaging and histological stainings. In comparison to the study results and previous work in juvenile animals, lead us to the conclusion that the response of the brain to acute obstruction of the intracranial CSF pathway is dependent on the age of onset. In the third study, hydrocephalic rat brains from the second study were used for further investigations on whether there were any vascular alterations due to the ventricular enlargement and contribute towards the mechanical properties. Samples were treated with CUBIC tissue clearing method and 3D images were obtained by the light sheet microscopy. Qualitative analysis showed that hydrocephalic periventricular arterials and arterioles volume ratio seemed lower than in the control, indicating a loss in arterial and arteriole numbers from the disease. To conclude, the research outlined in this dissertation extended our knowledge of the change in brain tissue properties in normal development and under pathological conditions like hydrocephalus. Brain tissue mechanical properties undergo dynamic changes during postnatal development, in parallel with complex microstructural changes such as neuronal proliferation, synaptic adaptation, and myelination. There are key differences in the brain response to obstructive hydrocephalus induced in young and adult rats. The findings are likely underpinned by differences in brain tissue microstructure and mechanical properties at the time of hydrocephalus induction. While young rats are undergoing critical cerebral development stages, mechanical forces associated with ventricular enlargement may also influence long term brain development, leading to irreversible neural deficits
Longitudinal measurements of postnatal rat brain mechanical properties in-vivo
Information on pediatric brain tissue mechanical properties and, more pertinently, how they change during postnatal development remains scarce despite its importance to investigate mechanisms of neural injury. The aim of this study is to determine whether brain mechanical properties change in-vivo during early postnatal development in a rat model. Rat brain viscoelastic properties were measured longitudinally in ten healthy Sprague Dawley rats at five different time points from postnatal week one to week six using magnetic resonance elastography at 800Hz. Myelination and cell density were assessed histologically at the same time points to understand how the underlying tissue microstructure may be associated with changes in mechanical properties at different brain regions. Longitudinal changes in each variable were assessed using a generalized linear model with pairwise comparisons of means between weeks. The brain shear modulus in the cortical gray matter at postnatal week one was 6.3±0.4 kPa, and increased significantly from week one to week two (pairwise comparison, p<0.01), remained stable from week two to week four and decreased significantly by week six (pairwise comparison, p<0.001). In the deep gray matter, brain tissue stiffness at postnatal week one was 6.1±2.0 kPa, and increased significantly from one to week four (pairwise comparison, p<0.05) before decreasing significantly by week six (pairwise comparison, p<0.001). Stiffness changes were not directly correlated to histological observations. These data suggest that brain tissue shear modulus initially increases during a period equivalent to early childhood, and then decreases during a period equivalent to adolescence.6 page(s
Changes in Rat Brain Tissue Microstructure and Stiffness during the Development of Experimental Obstructive Hydrocephalus.
Understanding neural injury in hydrocephalus and how the brain changes during the course of the disease in-vivo remain unclear. This study describes brain deformation, microstructural and mechanical properties changes during obstructive hydrocephalus development in a rat model using multimodal magnetic resonance (MR) imaging. Hydrocephalus was induced in eight Sprague-Dawley rats (4 weeks old) by injecting a kaolin suspension into the cisterna magna. Six sham-injected rats were used as controls. MR imaging (9.4T, Bruker) was performed 1 day before, and at 3, 7 and 16 days post injection. T2-weighted MR images were collected to quantify brain deformation. MR elastography was used to measure brain stiffness, and diffusion tensor imaging (DTI) was conducted to observe brain tissue microstructure. Results showed that the enlargement of the ventricular system was associated with a decrease in the cortical gray matter thickness and caudate-putamen cross-sectional area (P < 0.001, for both), an alteration of the corpus callosum and periventricular white matter microstructure (CC+PVWM) and rearrangement of the cortical gray matter microstructure (P < 0.001, for both), while compression without gross microstructural alteration was evident in the caudate-putamen and ventral internal capsule (P < 0.001, for both). During hydrocephalus development, increased space between the white matter tracts was observed in the CC+PVWM (P < 0.001), while a decrease in space was observed for the ventral internal capsule (P < 0.001). For the cortical gray matter, an increase in extracellular tissue water was significantly associated with a decrease in tissue stiffness (P = 0.001). To conclude, this study characterizes the temporal changes in tissue microstructure, water content and stiffness in different brain regions and their association with ventricular enlargement. In summary, whilst diffusion changes were larger and statistically significant for majority of the brain regions studied, the changes in mechanical properties were modest. Moreover, the effect of ventricular enlargement is not limited to the CC+PVWM and ventral internal capsule, the extent of microstructural changes vary between brain regions, and there is regional and temporal variation in brain tissue stiffness during hydrocephalus development
Development of acute hydrocephalus does not change brain tissue mechanical properties in adult rats, but in juvenile rats
<div><p>Introduction</p><p>Regional changes in brain stiffness were previously demonstrated in an experimental obstructive hydrocephalus juvenile rat model. The open cranial sutures in the juvenile rats have influenced brain compression and mechanical properties during hydrocephalus development and the extent by which closed cranial sutures in adult hydrocephalic rat models affect brain stiffness in-vivo remains unclear. The aims of this study were to determine changes in brain tissue mechanical properties and brain structure size during hydrocephalus development in adult rat with fixed cranial volume and how these changes were related to brain tissue deformation.</p><p>Methods</p><p>Hydrocephalus was induced in 9 female ten weeks old Sprague-Dawley rats by injecting 60 μL of a kaolin suspension (25%) into the cisterna magna under anaesthesia. 6 sham-injected age-matched female SD rats were used as controls. MR imaging (9.4T, Bruker) was performed 1 day before and then at 3 days post injection. T2-weighted anatomical MR images were collected to quantify ventricle and brain tissue cross-sectional areas. MR elastography (800 Hz) was used to measure the brain stiffness (G*, shear modulus).</p><p>Results</p><p>Brain tissue in the adult hydrocephalic rats was more compressed than the juvenile hydrocephalic rats because the skulls of the adult hydrocephalic rats were unable to expand like the juvenile rats. In the adult hydrocephalic rats, the cortical gray matter thickness and the caudate-putamen cross-sectional area decreased (Spearman, P < 0.001 for both) but there were no significant changes in cranial cross-sectional area (Spearman, P = 0.35), cortical gray matter stiffness (Spearman, P = 0.24) and caudate-putamen (Spearman, P = 0.11) stiffness. No significant changes in the size of brain structures were observed in the controls.</p><p>Conclusions</p><p>This study showed that although brain tissue in the adult hydrocephalic rats was severely compressed, their brain tissue stiffness did not change significantly. These results are in contrast with our previous findings in juvenile hydrocephalic rats which had significantly less brain compression (as the brain circumference was able to stretch with the cranium due to the open skull sutures) and had a significant increase in caudate putamen stiffness. These results suggest that change in brain mechanical properties in hydrocephalus is complex and is not solely dependent on brain tissue deformation. Further studies on the interactions between brain tissue stiffness, deformation, tissue oedema and neural damage are necessary before MRE can be used as a tool to track changes in brain biomechanics in hydrocephalus.</p></div
Regions of interest to characterise the effects of hydrocephalus on changes in brain structure size and stiffness in adult rats.
<p>Changes in brain structure size were characterised using high resolution anatomical T2-weighted images by quantifying: a) ventricle size (i.e cross-sectional area of the ventricular system), b) head size (i.e cranial cross-sectional area), c) cortical gray matter thickness (from the pial surface to the subcortical white matter averaged over 5 locations) and d) caudate putamen cross-sectional area (sum of the right and left caudate-putamen). Brightness of the images was increased by 20% for visualization. White lines indicate each region of interest in a—d. Brain stiffness was then quantified by calculating the shear modulus (G*, kPa) at e) baseline and in f) day 3 in the cortical gray matter and the caudate putamen (black ROIs) using MRE performed at 800 Hz. For visualization, the outer boundary of the brain tissue and brain ventricle boundaries have been outlined in red on G* maps.</p
Statistical results from Spearman correlation analyses between normalised brain tissue area and changes in brain structure size and stiffness with respect to their baseline conditions.
<p>Data is presented graphically in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182808#pone.0182808.g005" target="_blank">Fig 5</a>.</p
Effect of ventricular enlargement on brain tissue deformation and stiffness in adult hydrocephalic rats.
<p>Relationships between the ventricle system cross-sectional area and (a) the cranial cross-sectional area, (b) cortical gray matter thickness, (c) caudate-putamen cross-sectional area, and shear modulus (G*) of the (d) cortical gray matter and (e) caudate-putamen in adult hydrocephalic rats. Relationships were evaluated using generalized estimating equations accounting for the repeated measures. For relationships that were significant, the parameter B represents the increase in that parameter per mm<sup>2</sup> of ventricle system area.</p
Effect of the brain compression on brain tissue deformation and stiffness in adult and juvenile hydrocephalic rats, three days post-hydrocephalus induction.
<p>Relationships between the normalised brain tissue area and (a) normalised ventricular system cross-sectional area, (b) normalised cranial cross-sectional area, (c) normalised cortical gray matter thickness, (d) normalised caudate-putamen cross-sectional area, and normalised shear modulus (G*) of the (e) cortical gray matter and (f) caudate-putamen. Relationships were evaluated with Spearman correlations (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182808#pone.0182808.t001" target="_blank">Table 1</a>). Note: In juvenile rats, four normalised G* measurements of the cortical gray matter and two of the caudate-putamen could not be calculated because the measurement was missing either at baseline or day 3.</p