Hierarchical topological network analysis of anatomical human brain connectivity and differences related to sex and kinship

Modern non-invasive brain imaging technologies, such as diffusion weighted magnetic resonance imaging (DWI), enable the mapping of neural fiber tracts in the white matter, providing a basis to reconstruct a detailed map of brain structural connectivity networks. Brain connectivity networks differ from random networks in their topology, which can be measured using small worldness, modularity, and high-degree nodes (hubs). Still, little is known about how individual differences in structural brain network properties relate to age, sex, or genetic differences. Recently, some groups have reported brain network biomarkers that enable differentiation among individuals, pairs of individuals, and groups of individuals. In addition to studying new topological features, here we provide a unifying general method to investigate topological brain networks and connectivity differences between individuals, pairs of individuals, and groups of individuals at several levels of the data hierarchy, while appropriately controlling false discovery rate (FDR) errors. We apply our new method to a large dataset of high quality brain connectivity networks obtained from High Angular Resolution Diffusion Imaging (HARDI) tractography in 303 young adult twins, siblings, and unrelated people. Our proposed approach can accurately classify brain connectivity networks based on sex (93% accuracy) and kinship (88.5% accuracy). We find statistically significant differences associated with sex and kinship both in the brain connectivity networks and in derived topological metrics, such as the clustering coefficient and the communicability matrix.

Variations in vertebral venous vasculature

INTRODUCTION Cadaveric studies have previously documented typical patterns of venous drainage within vertebral bodies (VBs) [1,2,3], comprised primarily of the basivertebral vein, a planar tree like structure at the mid-height of the VB. These studies, however, are limited in the number of samples available, and so have not examined any potential differences in this anatomy in conditions such as scoliosis. MRI is able to create 3D images of soft tissue structures in the spine, including the basivertebral vein without the use of contrast. As a non-invasive imaging technique this opens up the possibility of examining the venous network in multiple VBs within the same subject, in healthy controls as well as in subjects with abnormal anatomy such as adolescent idiopathic scoliosis (AIS). CONCLUSIONS High resolution MRI scans allow in vivo quantification of the vertebral venous system at multiple levels on healthy and scoliotic populations for the first time. The length of the basivertebral vein was seen to have a significant bias to the right hand side of the VB in both healthy and AIS adolescents. The spatial pattern of this vein showed large variations in branching both within and across individuals.

Numerical study of LSF floors made of hollow flange channels in fire

Light gauge steel frame (LSF) floor systems are generally made of lipped channel section joists and lined with gypsum plasterboards to provide adequate fire resistance rating under fire conditions. Recently a new LSF floor system made of welded hollow flange channel (HFC) section was developed and its fire performance was investigated using full scale fire tests. The new floor systems gave higher fire resistance ratings in comparison to conventional LSF floor systems. To avoid expensive and time consuming full scale fire tests, finite element analyses were also performed to simulate the fire performance of LSF floors made of HFC joists using both steady and transient state methods. This paper presents the details of the developed finite element models of HFC joists to simulate the structural fire performance of the LSF floor systems under standard fire conditions. Finite element analyses were performed using the measured time–temperature profiles of the failed joists from the fire tests, and their failure times, temperatures and modes, and deflection versus time curves were obtained. The developed finite element models successfully predicted the structural performance of LSF floors made of HFC joists under fire conditions. They were able to simulate the complex behaviour of thin cold-formed steel joists subjected to non-uniform temperature distributions, and local buckling and yielding effects. This study also confirmed the superior fire performance of the newly developed LSF floors made of HFC joists.

Limited utility of exercise stress testing in the evaluation of suspected acute coronary syndrome in patients aged less than 40 years with intermediate risk features

Objective National guidelines for management of intermediate risk patients with suspected acute coronary syndrome, in whom AMI has been excluded, advocate provocative testing to final risk stratify these patients into low risk (negative testing) or high risk (positive testing suggestive of unstable angina). Adults less than 40 years have a low pretest probability of acute coronary syndrome. The utility of exercise stress testing in young adults with chest pain suspected of acute coronary syndrome who have National Heart Foundation intermediate risk features was evaluated Methods A retrospective analysis of exercise stress testing performed on patients less than 40 years was evaluated. Patients were enrolled on a chest pain pathway and had negative serial ECGs and cardiac biomarkers before exercise stress testing to rule-out acute coronary syndrome. Chart review was completed on patients with positive stress tests. Results The 3987 patients with suspected intermediate risk acute coronary syndrome underwent exercise stress testing. One thousand and twenty-seven (25.8%) were aged less than 40 years (age 33.3 ± 4.8 years). Four of these 1027 patients had a positive exercise stress test (0.4% incidence of positive exercise stress testing). Of those, three patients had subsequent non-invasive functional testing that yielded a negative result. One patient declined further investigations. Assuming this was a true positive exercise stress test, the incidence of true positive exercise stress testing would have been 0.097% (95% confidence interval: 0.079–0.115%) (one of 1027 patients). Conclusions Routine exercise stress testing has limited value in the risk stratification of adults less than 40 years with suspected intermediate risk of acute coronary syndrome

Predicting the performance of LSF walls made of hollow flange channel sections in fire

Fire resistance of load bearing Light Gauge Steel Frame (LSF) wall systems is important to protect lives and properties in fire accidents. Recent fire tests of LSF walls made of the new cold-formed and welded hollow flange channel (HFC) section studs and the commonly used lipped channel section (LCS) studs have shown the influence of stud sections on the fire resistance rating (FRR) of LSF walls. To advance the use of HFC section studs and to verify the outcomes from the fire tests, finite element models were developed to predict the structural fire performance of LSF walls made of welded HFC section studs. The developed models incorporated the measured non-uniform temperature distributions in LSF wall studs due to the exposure of standard fire on one side, and accurate elevated temperature mechanical properties of steel used in the stud sections. These models simulated the various complexities involved such as thermal bowing and neutral axis shift caused by the non-uniform temperature distribution in the studs. The finite element analysis (FEA) results agreed well with the full scale fire test results including the FRR, outer hot and cold flange temperatures at failure and axial deformation and lateral displacement profiles. They also confirmed the superior fire performance of LSF walls made of HFC section studs. The applicability of both transient and steady state FEA of LSF walls under fire conditions was verified in this study, which also investigated the effects of using various temperature distribution patterns across the cross-section of HFC section studs on the FRR of LSF walls. This paper presents the details of this numerical study and the results.

Melanopsin mediated post-illumination pupil response in early age-related macular degeneration

Purpose To determine whether melanopsin expressing intrinsically photosensitive Retinal Ganglion Cell (ipRGC) inputs to the pupil light reflex (PLR) are affected in early age-related macular degeneration (AMD). Methods The PLR was measured in 40 participants (20 early AMD and 20 age-matched controls) using a custom-built Maxwellian-view pupillometer. Sinusoidal stimuli (0.5 Hz, 11.9 s duration, 35.6° diameter) were presented to the study eye and the consensual pupil response was measured for stimuli with high melanopsin excitation (464nm; blue) and with low melanopsin excitation (638 nm; red) that biased activation to the outer retina. Two melanopsin PLR metrics were quantified: the Phase Amplitude Percentage (PAP) during the sinusoidal stimulus presentation and the Post-Illumination Pupil Response (PIPR). The PLR during stimulus presentation was analyzed using latency to constriction, transient pupil response and maximum pupil constriction metrics. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curves. Results The blue PIPR was significantly less sustained in the early AMD group (p<0.001). The red PIPR was not significantly different between groups (p>0.05). The PAP and blue stimulus constriction amplitude were significantly lower in the early AMD group (p < 0.05). There was no significant difference between groups in the latency or transient amplitude for both stimuli (p>0.05). ROC analysis showed excellent diagnostic accuracy for the blue PIPR metrics (AUC>0.9). Conclusions This is the initial report that the melanopsin controlled PIPR is dysfunctional in early AMD. The non-invasive, objective measurement of the ipRGC controlled PIPR has excellent diagnostic accuracy for early AMD.

Effect of age and refractive error on the melanopsin mediated Post-Illumination Pupil Response (PIPR)

Melanopsin containing intrinsically photosensitive Retinal Ganglion cells (ipRGCs) mediate the pupil light reflex (PLR) during light onset and at light offset (the post-illumination pupil response, PIPR). Recent evidence shows that the PLR and PIPR can provide non-invasive, objective markers of age-related retinal and optic nerve disease, however there is no consensus on the effects of healthy ageing or refractive error on the ipRGC mediated pupil function. Here we isolated melanopsin contributions to the pupil control pathway in 59 human participants with no ocular pathology across a range of ages and refractive errors. We show that there is no effect of age or refractive error on ipRGC inputs to the human pupil control pathway. The stability of the ipRGC mediated pupil response across the human lifespan provides a functional correlate of their robustness observed during ageing in rodent models.

Melanopsin ganglion cell function in early age-related macular degeneration

Purpose Melanopsin-expressing retinal ganglion cells (mRGCs) have non-image forming functions including mediation of the pupil light reflex (PLR). There is limited knowledge about mRGC function in retinal disease. Initial retinal changes in age-related macular degeneration (AMD) occur in the paracentral region where mRGCs have their highest density, making them vulnerable during disease onset. In this cross-sectional clinical study, we measured the PLR to determine if mRGC function is altered in early stages of macular degeneration. Methods Pupil responses were measured in 8 early AMD patients (AREDS 2001 classification; mean age 72.6 ± 7.2 years, 5M, and 3F) and 12 healthy control participants (mean age 66.6 ± 6.1 years, 8M and 4F) using a custom-built Maxwellian-view pupillometer. Stimuli were 0.5 Hz sinewaves (10 s duration, 35.6° diameter) of short wavelength light (464nm, blue; retinal irradiance = 14.5 log quanta.cm-2.s-1) to produce high melanopsin excitation and of long wavelength light (638nm, red; retinal irradiance = 14.9 log quanta.cm-2.s-1), to bias activation to outer retina and provide a control. Baseline pupil diameter was determined during a 10 s pre-stimulus period. The post illumination pupil response (PIPR) was recorded for 40 s. The 6 s PIPR and maximum pupil constriction were expressed as percentage baseline (M ± SD). Results The blue PIPR was significantly less sustained (p<0.01) in the early AMD group (75.49 ± 7.88%) than the control group (58.28 ± 9.05%). The red PIPR was not significantly different (p>0.05) between the early AMD (84.79 ± 4.03%) and control groups (82.01 ± 5.86%). Maximum constriction amplitude in the early AMD group for blue (43.67 ± 6.35%) and red (48.64 ± 6.49%) stimuli were not significantly different to the control group for blue (39.94 ± 3.66%) and red (44.98 ± 3.15%) stimuli (p>0.05). Conclusions These results are suggestive of inner retinal mRGC deficits in early AMD. This non-invasive, objective measure of pupil responses may provide a new method for quantifying mRGC function and monitoring AMD progression.

A liquid biopsy for head and neck cancers

Head and neck cancer patients often present with advanced metastatic disease resulting in a poor 5-year survival. Therefore, there is a need for non-invasive diagnostic tools that could complement conventional imaging to inform clinicians of patient outcomes and treatment responses. A liquid biopsy addresses this unmet clinical need; a simple peripheral blood draw could provide information about the disseminated disease in terms of circulating tumor cells and circulating tumor DNA. Moreover, detectable tumor DNA in the saliva of head and neck cancer patients could signify the early signs of the disease and present an opportunity for clinical intervention. This review provides an overview of the current literature with regard to the feasibility of such a test in the head and neck cancer field and highlights the need for such a test.

Magnetic resonance microimaging of cancer cell spheroid constructs

BACKGROUND Hydrogel-based cell cultures are excellent tools for studying physiological events occurring in the growth and proliferation of cells, including cancer cells. Diffusion magnetic resonance is a physical technique that has been widely used for the characterisation of biological systems as well as hydrogels. In this work, we applied diffusion magnetic resonance imaging (MRI) to hydrogel-based cultures of human ovarian cancer cells. METHODS Diffusion-weighted spin-echo MRI measurements were used to obtain spatially-resolved maps of apparent diffusivities for hydrogel samples with different compositions, cell loads and drug (Taxol) treatment regimes. The samples were then characterised using their diffusivity histograms, mean diffusivities and the respective standard deviations, and pairwise Mann-Whitney tests. The elastic moduli of the samples were determined using mechanical compression testing. RESULTS The mean apparent diffusivity of the hydrogels was sensitive to the polymer content, cell load and Taxol treatment. For a given sample composition, the mean apparent diffusivity and the elastic modulus of the hydrogels exhibited a negative correlation. CONCLUSIONS Diffusivity of hydrogel-based cancer cell culture constructs is sensitive to both cell proliferation and Taxol treatment. This suggests that diffusion-weighted imaging is a promising technique for non-invasive monitoring of cancer cell proliferation in hydrogel-based, cellularly-sparse 3D cell cultures. The negative correlation between mean apparent diffusivity and elastic modulus suggests that the diffusion coefficient is indicative of the average density of the physical microenvironment within the hydrogel construct.

Research update: LANDMark study: Longitudinal assessment of neuropathy in diabetes using novel ophthalmic MARKers

The eye is a simple, non-invasive location for screening, diagnosing and follow up of diabetic peripheral neuropathy.

Editorial: Measuring refractive index distribution in the human eye lens

Non-invasive measurements of the age dependence of refractive index distribution in human eye lenses in vitro using a novel X-ray Talbot Interferometry method. In their paper, the authors make frequent reference to our own work in which we employed magnetic resonance imaging (MRI) to make similar non-invasive measurements of the refractive index distribution in the human eye lens [2, 3]. Prior to the current work, ours was the only method for making such measurements both non-invasively and without prior assumptions about the shape of the refractive index distribution. For this reason, the latest work is to be welcomed. However at several points in the paper, Pierscionek et al. [1] make statements about our technique which are factually incorrect...

Enrichment and identification of glycoproteins in human saliva using lectin magnetic bead arrays

Aberrant glycosylation of proteins is a hallmark of tumorigenesis, and could provide diagnostic value in cancer detection. Human saliva is an ideal source of glycoproteins due to the relatively high proportion of glycosylated proteins in the salivary proteome. Moreover, saliva collection is non-invasive, technically straightforward and the sample collection and storage is relatively easy. Although, differential glycosylation of proteins can be indicative of disease states, identification of differential glycosylation from clinical samples is not trivial. To facilitate salivary glycoprotein biomarker discovery, we optimised a method for differential glycoprotein enrichment from human saliva based on lectin magnetic bead arrays (saLeMBA). Selected lectins from distinct reactivity groups were used in the saLeMBA platform to enrich salivary glycoproteins from healthy volunteer saliva. The technical reproducibility of saLeMBA was analysed with LC-MS/MS to identify the glycosylated proteins enriched by each lectin. Our saLeMBA platform enabled robust glycoprotein enrichment in a glycoprotein- and lectin-specific manner consistent with known protein-specific glycan profiles. We demonstrated that saLeMBA is a reliable method to enrich and detect glycoproteins present in human saliva.

Assessment of conjunctival goblet cell density using laser scanning confocal microscopy versus impression cytology

Purpose To determine the association between conjunctival goblet cell density (GCD) assessed using in vivo laser scanning confocal microscopy and conjunctival impression cytology in a healthy population. Methods Ninety (90) healthy participants undertook a validated 5-item dry eye questionnaire, non-invasive tear film break-up time measurement, ocular surface fluorescein staining and phenol red thread test. These tests where undertaken to diagnose and exclude participants with dry eye. The nasal bulbar conjunctiva was imaged using laser scanning confocal microscopy (LSCM). Conjunctival impression cytology (CIC) was performed in the same region a few minutes later. Conjunctival goblet cell density was calculated as cells/mm2. Results There was a strong positive correlation of conjunctival GCD between LSCM and CIC (ρ = 0.66). Conjunctival goblet cell density was 475 ± 41 cells/mm2 and 466 ± 51 cells/mm2 measured by LSCM and CIC, respectively. Conclusions The strong association between in vivo and in vitro cellular analysis for measuring conjunctival GCD suggests that the more invasive CIC can be replaced by the less invasive LSCM in research and clinical practice.

Chlamydial infertility in women: Diagnosis, epidemiology and immune response

This project primarily focused on the development of a novel, non-invasive peptide-based ELISA to diagnose C. trachomatis-related infertility in women. In this study, an in silico approach was applied to identify and design novel peptide antigens that are specific to women with C. trachomatis-related infertility. The serological assay was developed such that it could potentially replace invasive techniques for early infertility investigation. The thesis further investigated the sero-prevalence of chlamydial infertility in women from a low-resource, high prevalence setting. In addition, the thesis also identified immune markers that were associated with the C. trachomatis-related infertility in women.