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Purpose: To evaluate potential modeling paradigms and the impact of relaxation time effects on human blood-brain barrier (BBB) water exchange measurements using FEXI (BBB-FEXI), and to quantify the accuracy, precision, and repeatability of BBB-FEXI exchange rate estimates at 3 (Formula presented.). Methods: Three modeling paradigms were evaluated: (i) the apparent exchange rate (AXR) model; (ii) a two-compartment model ((Formula presented.)) explicitly representing intra- and extravascular signal components, and (iii) a two-compartment model additionally accounting for finite compartmental (Formula presented.) and (Formula presented.) relaxation times ((Formula presented.)). Each model had three free parameters. Simulations quantified biases introduced by the assumption of infinite relaxation times in the AXR and (Formula presented.) models, as well as the accuracy and precision of all three models. The scan–rescan repeatability of all paradigms was quantified for the first time in vivo in 10 healthy volunteers (age range 23–52 years; five female). Results: The assumption of infinite relaxation times yielded exchange rate errors in simulations up to 42%/14% in the AXR/ (Formula presented.) models, respectively. Accuracy was highest in the compartmental models; precision was best in the AXR model. Scan–rescan repeatability in vivo was good for all models, with negligible bias and repeatability coefficients in grey matter of (Formula presented.) (Formula presented.), (Formula presented.) (Formula presented.), and (Formula presented.) (Formula presented.). Conclusion: Compartmental modelling of BBB-FEXI signals can provide accurate and repeatable measurements of BBB water exchange; however, relaxation time and partial volume effects may cause model-dependent biases.

Chemical-exchange spin-lock (CESL) MRI can map regional uptake and utilisation of glucose in the brain at high spatial resolution (i.e sub 0.2 mm3 voxels). We propose two quantitative kinetic models to describe glucose-induced changes in tissue R1ρ and apply them to glucoCESL MRI data acquired in tumour-bearing and healthy rats. When assuming glucose transport is saturable, the maximal transport capacity ( Tmax) measured in normal tissue was 3.2 ± 0.6 µmol/min/mL, the half saturation constant ( Kt) was 8.8 ± 2.2 mM, the metabolic rate of glucose consumption ( MRglc) was 0.21 ± 0.13 µmol/min/mL, and the cerebral blood volume ( vb) was 0.006 ± 0.005 mL/mL. Values in tumour were: Tmax = 7.1 ± 2.7 µmol/min/mL, Kt = 14 ± 1.7 mM, MRglc = 0.22 ± 0.09 µmol/min/mL, vb = 0.030 ± 0.035 mL/mL. Tmax and Kt were significantly higher in tumour tissue than normal tissue (p = 0.006 and p = 0.011, respectively). When assuming glucose uptake also occurs via free diffusion, the free diffusion rate ( kd) was 0.061 ± 0.017 mL/min/mL in normal tissue and 0.12 ± 0.042 mL/min/mL in tumour. These parameter estimates agree well with literature values obtained using other approaches (e.g. NMR spectroscopy).

The recent revolution in tissue-resident macrophage biology has resulted largely from murine studies performed in C57BL/6 mice. Here, using both C57BL/6 and BALB/c mice, we analyze immune cells in the pleural cavity. Unlike C57BL/6 mice, naive tissue-resident large-cavity macrophages (LCMs) of BALB/c mice failed to fully implement the tissue-residency program. Following infection with a pleural-dwelling nematode, these pre-existing differences were accentuated with LCM expansion occurring in C57BL/6, but not in BALB/c mice. While infection drove monocyte recruitment in both strains, only in C57BL/6 mice were monocytes able to efficiently integrate into the resident pool. Monocyte-to-macrophage conversion required both T cells and interleukin-4 receptor alpha (IL-4Rα) signaling. The transition to tissue residency altered macrophage function, and GATA6+ tissue-resident macrophages were required for host resistance to nematode infection. Therefore, during tissue nematode infection, T helper 2 (Th2) cells control the differentiation pathway of resident macrophages, which determines infection outcome.

A technique for quantifying regional blood-brain barrier (BBB) water exchange rates using contrast-enhanced arterial spin labelling (CE-ASL) is presented and evaluated in simulations and in vivo. The two-compartment ASL model describes the water exchange rate from blood to tissue,kb, but to estimatekbin practice it is necessary to separate the intra- and extravascular signals. This is challenging in standard ASL data owing to the small difference inT1values. Here, a gadolinium-based contrast agent is used to increase thisT1difference and enable the signal components to be disentangled. The optimal post-contrast bloodT1at 3T was determined in a sensitivity analysis, and the accuracy and precision of the method quantified using Monte Carlo simulations. Proof-of-concept data were acquired in six healthy volunteers (five female, age range 24 – 46 years). The sensitivity analysis identified the optimalat 3T as 0.8 s. Simulations showedkbcould be estimated in individual cortical regions with a relative errorϵ< 1% and coefficient of variation CoV = 30 %; however, a high dependence on bloodT1was also observed. In volunteer data, mean parameter values in grey matter were: arterial transit timetA= 1.15±0.49 s, cerebral blood flowf= 58.0±14.3 ml blood / min / 100 ml tissue, water exchange ratekb= 2.32 ± 2.49 s−1. CE-ASL can provide regional BBB water exchange rate estimates; however, the clinical utility of the technique is dependent on the achievable accuracy of measuredT1values.

Multi-diffusion-time diffusion-weighted MRI can probe tissue microstructure, but the method has not been widely applied to the microvasculature. At long diffusion-times, blood flow in capillaries is in the diffusive regime, and signal attenuation is dependent on blood velocity ([Formula: see text]) and capillary segment length ([Formula: see text]). It is described by the pseudo-diffusion coefficient ([Formula: see text]) of intravoxel incoherent motion (IVIM). At shorter diffusion-times, blood flow is in the ballistic regime, and signal attenuation depends on [Formula: see text], and not [Formula: see text]. In theory, [Formula: see text] could be estimated using [Formula: see text] and [Formula: see text]. In this study, we compare the accuracy and repeatability of three approaches to estimating [Formula: see text], and therefore [Formula: see text]: the IVIM ballistic model, the velocity autocorrelation model, and the ballistic approximation to the velocity autocorrelation model. Twenty-nine rat datasets from two strains were acquired at 7 T, with [Formula: see text]-values between 0 and 1000 smm−2 and diffusion times between 11.6 and 50 ms. Five rats were scanned twice to assess scan-rescan repeatability. Measurements of [Formula: see text] were validated using corrosion casting and micro-CT imaging. The ballistic approximation of the velocity autocorrelation model had lowest bias relative to corrosion cast estimates of [Formula: see text], and had highest repeatability.

Haemorrhagic stroke represents a significant public health burden, yet our knowledge and ability to treat this type of stroke are lacking. Previously we showed that we can target ischaemic-stroke lesions by selective translocation of lipid nanoparticles through the site of blood-brain barrier (BBB) disruption. The data we presented in this study provide compelling evidence that haemorrhagic stroke in mice induces BBB injury that mimics key features of the human pathology and, more importantly, provides a gate for entry of lipid nanoparticles-based therapeutics selectively to the bleeding site. [Methods] Haemorrhagic stroke was induced in mice by intra-striatal collagenase injection. lipid nanoparticles were injected intravenously at 3 h, 24 h & 48 h post-haemorrhagic stroke and accumulation in the brain studied using in-vivo optical imaging and histology. BBB integrity, brain water content and iron accumulation were characterised using dynamic contrast-enhanced MRI, quantitative T1 mapping, and gradient echo MRI. [Results] Using in-vivo SPECT/CT imaging and optical imaging revealed biphasic lipid nanoparticles entry into the bleeding site, with an early phase of increased uptake at 3-24 h post-haemorrhagic stroke, followed by a second phase at 48-72 h. Lipid nanoparticles entry into the brain post-haemorrhage showed an identical entry pattern to the trans-BBB leakage rate (K [min]) of Gd-DOTA, a biomarker for BBB disruption, measured using dynamic contrast-enhanced MRI. [Discussion] Our findings suggest that selective accumulation of liposomes into the lesion site is linked to a biphasic pattern of BBB hyper-permeability. This approach provides a unique opportunity to selectively and efficiently deliver therapeutic molecules across the BBB, an approach that has not been utilised for haemorrhagic stroke therapy and is not achievable using free small drug molecules., The authors acknowledge Lipoid Co. (Germany) for the lipid sample gifts, the staff at the bioimaging facility at the University of Manchester and NTU for advice on confocal imaging and data analysis. The authors also would like to acknowledge the access to the Leica Thunder Imager 3D Cell Culture system funded by the Office for Students at NTU. They also wish to thank the Biological Services Facility at the University of Manchester for the excellent animal husbandry. The cost of this study has been covered by: a) Dr Z Al-Ahmady research fellowship (School of Pharmacy and Optometry, University of Manchester), b) QR fund and Vice-Chancellor PhD studentship awarded for Dr Zahraa Al-Ahmady and Satinderdeep Kaur, Nottingham Trent University, c) BBSRC DTP Studentship awarded to Jessica Bates, Nottingham Trent University, d) MRC DTP studentship to Jack Barrington at University of Manchester. Jack Barrington also received support from the Natalie Kate Moss Trust, e) MRC grant (MR/N003586/1) for Eloise Lemarchand at University of Manchester, and f) EPSRC grant for Dr Ben Dickie at the University of Manchester (EP/S021510). Graphical abstract and schematic graphes were performed using Biorender.

Amyloid plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Animals were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4 T Bruker scanner. MnCl2 improved signal-to-noise ratio but was not necessary to detect plaques in high-resolution images. Plaques were visible in all transgenic animals and no wild-types, and quantitative susceptibility mapping showed that they were more paramagnetic than the surrounding tissue. This, combined with beta-amyloid and iron staining, indicate that plaque MR visibility in both animal models was driven by plaque size and iron load. Longitudinal relaxation rate mapping revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. This was limited to the rhinencephalon in the TgF344-AD rats, while it was most significantly increased in the cortex of the 5xFAD mice. Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting amyloid plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present the first in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.

Introduction: Alzheimer's disease (AD) is characterized by cerebral glucose hypometabolism. Hypometabolism may be partly due to reduced glucose transport at the blood-brain barrier (BBB) and across astrocytic and neuronal cell membranes. Glucose transporters (GLUTs) are integral membrane proteins responsible for moving glucose from the bloodstream to parenchymal cells where it is metabolized, and evidence indicates vascular and non-vascular GLUTs are altered in AD brains, a process which could starve the brain of glucose and accelerate cognitive decline. Here we review the literature on glucose transport alterations in AD from human and rodent studies.Methods: Literature published between 1st January 1946 and 1st November 2020 within EMBASE and MEDLINE databases was searched for the terms “glucose transporters” AND “Alzheimer's disease”. Human and rodent studies were included while reviews, letters, and in-vitro studies were excluded.Results: Forty-three studies fitting the inclusion criteria were identified, covering human (23 studies) and rodent (20 studies). Post-mortem studies showed consistent reductions in GLUT1 and GLUT3 in the hippocampus and cortex of AD brains, areas of the brain closely associated with AD pathology. Tracer studies in rodent models of AD and human AD also exhibit reduced uptake of glucose and glucose-analogs into the brain, supporting these findings. Longitudinal rodent studies clearly indicate that changes in GLUT1 and GLUT3 only occur after amyloid-β pathology is present, and several studies indicate amyloid-β itself may be responsible for GLUT changes. Furthermore, evidence from human and rodent studies suggest GLUT depletion has severe effects on brain function. A small number of studies show GLUT2 and GLUT12 are increased in AD. Anti-diabetic medications improved glucose transport capacity in AD subjects.Conclusions: GLUT1 and GLUT3 are reduced in hippocampal and cortical regions in patients and rodent models of AD, and may be caused by high levels of amyloid-β in these regions. GLUT3 reductions appear to precede the onset of clinical symptoms. GLUT2 and GLUT12 appear to increase and may have a compensatory role. Repurposing anti-diabetic drugs to modify glucose transport shows promising results in human studies of AD.

Purpose: Dynamic contrast-enhanced (DCE) -MRI with Patlak model analysis is increasingly used to quantify low-level blood-brain barrier (BBB) leakage in studies of pathophysiology. We aimed to investigate systematic errors due to physiological, experimental, and modeling factors influencing quantification of the permeability-surface area product PS and blood plasma volume v p, and to propose modifications to reduce the errors so that subtle differences in BBB permeability can be accurately measured. Methods: Simulations were performed to predict the effects of potential sources of systematic error on conventional PS and v p quantification: restricted BBB water exchange, reduced cerebral blood flow, arterial input function (AIF) delay and (Formula presented.) error. The impact of targeted modifications to the acquisition and processing were evaluated, including: assumption of fast versus no BBB water exchange, bolus versus slow injection of contrast agent, exclusion of early data from model fitting and (Formula presented.) correction. The optimal protocol was applied in a cohort of recent mild ischaemic stroke patients. Results: Simulation results demonstrated substantial systematic errors due to the factors investigated (absolute PS error ≤ 4.48 × 10 −4 min −1). However, these were reduced (≤0.56 × 10 −4 min −1) by applying modifications to the acquisition and processing pipeline. Processing modifications also had substantial effects on in-vivo normal-appearing white matter PS estimation (absolute change ≤ 0.45 × 10 −4 min −1). Conclusion: Measuring subtle BBB leakage with DCE-MRI presents unique challenges and is affected by several confounds that should be considered when acquiring or interpreting such data. The evaluated modifications should improve accuracy in studies of neurodegenerative diseases involving subtle BBB breakdown.

The effects of Alzheimer's disease (AD) and ageing on blood-brain barrier (BBB) breakdown are investigated in TgF344-AD and wild-type rats aged 13, 18 and 21 months. Permeability surface area products of the BBB to water (PSw ) and gadolinium-based contrast agent (PSg ) were measured in grey matter using multiflip angle multiecho dynamic contrast-enhanced MRI. At 13 months of age, there was no significant difference in PSw between TgF344-AD and wild-types (p = 0.82). Between 13 and 18 months, PSw increased in TgF344-AD rats (p = 0.027), but not in wild-types (p = 0.99), leading to significantly higher PSw in TgF344-AD rats at 18 months, as previously reported (p = 0.012). Between 18 and 21 months, PSw values increased in wild-types (p = 0.050), but not in TgF344-AD rats (p = 0.50). These results indicate that BBB water permeability is affected by both AD pathology and ageing, but that changes occur earlier in the presence of AD pathology. There were no significant genotype or ageing effects on PSg (p > 0.05). In conclusion, we detected increases in BBB water permeability with age in TgF344-AD and wild-type rats, and found that changes occurred at an earlier age in rats with AD pathology.

Senile plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats.Fourteen mice (eight transgenic, six wild-type) and eight rats (four transgenic, four wild-type) were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4T Bruker scanner. Susceptibility-weighted images, transverse relaxation rate (R2*) maps, and quantitative susceptibility maps were derived from high-resolution 3D multi-gradient-echo (MGE) data to directly visualize plaques. Longitudinal relaxation rate (R1) maps were derived from MP2RAGE data to measure regional manganese uptake. After scanning, the brains were processed for histology and stained for beta-amyloid (4G8 antibody), iron (Perl’s), and calcium/manganese (Alizarin Red).MnCl2 improved signal-to-noise ratio (1.55±0.39-fold increase in MGE images) as expected, although this was not necessary for detection of plaques in the high-resolution images. Plaques were visible in susceptibility-weighted images, R2* maps, and quantitative susceptibility maps, with increased R2* and more positive magnetic susceptibility compared to surrounding tissue.In the 5xFAD mice, most MR-visible plaques were in the hippocampus, though histology confirmed plaques in the cortex and thalamus as well. In the TgF344-AD rats, many more plaques were MR-visible throughout the hippocampus and cortex. Beta-amyloid and iron staining indicate that, in both models, MR visibility was driven by plaque size and iron load.Voxel-wise comparison of R1 maps revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. Interestingly, in contrast to plaque visibility in the high-resolution images, the increased manganese uptake was limited to the rhinencephalon in the TgF344-AD rats (family-wise error (FWE)-corrected p < 0.05) while it was most significantly increased in the cortex of the 5xFAD mice (FWE-corrected p < 0.3). Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats.Multi-parametric MEMRI is a simple, viable method for detecting senile plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.HighlightsThis is the first study to use manganese-enhanced MRI (MEMRI) for direct visualization of senile plaques in rodent models of Alzheimer’s disease, in vivo.Manganese enhancement is not necessary to detect plaques but improves image contrast and signal-to-noise ratio.Manganese binds to plaques in 5xFAD mice but not in TgF344-AD rats, demonstrating potential as a targeted contrast agent for imaging plaques in certain models of AD.

BackgroundPhysiological brain function depends on tight glucose regulation, including transport and phosphorylation, the first step in its metabolism. Impaired glucose regulation is increasingly implicated in the pathophysiology of Alzheimer's disease (AD). Glucose hypometabolism in AD may be at least partly due to impaired glucose transport at the blood-brain barrier (BBB). Glucose transporters (GLUTs) are an integral component of the BBB. There is evidence of a significant reduction in vascular and non-vascular forms of GLUT1 and GLUT3 in AD brains compared to age-matched controls. Glucose transport, as well as phosphorylation, appears to be a rate limiting step for glucose metabolism in the brain. We have reviewed the literature on glucose transport abnormalities in AD and the effect such abnormalities have on the brain.MethodPublished literature between 1st January 1946 and 1st November 2019 was identified using EMBASE and MEDLINE databases and titles and abstracts were scanned. Human studies (autopsy and imaging) and data from animal models were included while reviews, letters and cellular or molecular studies were excluded from the search.ResultAutopsy studies in AD patients show significant reductions in GLUT3 in areas of the brain closely associated with AD pathology. Patients with AD and diabetes showed greater reductions of GLUT1 and GLUT3. A longitudinal study showed significant reductions in GLUT3 levels which correlated with greater amyloid-β (Aβ) and neurofibrillary tangle pathological burden in participants with AD pathology at post-mortem but without evidence of cognitive dysfunction in their lifetime. Some studies showed increased GLUT1, with others showing reduced GLUT1, levels in AD brain. A newly recognised GLUT12 appears to be increased in AD. Animal studies showed similar results with GLUT1 and GLUT3 knockout animal models exhibiting AD pathology, while overexpression of GLUT1 or treatment with metformin decreased Aβ toxicity in a Drosophila model of AD. GLUT2 levels were increased in both human AD brain and in an animal model of AD. Imaging studies using fluorodeoxyglucose [18F]FDG with positron emission tomography (FDG-PET) in AD subjects show reductions in glucose transport and glucose metabolism in areas most affected in AD. A small randomised control trial showed anti-diabetic medications improved the glucose transport in AD subjects.ConclusionGLUTs play a significant role in AD pathology with evidence suggesting that GLUT3 reductions may precede the onset of clinical symptoms, while GLUT2 and GLUT12 may have a compensatory role. Repurposing anti-diabetic drugs shows promising results in both animal and human studies of AD.

The blood-brain barrier (BBB) regulates the transfer of solutes and essential nutrients into the brain. Growing evidence supports BBB dysfunction in a range of acute and chronic brain diseases, justifying the need for novel research and clinical tools that can non-invasively detect, characterize, and quantify BBB dysfunction in-vivo. Many approaches already exist for measuring BBB dysfunction in man using positron emission tomography and magnetic resonance imaging (e.g. dynamic contrast-enhanced MRI measurements of gadolinium leakage). This review paper focusses on MRI measurements of water exchange across the BBB, which occurs through a wide range of pathways, and is likely to be a highly sensitive marker of BBB dysfunction. Key mathematical models and acquisition methods are discussed for the two main approaches: those that utilize contrast agents to enhance relaxation rate differences between the intravascular and extravascular compartments and so enhance the sensitivity of MRI signals to BBB water exchange, and those that utilize the dynamic properties of arterial spin labelling to first isolate signal from intravascular spins and then estimate the impact of water exchange on the evolving signal. Data from studies in healthy and pathological brain tissue are discussed, in addition to validation studies in rodents.

Information on what aerosol particle types are the major sources of ice nucleating particles (INPs) in the atmosphere is needed for climate predictions. To determine which aerosol particles are the major sources of immersion-mode INPs at a coastal site in Western Canada, we investigated correlations between INP number concentrations and both concentrations of different atmospheric particles and meteorological conditions. We show that INP number concentrations are strongly correlated with the number concentrations of fluorescent bioparticles between −15 and −25 °C, and that the size distribution of INPs is most consistent with the size distribution of fluorescent bioparticles. We conclude that biological particles were likely the major source of ice nuclei at freezing temperatures between −15 and −25 °C at this site for the time period studied. At −30 °C, INP number concentrations are also well correlated with number concentrations of the total aerosol particles ≥ 0.5 μm, suggesting that non-biological particles may have an important contribution to the population of INPs active at this temperature. As we found that black carbon particles were unlikely to be a major source of ice nuclei during this study, these non-biological INPs may include mineral dust. Furthermore, correlations involving chemical tracers of marine aerosols and marine biological activity, sodium and methanesulfonic acid, indicate that the majority of INPs measured at the coastal site likely originated from terrestrial rather than marine sources. Finally, six existing empirical parameterizations of ice nucleation were tested to determine if they accurately predict the measured INP number concentrations. We found that none of the parameterizations selected are capable of predicting INP number concentrations with high accuracy over the entire temperature range investigated. This finding illustrates that additional measurements are needed to improve parameterizations of INPs and their subsequent climatic impacts.

Purpose To improve the accuracy and precision of tracer kinetic model parameter estimates for use in dynamic contrast enhanced (DCE) MRI studies of solid tumors. Theory Quantitative DCE-MRI requires an estimate of precontrast T1, which is obtained prior to fitting a tracer kinetic model. As T1 mapping and tracer kinetic signal models are both a function of precontrast T1 it was hypothesized that its joint estimation would improve the accuracy and precision of both precontrast T1 and tracer kinetic model parameters. Methods Accuracy and/or precision of two-compartment exchange model (2CXM) parameters were evaluated for standard and joint fitting methods in well-controlled synthetic data and for 36 bladder cancer patients. Methods were compared under a number of experimental conditions. Results In synthetic data, joint estimation led to statistically significant improvements in the accuracy of estimated parameters in 30 of 42 conditions (improvements between 1.8% and 49%). Reduced accuracy was observed in 7 of the remaining 12 conditions. Significant improvements in precision were observed in 35 of 42 conditions (between 4.7% and 50%). In clinical data, significant improvements in precision were observed in 18 of 21 conditions (between 4.6% and 38%). Conclusion Accuracy and precision of DCE-MRI parameter estimates are improved when signal models are fit jointly rather than sequentially. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

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Background: The microvascular contrast agent transfer constant Ktrans has shown prognostic value in cervical cancer patients treated with chemoradiotherapy. This study aims to determine whether this is explained by the contribution to Ktrans of plasma flow (Fp), vessel permeability surface-area product (PS), or a combination of both.Methods: Pre-treatment dynamic contrast-enhanced MRI (DCE-MRI) data from 36 patients were analysed using the two-compartment exchange model. Estimates of Fp, PS, Ktrans, and fractional plasma and interstitial volumes (vp and ve) were made and used in univariate and multivariate survival analyses adjusting for clinicopathologic variables tumour stage, nodal status, histological subtype, patient age, tumour volume, and treatment type (chemoradiotherapy vs radiotherapy alone). Results: In univariate analyses, Fp (HR=0.25, P=0.0095) and Ktrans (HR=0.20, P=0.032) were significantly associated with disease-free survival while PS, vp and ve were not. In multivariate analyses adjusting for clinicopathologic variables, Fp and Ktrans significantly increased the accuracy of survival predictions (P=0.0089).Conclusions: The prognostic value of Ktrans in cervical cancer patients treated with chemoradiotherapy is explained by microvascular plasma flow (Fp) rather than vessel permeability surface-area product (PS).

Detailed information on the size of ice-nucleating particles (INPs) may be useful in source identification, modeling their transport in the atmosphere to improve climate predictions, and determining how effectively or ineffectively instrumentation used for quantifying INPs in the atmosphere captures the full INP population. In this study we report immersion-mode INP number concentrations as a function of size at six ground sites in North America and one in Europe using the micro-orifice uniform-deposit impactor droplet freezing technique (MOUDI-DFT), which combines particle size-segregation by inertial impaction and a microscope-based immersion freezing apparatus. The lowest INP number concentrations were observed at Arctic and alpine locations and the highest at suburban and agricultural locations, consistent with previous studies of INP concentrations in similar environments. We found that 91 ± 9, 79 ± 17, and 63 ± 21 % of INPs had an aerodynamic diameter > 1 µm at ice activation temperatures of −15, −20, and −25 °C, respectively, when averaging over all sampling locations. In addition, 62 ± 20, 55 ± 18, and 42 ± 17 % of INPs were in the coarse mode (> 2.5 µm) at ice activation temperatures of −15, −20, and −25 °C, respectively, when averaging over all sampling locations. These results are consistent with six out of the nine studies in the literature that have focused on the size distribution of INPs in the atmosphere. Taken together, these findings strongly suggest that supermicron and coarse-mode aerosol particles are a significant component of the INP population in many different ground-level environments. Further size-resolved studies of INPs as a function of altitude are required since the size distribution of INPs may be different at high altitudes due to size-dependent removal processes of atmospheric particles.

Star light suppression technologies to find and characterize faint exoplanets include internal coronagraph instruments as well as external star shade occulters. Currently, the NASA WFIRST-AFTA mission study includes an internal coronagraph instrument to find and characterize exoplanets. Various types of masks could be employed to suppress the host star light to about 10 -9 level contrast over a broad spectrum to enable the coronagraph mission objectives. Such masks for high contrast internal coronagraphic imaging require various fabrication technologies to meet a wide range of specifications, including precise shapes, micron scale island features, ultra-low reflectivity regions, uniformity, wave front quality, achromaticity, etc. We present the approaches employed at JPL to produce pupil plane and image plane coronagraph masks by combining electron beam, deep reactive ion etching, and black silicon technologies with illustrative examples of each, highlighting milestone accomplishments from the High Contrast Imaging Testbed (HCIT) at JPL and from the High Contrast Imaging Lab (HCIL) at Princeton University. We also present briefly the technologies applied to fabricate laboratory scale star shade masks.

Optical devices with features exhibiting ultra low reflectivity on the order of 10-7 specular reflectance in the visible spectrum are required for coronagraph instruments and some spectrometers employed in space research. Nanofabrication technologies have been developed to produce such devices with various shapes and feature dimensions to meet these requirements. Infrared reflection is also suppressed significantly with chosen wafers and processes. Particularly, devices with very high (>0.9) and very low reflectivity (

To improve the accuracy and precision of tracer kinetic model parameter estimates for use in dynamic contrast enhanced (DCE) MRI studies of solid tumors.Quantitative DCE-MRI requires an estimate of precontrast T1 , which is obtained prior to fitting a tracer kinetic model. As T1 mapping and tracer kinetic signal models are both a function of precontrast T1 it was hypothesized that its joint estimation would improve the accuracy and precision of both precontrast T1 and tracer kinetic model parameters.Accuracy and/or precision of two-compartment exchange model (2CXM) parameters were evaluated for standard and joint fitting methods in well-controlled synthetic data and for 36 bladder cancer patients. Methods were compared under a number of experimental conditions.In synthetic data, joint estimation led to statistically significant improvements in the accuracy of estimated parameters in 30 of 42 conditions (improvements between 1.8% and 49%). Reduced accuracy was observed in 7 of the remaining 12 conditions. Significant improvements in precision were observed in 35 of 42 conditions (between 4.7% and 50%). In clinical data, significant improvements in precision were observed in 18 of 21 conditions (between 4.6% and 38%).Accuracy and precision of DCE-MRI parameter estimates are improved when signal models are fit jointly rather than sequentially. Magn Reson Med 76:1270-1281, 2016. © 2015 Wiley Periodicals, Inc.

Following developmental attachment theory, we predicted a path in which nurturing parents affect young adults' self-concepts and self-esteem, which in turn predicts the image of a nurturing God. To ascertain how images of parents and images of self predict God images, 132 young adults aged 18-22 (M = 19) completed the Tennessee Self-Concept Scale, and a six-item measure of God's perceived involvement in their lives (religiosity scale). In a follow-up interview, they rated their parents, God, and selves on scales of closeness, nurturing, power, and punishing/judging. For men, mothers were responsible, more than fathers, for creating a climate for sons' self-esteem through nurturance and discipline, which in turn contributed to seeing God as nurturing, feeling close to God, and being more religious. For women, mothers and fathers created a model of nurturance and power, which contributed to seeing God as nurturing and powerful. Punishing/judging parents directly affected punishing/judging God images in these young adults. Men perceived God to be more punishing/judging than did women, while women perceived God to be more nurturing. Even in adulthood, parents, especially mothers, continue to exert influences on young adults' faith and images of God.

This study explored children's perceived distance from and involvelnent with God as related to (a) parents' involvelnent in parenting, (b) children's perceptions of God's gender, and (c) God's involvelnent in problematic situations. Forty-nine children ages 4-10 were interviewed and their parents colnpleted questionnaires. Children who were older, or whoseparents were less involved, perceived God as closer; when children perceived God as male, boys perceived God as closer; when children per- ceived God as female or not male, girls perceived God as closer. Attachment (Kirpatrick & Shaver, 1990) and gender (Chodorow, 1978; Gilligan & Wiggins, 1988) theories are used to interpret the results.

Masks for high contrast internal and external coronagraphic imaging require a variety of masks depending on different architectures to suppress star light. Various fabrication technologies are required to address a wide range of needs including gradient amplitude transmission, tunable phase profiles, ultra-low reflectivity, precise small scale features, and low-chromaticity. We present the approaches employed at JPL to produce pupil plane and image plane coronagraph masks, and lab-scale external occulter type masks by various techniques including electron beam, ion beam, deep reactive ion etching, and black silicon technologies with illustrative examples of each. Further development is in progress to produce circular masks of various kinds for obscured aperture telescopes.

The authors report here on a new technique, combining the atomic precision of molecular beam epitaxy and atomic layer deposition, to fabricate back illuminated silicon CCD detectors that demonstrate world record detector quantum efficiency (>50%) in the near and far ultraviolet (155–300 nm). This report describes in detail the unique surface engineering approaches used and demonstrates the robustness of detector performance that is obtained by achieving atomic level precision at key steps in the fabrication process. The characterization, materials, and devices produced in this effort will be presented along with comparison to other approaches.

The Lower and Middle Jurassic Laberge Group consists of conglomerates, sandstone turbidites and shales that were deposited within a deep-water fore-arc trough. The conglomerate of the Laberge Group accounts for most of the preserved basin-fill within the Whitehorse Trough, and was derived from exhumed plutons, comprising multiple intrusives and extrusives of varying composition, that formed an island arc terrane in the western margin of the Whitehorse Trough. The island arc complex docked against North America in the Late Triassic and the Laberge conglomerates record the sedimentary and unroofing processes that predominated in the intervening trough during arc-continent collision and accretion. Coarse-grained sediment shed from the arc constructed fan deltas along the western margin of the basin. These deposits were resedimented into deep water (below wave base) through shelf-break chutes and submarine channels. Gravel was emplaced within submarine channel-and-fan complexes; sandy turbidites formed lobes along the margins of the gravelly submarine fans and muds were deposited in inter-fan settings. Stratigraphic change within the Laberge Group reflect: (1) collision of the arc, with plutonism and resultant uplift, and subsequent unroofing of the arc highlands; and (2) overlap of coarse-grained deep-water fans across the shelf as a response of crustal flexure to collisional tectonism and/or a eustatic sea-level change. Later deposition of the overlying Tantalus Formation records a diachronous overlap of successor paralic-alluvial deposits over the Laberge sediments associated with final-stage accretion events in the Whitehorse Trough.

Background:Hikikomori (acute social withdrawal) is a social issue in Japan that affects both the society and the lives of the individual sufferers.Aims:This study aims to connect attachment theory and hikikomori by using a culturally sensitive psychosocial developmental model that outlines the various stages of attachment throughout the developmental years.Method:Twenty–four hikikomori sufferers and 60 comparison group participants were given questionnaires assessing parent and peer relationships, temperament and school experiences.Results:We found the hikikomori participants had a higher incidence of ambivalent attachment, reported more parental and peer rejection and bullying, and expressed greater temperamental shyness. Path analysis supported our developmental model. We found that shy temperament and parental rejection predicted ambivalent attachment, which when coupled with peer rejection predicted hikikomori. Our model implies that treatment and prevention may require attention to attachment insecurities in early childhood, peer rejection in middle childhood and/or early adolescence.Conclusion:We believe it is helpful in understanding hikikomori to first understand how the attachment system balances security with exploration and the anxiety associated with novelty and challenge. Finally, we examine implications of the model for intervention, treatment and future research.

The Princeton occulter testbed uses long-distance propagation with a diverging beam and an optimized occulter mask to simulate the performance of external occulters for finding extrasolar planets. We present new results from the testbed in both monochromatic and broadband light. In addition, we examine sensing and control of occulter position using out-of-band spectral leak around the occulter and occulter position tolerancing. These results are validated by numerical simulations of propagation through the system.

We report on development of antireflective coatings optimized for a telescope detector in a UV spectrograph. We discuss progress in the development of a CCD with theoretical QE greater than 60% from 100 to 300nm.

In this paper, we report the latest results on our development of delta-doped, thinned, back-illuminated CMOS imaging arrays. As with charge-coupled devices, thinning and back-illumination are essential to the development of high performance CMOS imaging arrays. Problems with back surface passivation have emerged as critical to the prospects for incorporating CMOS imaging arrays into high performance scientific instruments, just as they did for CCDs over twenty years ago. In the early 1990's, JPL developed delta-doped CCDs, in which low temperature molecular beam epitaxy was used to form an ideal passivation layer on the silicon back surface. Comprising only a few nanometers of highly-doped epitaxial silicon, delta-doping achieves the stability and uniformity that are essential for high performance imaging and spectroscopy. Delta-doped CCDs were shown to have high, stable, and uniform quantum efficiency across the entire spectral range from the extreme ultraviolet through the near infrared. JPL has recently bump-bonded thinned, delta-doped CMOS imaging arrays to a CMOS readout, and demonstrated imaging. Delta-doped CMOS devices exhibit the high quantum efficiency that has become the standard for scientific-grade CCDs. Together with new circuit designs for low-noise readout currently under development, delta-doping expands the potential scientific applications of CMOS imaging arrays, and brings within reach important new capabilities, such as fast, high-sensitivity imaging with parallel readout and real-time signal processing. It remains to demonstrate manufacturability of delta-doped CMOS imaging arrays. To that end, JPL has acquired a new silicon MBE and ancillary equipment for delta-doping wafers up to 200mm in diameter, and is now developing processes for high-throughput, high yield delta-doping of fully-processed wafers with CCD and CMOS imaging devices.

An occulter is used in conjunction with a separate telescope to suppress the light of a distant star. To demonstrate the performance of this system, we are building an occulter experiment in the laboratory at Princeton. This experiment will use an etched silicon mask as the occulter, with some modifications to try to improve the performance. The occulter is illuminated by a diverging laser beam to reduce the aberrations from the optics before the occulter. We present the progress of this experiment and expectations for future work.

NASA WFIRST-AFTA mission study includes a coronagraph instrument to find and characterize exoplanets. Various types of masks could be employed to suppress the host starlight to about 10−9 level contrast over a broad spectrum to enable the coronagraph mission objectives. Such masks for high-contrast internal coronagraphic imaging require various fabrication technologies to meet a wide range of specifications, including precise shapes, micron scale island features, ultralow reflectivity regions, uniformity, wave front quality, and achromaticity. We present the approaches employed at JPL to produce pupil plane and image plane coronagraph masks by combining electron beam, deep reactive ion etching, and black silicon technologies with illustrative examples of each, highlighting milestone accomplishments from the High Contrast Imaging Testbed at JPL and from the High Contrast Imaging Lab at Princeton University.

Mediastinitis and sternal wound dehiscence are devastating and life-threatening complications of median sternotomy incision. Ten consecutive patients between July 2001 and May 2005 were diagnosed with sternal wound infection and dehiscence following median sternotomy. Patients were managed by precise debridement and wound excision in the operating room and then dressed with vacuum-assisted closure device. Intravenous antibiotics were prescribed for wound and blood culture microbiological sensitivity. When wounds were bacteriologically controlled, patients returned to the operating room for definitive closure using rigid sternal plating. All patients were extubated postoperatively. No patients died. Average total hospital stay was 21 days. The pectoralis advancement flap was exclusively used for soft tissue reconstruction in 7 patients. There were 2 cases of chronic superficial sternal infection requiring plate removal; however, bony union of the sternum was achieved in all patients. This treatment algorithm provides a useful management strategy for patients with complicated median sternotomy.

The Jet Propulsion Laboratory has, for several years now, maintained a thermopile detector array program to address NASA application niches. An established process exists for producing thermopile single detectors and linear arrays using Bi-Te and Bi-Sb-Te thermoelectric materials and bulk silicon micromachining techniques. The detectors and arrays typically have D* values of 1-2 /spl times/ 10/sup 9/ cmHz/sup 1/2//W in vacuum. Arrays are being fabricated for the Mars Climate Sounder instrument on NASA's Mars Reconnaissance Orbiter spacecraft, to launch in 2005. A second effort is seeking to develop high performance two-dimensional arrays of thermopile detectors using surface micromachining to fabricate pixels on a substrate containing readout electronics.

Thermal detectors, while typically less sensitive than quantum detectors, are useful when the combination of long wavelength signals and relatively high temperature operation makes quantum detectors unsuitable. Thermal detectors are also appropriate in applications requiring flat spectral response over a broad wavelength range. JPL produces thermopile detectors and linear arrays to meet space science requirements in these categories. Thermopile detectors and arrays are currently being fabricated for two space applications. The first is the Mars Climate Sounder (MCS) instrument, to fly on the Mars Reconnaissance Orbiter mission, scheduled to launch in 2005. MCS is an atmospheric limb sounder utilizing nine 21-element thermopile arrays. The second application is the Earth Radiation Budget Suite (ERBS), part of the National Polar Orbiting Environmental Satellite System (NPOESS). This instrument measures upwelling radiation from the earth in the spectral range 0.3-100 μm.

The structure and function of the oviducts of members of the three Orders of the Class Amphibia (Anura, frogs and toads; Urodela, salamanders and newts; Gymnophiona, caecilians) are well described for only a few species. Further, the majority of such descriptions relate only to temperate species that breed in water, lay their eggs there, and have free-living larvae, the presumed ancestral condition of oviparity. Many species of amphibians have derived reproductive modes. Such modes include breeding terrestrially and arboreally, making foam nests, parental transport of eggs and/or tadpoles, direct development (copulating on land, laying the eggs in terrestrial sites, fully metamorphosed juveniles hatching, obviating the free-living larval stage). Other derived modes are ovoviviparity (developing embryos retained in the oviducts, born at a diversity stages of development, no maternal nutrition in addition to yolk) and viviparity (oviductal retention of developing young, maternal nutrition after yolk is resorbed, young born as fully metamorphosed juveniles). The amphibian oviduct is regionally differentiated to secrete varying numbers of layers of material around each egg, which function in fertilization, etc.; it is responsive to endocrine output and environmental mediation during the reproductive cycle; and it maintains developing embryos in some members of all three orders, some with oviductal epithelial secretion of nutrients. However, little is known of the structure-function relationships of the oviduct in species with derived reproductive modes. A comparison of oviduct morphology, function, endocrinology, ecology and phylogeny in amphibians with diverse reproductive modes suggests a number of highly productive avenues of investigation.

Flip chip hybridization, also known as bump bonding, is a packaging technique for microelectronic devices which directly connects an active element or a detector to a substrate readout face down, eliminating the need for wire bonding. Indium bump technology has been a part of hybridization for many years and has been extensively employed in the infrared imager industry. However, obtaining a reliable, high yield process for high density patterns of bumps can be quite difficult in part due to the tendency of the indium bumps to oxidize during exposure to air. In this study, plasma, thermal, and wet chemical methods were screened to determine their ability to remove indium oxide from indium bumps. A novel two-step plasma process using methane, argon, and hydrogen was developed that removes indium oxide from indium bumps after prolonged air exposure while maintaining a low sample temperature. This method was tested by fabricating a fully hybridized scientific grade visible complementary metal oxide semiconductor detector and imaging a standard test pattern.