DUAL-PARTICLE DOSEMETER BASED ON ORGANIC SCINTILLATOR.

Traditionally available handheld dosemeters are generally sensitive to only one type of radiation: neutrons or photons. Some dosemeters also rely on very specific attenuation correlations between response and dose, are not scalable in size and multiple dosemeters are required to characterise mixed-particle fields. The research presented here serves as a proof-of-concept for a method to simultaneously measure dose rates from neutrons and photons using a particle discriminating organic scintillation detector without the need for spectral deconvolution. The method was compared with traditional instruments and to simulation. Isotopic photon dose rates measured with this method were within 4% of simulated truth, whereas fission spectrum neutron dose rates were measured within 21%. Measurements of dose rates from both particles agree with simulated truth better than traditional instruments. This new method allows for measurement of dose equivalent from both neutrons and photons with a single instrument and no reliance on spectral deconvolution.

A Framework for Climate Change-Related Research to Inform Environmental Protection.

A critical charge for science to inform environmental protection is to characterize the risks associated with climate change, to support development of appropriate responses. The nature of climate change, however, presents significant challenges that must be overcome to do so, including the need for integration and synthesis across the many disciplines that contain knowledge relevant for achieving environmental protection goals. This paper describes an interdisciplinary research framework organized around three "Science Challenges" that directly respond to the needs of environmental protection organizations. Broadly, these Science Challenges refer to the research needed to: inform actions to enhance resilience across a broad range of environmental and social stresses to environmental management endpoints; actions to limit GHG emissions and slow the underlying rate of climate change; and the transition to sustainability across the full spectrum of climate change impacts and solutions; all as situated within an overarching risk management perspective. These Challenges span all media and systems critical to effective environmental protection, highlighting the cross-cutting nature of climate change and the need to address its impacts across systems and places. While this framework uses EPA's programs as an illustrative example, the research directions articulated herein are broadly applicable across the spectrum of environmental protection organizations. Going forward, we recommend that climate-related research to inform environmental protection efforts should accelerate its evolution toward research that is inherently cross-media and cross-scale; explicitly considers the social dimensions of change; and focuses on designing solutions to the specific risks climate change poses to the environment and society.

ClonEvol: clonal ordering and visualization in cancer sequencing.

BACKGROUND: Reconstruction of clonal evolution is critical for understanding tumor progression and implementing personalized therapies. This is often done by clustering somatic variants based on their cellular prevalence estimated via bulk tumor sequencing of multiple samples. The clusters, consisting of the clonal marker variants, are then ordered based on their estimated cellular prevalence to reconstruct clonal evolution trees, a process referred to as 'clonal ordering'. However, cellular prevalence estimate is confounded by statistical variability and errors in sequencing/data analysis, and therefore inhibits accurate reconstruction of the clonal evolution. This problem is further complicated by intra- and inter-tumor heterogeneity. Furthermore, the field lacks a comprehensive visualization tool to facilitate the interpretation of complex clonal relationships. To address these challenges we developed ClonEvol, a unified software tool for clonal ordering, visualization, and interpretation. MATERIALS AND METHODS: ClonEvol uses a bootstrap resampling technique to estimate the cellular fraction of the clones and probabilistically models the clonal ordering constraints to account for statistical variability. The bootstrapping allows identification of the sample founding- and sub-clones, thus enabling interpretation of clonal seeding. ClonEvol automates the generation of multiple widely used visualizations for reconstructing and interpreting clonal evolution. RESULTS: ClonEvol outperformed three of the state of the art tools (LICHeE, Canopy and PhyloWGS) for clonal evolution inference, showing more robust error tolerance and producing more accurate trees in a simulation. Building upon multiple recent publications that utilized ClonEvol to study metastasis and drug resistance in solid cancers, here we show that ClonEvol rediscovered relapsed subclones in two published acute myeloid leukemia patients. Furthermore, we demonstrated that through noninvasive monitoring ClonEvol recapitulated the emerging subclones throughout metastatic progression observed in the tumors of a published breast cancer patient. CONCLUSIONS: ClonEvol has broad applicability for longitudinal monitoring of clonal populations in tumor biopsies, or noninvasively, to guide precision medicine. AVAILABILITY: ClonEvol is written in R and is available at https://github.com/ChrisMaherLab/ClonEvol.

The relationship between particle morphology and rheological properties in injectable nano-hydroxyapatite bone graft substitutes.

Biomaterials composed of hydroxyapatite (HA) are currently used for the treatment of bone defects resulting from trauma or surgery. However, hydroxyapatite supplied in the form of a paste is considered a very convenient medical device compared to the materials where HA powder and liquid need to be mixed immediately prior to the bone treatment during surgery. In this study we have tested a series of hydroxyapatite (HA) pastes with varying microstructure and different rheological behaviour to evaluate their injectability and biocompatibility. The particle morphology and chemical composition were evaluated using HRTEM, XRD and FTIR. Two paste-types were compared, with the HA particles of both types being rod shaped with a range of sizes between 20 and 80nm while differing in the particle aspect ratio and the degree of roundness or sharpness. The pastes were composed of pure HA phase with low crystallinity. The rheological properties were evaluated and it was determined that the pastes behaved as shear-thinning, non-Newtonian liquids. The difference in viscosity and yield stress between the two pastes was investigated. Surprisingly, mixing of these pastes at different ratios did not alter viscosity in a linear manner, providing an opportunity to produce a specific viscosity by mixing the two materials with different characteristics. Biocompatibility studies suggested that there was no difference in vitro cell response to either paste for primary osteoblasts, bone marrow mesenchymal stromal cells, osteoblast-like cells, and fibroblast-like cells. This class of nanostructured biomaterial has significant potential for use as an injectable bone graft substitute where the properties may be tailored for different clinical indications.

Preparation and Antibacterial Properties of Silver-Doped Nanoscale Hydroxyapatite Pastes for Bone Repair and Augmentation.

The treatment of deep bone infections remains a significant challenge in orthopaedic and dental surgery. The relatively recent commercial manufacture of nanoscale hydroxyapatite has provided surgeons with an injectable biomaterial that promotes bone tissue regeneration, and with further modification it may be possible to incorporate antimicrobial properties into these devices. Silver-doped nanoscale hydroxyapatite pastes (0, 2, 5 and 10 mol.% silver) were prepared using a rapid mixing method. When the process was modified to prepare a 10 mol.% silver-doped material, silver phosphate was detected in addition to nanoscale hydroxyapatite. Thermal decomposition occurred more readily with greater silver content following calcination at 1000 °C for 2 h. Silver-doped nanoscale hydroxyapatite pastes showed antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa in a dose dependent manner using both agar diffusion assays and suspension cultures. It was concluded that the enhanced antibacterial activity of the silver-doped pastes was due to the action of diffusible silver ions. Based on these results, silver-doped nanoscale hydroxyapatite pastes represent a highly promising new biomaterial system for the prevention and treatment of deep infections in bone tissue.

Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy.

Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.

Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use.

Memories associated with drug use increase vulnerability to relapse in substance use disorder (SUD), and there are no pharmacotherapies for the prevention of relapse. Previously, we reported a promising finding that storage of memories associated with methamphetamine (METH), but not memories for fear or food reward, is vulnerable to disruption by actin depolymerization in the basolateral amygdala complex (BLC). However, actin is not a viable therapeutic target because of its numerous functions throughout the body. Here we report the discovery of a viable therapeutic target, nonmuscle myosin IIB (NMIIB), a molecular motor that supports memory by directly driving synaptic actin polymerization. A single intra-BLC treatment with Blebbistatin (Blebb), a small-molecule inhibitor of class II myosin isoforms, including NMIIB, produced a long-lasting disruption of context-induced drug seeking (at least 30 days). Further, postconsolidation genetic knockdown of Myh10, the heavy chain of the most highly expressed NMII in the BLC, was sufficient to produce METH-associated memory loss. Blebb was found to be highly brain penetrant. A single systemic injection of the compound selectively disrupted the storage of METH-associated memory and reversed the accompanying increase in BLC spine density. This effect was specific to METH-associated memory, as it had no effect on an auditory fear memory. The effect was also independent of retrieval, as METH-associated memory was disrupted 24 h after a single systemic injection of Blebb delivered in the home cage. Together, these results argue for the further development of small-molecule inhibitors of NMII as potential therapeutics for the prevention of SUD relapse triggered by drug associations.

Spatially weighted functional clustering of river network data.

Incorporating spatial covariance into clustering has previously been considered for functional data to identify groups of functions which are similar across space. However, in the majority of situations that have been considered until now the most appropriate metric has been Euclidean distance. Directed networks present additional challenges in terms of estimating spatial covariance due to their complex structure. Although suitable river network covariance models have been proposed for use with stream distance, where distance is computed along the stream network, these models have not been extended for contexts where the data are functional, as is often the case with environmental data. The paper develops a method of calculating spatial covariance between functions from sites along a river network and applies the measure as a weight within functional hierarchical clustering. Levels of nitrate pollution on the River Tweed in Scotland are considered with the aim of identifying groups of monitoring stations which display similar spatiotemporal characteristics.

Moderate drop in water table increases peatland vulnerability to post-fire regime shift.

Northern and tropical peatlands represent a globally significant carbon reserve accumulated over thousands of years of waterlogged conditions. It is unclear whether moderate drying predicted for northern peatlands will stimulate burning and carbon losses as has occurred in their smaller tropical counterparts where the carbon legacy has been destabilized due to severe drainage and deep peat fires. Capitalizing on a unique long-term experiment, we quantify the post-wildfire recovery of a northern peatland subjected to decadal drainage. We show that the moderate drop in water table position predicted for most northern regions triggers a shift in vegetation composition previously observed within only severely disturbed tropical peatlands. The combined impact of moderate drainage followed by wildfire converted the low productivity, moss-dominated peatland to a non-carbon accumulating shrub-grass ecosystem. This new ecosystem is likely to experience a low intensity, high frequency wildfire regime, which will further deplete the legacy of stored peat carbon.

Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells.

HOX genes are highly expressed in many acute myeloid leukemia (AML) samples, but the patterns of expression and associated regulatory mechanisms are not clearly understood. We analyzed RNA sequencing data from 179 primary AML samples and normal hematopoietic cells to understand the range of expression patterns in normal versus leukemic cells. HOX expression in AML was restricted to specific genes in the HOXA or HOXB loci, and was highly correlated with recurrent cytogenetic abnormalities. However, the majority of samples expressed a canonical set of HOXA and HOXB genes that was nearly identical to the expression signature of normal hematopoietic stem/progenitor cells. Transcriptional profiles at the HOX loci were similar between normal cells and AML samples, and involved bidirectional transcription at the center of each gene cluster. Epigenetic analysis of a subset of AML samples also identified common regions of chromatin accessibility in AML samples and normal CD34(+) cells that displayed differences in methylation depending on HOX expression patterns. These data provide an integrated epigenetic view of the HOX gene loci in primary AML samples, and suggest that HOX expression in most AML samples represents a normal stem cell program that is controlled by epigenetic mechanisms at specific regulatory elements.

Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia.

Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single-nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

Mutual information as a measure of image quality for 3D dynamic lung imaging with EIT.

We report on a pilot study of dynamic lung electrical impedance tomography (EIT) at the University of Manchester. Low-noise EIT data at 100 frames per second were obtained from healthy male subjects during controlled breathing, followed by magnetic resonance imaging (MRI) subsequently used for spatial validation of the EIT reconstruction. The torso surface in the MR image and electrode positions obtained using MRI fiducial markers informed the construction of a 3D finite element model extruded along the caudal-distal axis of the subject. Small changes in the boundary that occur during respiration were accounted for by incorporating the sensitivity with respect to boundary shape into a robust temporal difference reconstruction algorithm. EIT and MRI images were co-registered using the open source medical imaging software, 3D Slicer. A quantitative comparison of quality of different EIT reconstructions was achieved through calculation of the mutual information with a lung-segmented MR image. EIT reconstructions using a linear shape correction algorithm reduced boundary image artefacts, yielding better contrast of the lungs, and had 10% greater mutual information compared with a standard linear EIT reconstruction.

The association of weather and bathing water quality on the incidence of gastrointestinal illness in the west of Scotland.

SUMMARY: The associations with weather and bathing water quality on infectious intestinal disease (IID) were investigated using data from two Scottish NHS Board areas. Monthly counts of viral and non-viral gastrointestinal infections were modelled as a smooth function of temperature, relative humidity and average monthly counts of faecal indicator organisms, respectively, adjusting for season and long-term trend effects. Strong seasonal patterns were observed for each group of pathogens. Peak viral gastrointestinal infection was in May while that of non-viral gastrointestinal infections was in July. A statistically significant negative association existed between weather (temperature and humidity) and viral infection. Average levels of non-viral gastrointestinal infections increased as temperature and relative humidity increased. Increasing levels of faecal indicator organisms in bathing waters were also associated with an increase in the average number of viral and non-viral gastrointestinal infections at the ecological level. Future climate change and prolonged precipitation events may result in increasing levels of faecal indicator organisms in bathing waters leading to likely increases in IIDs.

The effect of denture design and fixatives on the retention of mandibular complete dentures tested on a novel in-vitro edentulous model.

The aim of this study was to evaluate the effect of the design (extension and adaptation) of a mandibular complete acrylic denture and the use of denture adhesives using a novel in-vitro edentulous model. The model is a highly anatomically accurate replica based on a moderately resorbed human mandibular edentulous arch. The model has been designed and fabricated by means of an elaborate clinical and technical process that employs synthetic elastomeric materials with properties that attempts to reproduce in-vitro characteristics of the soft tissues overlying the ridges and immediate reflected tissues. This model was used to measure and compare the retention of mandibular dentures ofvarying designs (well-fitting, over- and under-extended) with and without the aid of denture fixatives. Retention tests were conducted with different volumes of artificial saliva at a cross head speed of 50 mm/min with 4 equidistant holding points on the denture occlusal surface, using a universal tensile testing machine in an axial pull direction. The effect of three denture adhesives on denture retention was also tested on the same denture types at different times over a period of 5 hours and beyond. The in-vitro model presented can be effectively used to test the retention of mandibular complete dentures. The speed of dislodgement force and amount of saliva are important variables in mandibular denture retention. The retention of well-fitting dentures was statistically higher than that of ill-fitting dentures. A significantly higher retention force was needed to dislodge mandibular dentures (well and ill-fitting dentures) when using a denture adhesive.

Clonal diversity of recurrently mutated genes in myelodysplastic syndromes.

Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ≤0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.

The effect of carbamide peroxide treatment on metal ion release from dental amalgam.

OBJECTIVES: There is concern that hydrogen peroxide generated by tooth bleaching agents may cause enhanced metal ion release (including mercury) from dental amalgam following contact. The aim of this in vitro study was therefore to investigate the effect of a carbamide peroxide (CP) based tooth bleaching gel on metal ion release from dental amalgam. METHODS: Dental amalgam discs were prepared according to the manufacturers' instructions. These were treated with either a 10% carbamide peroxide (CP) gel or a 0% CP gel for 24h. Discs were carefully wiped with cotton wool before immersion in distilled water (20 ml) for 24h at 37 degrees C. Following immersion, water samples were taken for metal ion release determination (Ag, Cu, Hg and Sn) using inductively coupled plasma mass spectrometry methods. The specimens were further evaluated for surface changes using scanning electron microscopy (SEM) and Talysurf surface roughness measurements. RESULTS: The differences in concentration of metal ions released after treatment with the 10% CP gel and a placebo gel treatment were not statistically significant (p>0.05). For example, mercury release following treatment with the 10% CP gel and the 0% CP gel was found to be 1.17(0.5) and 0.57(0.1)microgcm(-2), respectively. Roughness measurements for samples treated with the 10% CP gel and 0% CP gel were 2.23(0.47) and 1.74(0.16)microm, respectively, again showing no significant difference between groups (p>0.05). SEM images of the amalgam surfaces showed no apparent differences between treatments. SIGNIFICANCE: Treatment with a 10% CP gel did not significantly enhance subsequent metal ion release from dental amalgams compared to a control gel, contradicting previously published studies.

Frontotemporal dementia progresses to death faster than Alzheimer disease.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a common cause of non-Alzheimer dementia, but its natural history and the factors related to mortality in affected patients are not well understood. METHODS: This retrospective, longitudinal study compared survival in FTLD (n = 177) with Alzheimer disease (AD; n = 395). Hazards analysis investigated the contribution of various demographic, neuropsychiatric, and neuropsychological variables and associated neurologic and neuropathologic findings. RESULTS: The frontotemporal dementia (FTD) subtype of FTLD progressed faster than AD (median survival from retrospectively determined symptom onset, 8.7 +/- 1.2 vs 11.8 +/- 0.6 years, p < 0.0001; median survival from initial clinic presentation, 3.0 +/- 0.5 vs 5.7 +/- 0.1 years, p < 0.0001). Survival was similarly reduced in the related conditions corticobasal degeneration and progressive supranuclear palsy. Survival in the semantic dementia subtype of FTLD (11.9 +/- 0.2 years from onset and 5.3 +/- 0.4 years from presentation), however, was significantly longer than in FTD and did not differ from AD. Hazards analysis to determine factors affecting survival in FTLD showed no effect of age at onset, sex, education, family history, or neuropsychiatric profile. Among neuropsychological measures examined, impaired letter fluency had a significant association with reduced survival. Associated ALS significantly reduced survival in FTLD. The presence of tau-positive inclusions was associated with the slowest progression. CONCLUSIONS: Frontotemporal lobar degeneration progresses more rapidly than Alzheimer disease, and the fastest-progressing cases are those with the frontotemporal dementia clinical subtype, coexisting motor neuron disease, or tau-negative neuropathology.