Background and hypothesis Gordon syndrome (also pseudohypoaldosteronism type II (PHAII) or Familial Hyperkalemia with Hypertension (FHHt)) is a genetic condition characterised by hypertension, hyperkalaemia, hyperchloraemic metabolic acidosis and hypercalciuria caused by an activation of the thiazide-sensitive sodium-chloride cotransporter (NCC, encoded by SLC12A3) in the distal convoluted tubule of the kidney. Thiazides rescue the electrolyte and metabolic abnormalities however, it is not known whether they decrease urinary calcium excretion, nephrolithiasis and low bone mineral density. Methods We examined a cohort of 11 patients with genetically confirmed FHHt. Biochemical, radiological, and clinical data was obtained in patients before and after thiazide treatment. All patients gave informed consent. Results Among the FHHt cohort 5 of the 11 patients were female. 7 patients had heterozygous pathogenic variants in KLHL3, 3 patients had variants in WNK4, and one had a variant in WNK1. At baseline, only 1 patient was hypertensive, all patients were hyperkalemic, whereas only 40% of patients had low serum bicarbonate and increased urinary calcium excretion. 50% of patients also had low bone mineral density (either osteopenia or osteoporosis) and 1 patient had bilateral nephrolithiasis. 6 patients were treated with thiazide diuretic and therefore were suitable for comparison between pre and post treatment biochemistry and imaging data. While both serum and urinary biochemistry was completely reverted after thiazide treatment, bone mineral density had a worsening trend. 1 patient presented with bilateral nephrolithiasis after thiazide treatment. Conclusion We demonstrate that thiazide treatment normalizes serum and urinary biochemistry. Thiazide treatment therefore has clinical utility even if hypertension or hyperkalaemia are not problematic. According to our study, thiazide treatment does not seem to revert loss of bone mineral density, however, whether thiazides have an impact in nephrolithiasis is less clear and our results may require larger samples.### Competing Interest StatementSBW has received honoraria from Advicenne Pharmaceuticals. VDA received consultant fees from Allena Pharmaceuticals. PMF received consultant fees and grant/other support from Allena Pharmaceuticals, Alnylam, Amgen, AstraZeneca, Bayer, Gilead, Novo Nordisk, Otsuka Pharmaceuticals, Rocchetta, Vifor Fresenius, and royalties as an author for UpToDate.### Funding StatementThis research was funded in whole, or in part by the Wellcome Trust [Grant number 110282/Z/15/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was assessed by the Health Research Authority National Research Ethcis Service Ethics Committee of London-Bloomsbury (reference 05/Q0508/6). Ethical Approval was given.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

The evaluation of 3D printed osteological materials has highlighted the difficulties associated with accurately representing fine surface details on printed bones. Moreover, there is an increasing need for reconstructions to be demonstrably accurate and reliable for use in the criminal justice system. The aim of this study was to assess the surface quality of 3D prints (n = 9) that presented with micromorphological alterations from trauma, taphonomy and pathology processes. The archaeological bones were imaged using micro-CT scanning and 3D printed with selective laser sintering (SLS) printing. A multi-method experimental approach subsequently identified: (1) the 3D printed bones to be metrically accurate to within 1.0 mm; (2) good representation of micromorphological surface features overall, albeit with some loss of intricate details, depths, and fine textures that can be important for visual processing; (3) five of the nine 3D printed bones were quantitatively scored as accurate using the visual comparison method; and, (4) low mesh comparison distances (± 0.2 mm) between the original models and the digitised 3D print models. The findings offer empirical data that can be used to underpin 3D printed reconstructions of exhibits for use in courts of law. In addition, an adaptable pathway was presented that can be used to assess 3D print accuracy in future reconstructions.

Drug crystallisation in the skin is recognised as a significant problem in topical and transdermal drug delivery. Our recent investigations provided new evidence of drug crystallisation in the skin, however, confirming the precise location of crystals remains challenging. Of note, most approaches used have required disruption of the membrane by tape stripping, with crystal detection limited to the superficial skin layers. Hence, a non-destructive method for complete spatial resolution of crystallised drug in skin is still lacking. In this communication, we report the application of X-ray micro-computed tomography (microCT) to examine drug crystallisation in mammalian skin ex vivo. Permeation studies of a saturated solution of diclofenac sodium were conducted in porcine skin; subsequently, tissue samples were scanned using microCT to generate 2D and 3D maps. A layer of drug crystals was observed on the skin surface; microCT maps also confirmed the distribution of drug crystals up to a skin depth of 0.2 - 0.3 mm. MicroCT also allowed the identification of drug crystallisation as a distinct and confirmed event in the skin and as an extension from drug crystals formed on the skin. These preliminary results confirm the potential of microCT to study this important phenomenon in topical and transdermal drug delivery.

Energy dispersive X‐ray diffraction (EDXRD) and maximum likelihood principal component analysis multivariate curve resolution‐alternating least squares (MLPCA‐MCR‐ALS) with correlation constraint were used to quantify the composition of packaged pharmaceutical formulations. Recorded EDXRD profiles from unpackaged and packaged samples of ternary mixtures were modelled together in order to recover the concentrations as well as the pure profiles of the constituent compounds. MLPCA was used as a data pretreatment step to MCR‐ALS, accounting for the high noise and nonconstant variance observed in the EDXRD profiles and was shown to improve the resolution accuracy of MCR‐ALS for the data set. Local correlation constraints were applied in the MCR‐ALS procedure in order to model unpackaged and packaged samples simultaneously while accounting for the matrix effect of the packaging materials. The composition of the formulations was estimated with root‐mean‐square error of prediction for each component, including paracetamol, being approximately 2.5 %w/w for unpackaged and packaged samples. Paracetamol concentration was resolved simultaneously for the unpackaged and packaged samples to a greater degree of accuracy than achieved by partial least squares regression (PLSR) when modelling the contexts separately. By modelling the effects of the packaging and incorporating accurate reference information of unpackaged samples into the resolution of packaged samples, the potential of EDXRD and MLPCA‐MCR‐ALS for the identification and quantification of packaged solid‐dosage medicine in nondestructive screening and counterfeit medicine detection has been raised.

Metal-halide perovskite materials have begun to attract much attention recently for their potential use in radiation detection applications. This interest is mainly due to their favourable semi-conductive properties, high electron density, ease of manufacture and relatively low cost compared to popular detector materials. In this paper we investigate inorganic caesium lead bromide (CsPbBr 3 ). Polycrystalline powder samples were produced by solution growth and simple `sandwich' devices were fabricated. The powder was manually ground and then pressed to form pellets of a few mm thickness. Gold planar electrodes were deposited on the top and bottom perovskite surfaces by evaporation and were connected to an external circuit. We have made comparative measurements of the photoluminescence (PL), dark current and temporal radiation response. The PL measurements showed stable emissions centred at 525 nm for CsPbBr 3 ' which is typical of these materials and within a useful range for this application. A CsPbBr 3 device was exposed to X-rays and demonstrates a good increase in photocurrent over the dark current under both positive and negative bias with a sensitivity of 33.8 μCGy air -1 cm -2 and the temporal response was determined to be ~40 ms by measuring the photocurrent decay after X-ray illumination.

This paper reports on a novel technique for rapid and cost effective manufacture of bespoke X-ray shielding. This technique is particularly well suited for producing prototypes of complex collimators for proof of concept and/or short duration usage. Instead of heavily investing in state-of-the-art 3D metal printing to create X-ray collimators, a conventional plastic 3D printer was used to create a hollow shell of the correct geometry which was filled with tungsten powder as the X-ray attenuating material. In this paper we have applied this technique to produce a complex collimator for energy dispersive X-ray diffraction (EDXRD), which could not be manufactured using conventional machining methods. We compare the performance of this collimator to a solid tungsten 3D printed example of the same design. EDXRD shows that the two collimators have very similar performance with the backfilled collimator having marginally worse peak resolution in momentum transfer, which is attributed to X-ray transmission through the plastic walls and the much lower packing fraction of the tungsten powder. This technique is widely accessible and is capable of rapid prototyping complicated collimator designs, whilst at 1% the cost of using a tungsten 3D printing technique.

The materials used in detection of high energy photons are of primary importance in the construction of efficient, cost effective and sensitive detectors. Current research into Perovskites for solar cell technology has stimulated interest in their potential alternative uses, one of which is in direct photon conversion radiation detectors, owed primarily to their high-Z elemental composition twinned with exceptional charge carrier transport properties. Here, the Perovskite CsPbBr3 has been synthesised through solution growth. The raw CsPbBr3 was a granular powder which was formed into disks of 8 mm diameter and 1-2 mm thickness by two methods: 1). the powders were pressed into pellets using a hydraulic press or 2). sealed in a quartz ampoule under vacuum and then melted and quenched to form a polycrystalline solid which was cut to size. Metallic contacts were deposited on the front and back faces to permit charge collection. The results from the pressed devices are promising, particularly given that the production method is cost effective, repeatable and scalable. The solid-from-melt devices show similar performance but further development is required to optimise the production method.

X-ray diffraction is a material-specific technique, the results of which can be used as a material fingerprint to identify unknowns. In this paper we present an adaptation to a novel hybrid angular- and energy-dispersive X-ray diffraction technique, which, until now, has been limited in utility by sample thickness. Computed tomography techniques have been applied to spatially resolve the origin of the scattering signals and to reconstruct the diffraction pattern in each pixel. 2D cross-correlation has been used to compare the reconstructed data to a library of standards as a means of identifying the material present.

The main objective of this work is to test a new semiconductor Compton camera for prompt gamma imaging. Our device is composed of three active layers: a Si(Li) detector as a scatterer and two high purity Germanium detectors as absorbers of high-energy gamma rays. We performed Monte Carlo simulations using the Geant4 toolkit to characterise the expected gamma field during proton beam therapy and have made experimental measurements of the gamma spectrum with a 60 MeV passive scattering beam irradiating a phantom. In this proceeding, we describe the status of the Compton camera and present the first preliminary measurements with radioactive sources and their corresponding reconstructed images.

A system using energy-dispersive X-ray diffraction (EDXRD) has been developed and tested using multivariate calibration for the quantitative analysis of tablet-form mixtures of common pharmaceutical ingredients. A principal advantage of EDXRD over the more traditional and common angular dispersive X-ray diffraction technique (ADXRD) is the potential of EDXRD to analyse tablets within their packaging, due to the higher energy X-rays used. In the experiment, a series of caffeine, paracetamol and microcrystalline cellulose mixtures were prepared and pressed into tablets. EDXRD profiles were recorded on each sample and a principal component analysis (PCA) was carried out in both unpackaged and packaged scenarios. In both cases the first two principal components explained >98% of the between-sample variance. The PCA projected the sample profiles into two dimensional principal component space in close accordance to their ternary mixture design, demonstrating the discriminating potential of the EDXRD system. A partial least squares regression (PLSR) model was built with the samples and was validated using leave-one-out cross-validation. Low prediction errors of between 2% and 4% for both unpackaged and packaged tablets were obtained for all three chemical compounds. The prediction capability through packaging demonstrates a truly non-destructive method for quantifying tablet composition and demonstrates good potential for EDXRD to be applied in the field of counterfeit medicine screening and pharmaceutical quality control.

The Antikythera Mechanism is an extraordinarily complex ancient Greek astronomical calculating device whose mode of operation is now relatively well understood particularly since imaging studies in 2005 revealed gears and inscriptions which were previously illegible. Unfortunately, the highest resolution X-ray computed tomography image of the largest fragment had some errors which meant that the reconstructed images were not as clear as had been expected. Here, the original X-ray data have been reanalysed and reconstructed. The new X-ray computed tomography images have improved contrast and resolution, leading to better clarity and legibility. The improvement in image quality is characterised and some examples of writing on the Mechanism which can now be read with increased confidence are given.

The first step that is required to extract the correct information from a two-dimensional (2D) diffraction signature is to remove the background accurately. However, direct background subtraction inevitably overcorrects the signal as it does not take into account the attenuation by the sample. Other traditional background removal methods, such as the rolling ball technique, can separate sharp diffraction peaks of crystalline materials from their background. These methods are unsuitable for biological tissue, which is amorphous and does not have sharp diffraction peaks. This technical note proposes a novel method that combines peak fitting and experimental results to estimate the background for 2D XRD signals.

Calcifications are products of mineralization whose presence is usually associated with pathological conditions. The minerals mostly seen in several diseases are calcium oxalate (CaC2O4), calcium carbonate (CaCO3) and hydroxyapatite (HAp). Up to date, there is no in vivo method that could discriminate between minerals. To this aim, a dual energy x-ray method was developed in the present study. An analytical model was implemented for the determination of the Calcium/Phosphorus mass ratio ([Formula: see text]). The simulation was carried out using monoenergetic and polyenergetic x-rays and various calcification thicknesses (100-1000 [Formula: see text]) and types (CaC2O4, CaCO3, HAp). The experimental evaluation of the method was performed using the optimized irradiation conditions obtained from the simulation study. X-ray tubes, combined with energy dispersive and energy integrating (imaging) detectors, were used for the determination of the [Formula: see text] in phantoms of different mineral types and thicknesses. Based on the results of the experimental procedure, statistical significant difference was observed between the different types of minerals when calcification thicknesses were 300 [Formula: see text] or higher.

This pilot study examines the correlation of X-ray diffraction (XRD) measurements with the histopathological analysis of breast tissue. Eight breast cancer samples were investigated. Each sample contained a mixture of normal and cancerous tissues. In total, 522 separate XRD measurements were made at different locations across the samples (8 in total). The resulting XRD spectra were subjected to principal component analysis (PCA) in order to determine if there were any distinguishing features that could be used to identify different tissue components. 99.0% of the variation between the spectra were described by the first two principal components (PC). Comparing the location of points in PC space with the classification determined by histopathology indicated correlation between the shape/magnitude of the XRD spectra and the tissue type. These results are encouraging and suggest that XRD could be used for the intraoperative or postoperative classification of bulk tissue samples.

A system using energy dispersive X-ray diffraction has been tested to detect the presence of illicit drugs concealed within parcels typical of those which are imported into the UK via postal and courier services. The system was used to record diffraction data from calibration samples of diamorphine (heroin) and common cutting agents and a partial least squares regression model was established between diamorphine concentration and diffraction spectra. Parcels containing various crystalline and amorphous materials, including diamorphine, were then scanned to obtain multiple localised diffraction spectra and to form a hyperspectral image. The calibration model was used for the prediction of diamorphine concentration throughout the volume of parcels and enabled the presence and location of diamorphine to be determined from the visual inspection of concentration maps. This research demonstrates for the first time the potential of an EDXRD system to generate continuous hyperspectral images of real parcels from volume scanning in security applications and introduces the opportunity to explore hyperspectral image analysis in chemical and material identification. However, more work must be done to make the system ready for implementation in border control operations by bringing down the procedure time to operational requirements and by proving the system’s portability.

This paper introduces miniPixD: a new, compact system that utilises transmission X-ray imaging and X-ray diffraction (XRD) to locate and identify materials of interest within an otherwise opaque volume. The system and the embodied techniques have utility in security screening, medical diagnostics, non-destructive testing (NDT) and quality assurance (QA). This paper outlines the design of the system including discussion on the choice of components and presents some data from relevant samples which are compared to other energy dispersive and angular dispersive XRD techniques.