Observation of diffuse scattering in scanning helium microscopy.

In understanding the nature of contrast in the emerging field of neutral helium microscopy, it is important to identify if there is an atom-surface scattering distribution that can be expected to apply broadly across a range of sample surfaces. Here we present results acquired in a scanning helium microscope (SHeM) under typical operating conditions, from a range of surfaces in their native state, i.e. without any specialist sample preparation. We observe diffuse scattering, with an approximately cosine distribution centred about the surface normal. The 'cosine-like' distribution is markedly different from those distributions observed from the well-prepared, atomically pristine, surfaces typically studied in helium atom scattering experiments. Knowledge of the typical scattering distribution in SHeM experiments provides a starting basis for interpretation of topographic contrast in images, as well as a reference against which more exotic contrast mechanisms can be compared.

NT-proBNP and stem cell factor plasma concentrations are independently associated with cardiovascular outcomes in end-stage renal disease hemodialysis patients.

Aims: End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine. Methods and results: The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls (n = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with OlinkTM). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), n = 331 patients] in which 92 OlinkTM biomarkers were assessed. In AURORA, only N-terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths. Conclusions: Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.

Low-energy electron ionization mass spectrometer for efficient detection of low mass species.

The design of a high-efficiency mass spectrometer is described, aimed at residual gas detection of low mass species using low-energy electron impact, with particular applications in helium atom microscopy and atomic or molecular scattering. The instrument consists of an extended ionization volume, where electrons emitted from a hot filament are confined using a solenoidal magnetic field to give a high ionization probability. Electron space charge is used to confine and extract the gas ions formed, which are then passed through a magnetic sector mass filter before reaching an ion counter. The design and implementation of each of the major components are described in turn, followed by the overall performance of the detector in terms of mass separation, detection efficiency, time response, and background count rates. The linearity of response with emission current and magnetic field is discussed. The detection efficiency for helium is very high, reaching as much as 0.5%, with a time constant of (198 ± 6) ms and a background signal equivalent to an incoming helium flux of (8.7 ± 0.2) × 106 s-1.

Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma.

Glioblastoma remains the most malignant of all primary adult brain tumours with poor patient survival and limited treatment options. This study adopts a drug repurposing approach by investigating the anti-cancer activity of a derivative of the antipsychotic drug phenothiazine (DS00329) in malignant U251 and U87 glioblastoma cells. Results from MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and clonogenic assays showed that DS00329 inhibited short-term glioblastoma cell viability and long-term survival while sparing non-cancerous cells. Western blot analysis with an antibody to γH2AX showed that DS00329 induced DNA damage and flow cytometry and western blotting confirmed that it triggered a G1 cell cycle arrest which correlated with decreased levels in Cyclin A, Cyclin B, Cyclin D1 and cyclin dependent kinase 2 and an increase in levels of the cyclin dependent kinase inhibitor p21. DS00329 treated glioblastoma cells exhibited morphological and molecular markers typical of apoptotic cells such as membrane blebbing and cell shrinkage and an increase in levels of cleaved PARP. Flow cytometry with annexin V-FITC/propidium iodide staining confirmed that DS00329 induced apoptotic cell death in glioblastoma cells. We also show that DS00329 treatment of glioblastoma cells led to an increase in the autophagosome marker LC3-II and autophagy inhibition studies using bafilomycin A1 and wortmannin, showed that DS00329-induced-autophagy was a pro-death mechanism. Furthermore, DS00329 treatment of glioblastoma cells inhibited the phosphatidylinositol 3'-kinase/Akt cell survival pathway. Our findings suggest that DS00329 may be an effective treatment for glioblastoma and provide a rationale for further exploration and validation of the use of phenothiazines and their derivatives in the treatment of glioblastoma.

Observation of diffraction contrast in scanning helium microscopy.

Scanning helium microscopy is an emerging form of microscopy using thermal energy neutral helium atoms as the probe particle. The very low energy combined with lack of charge gives the technique great potential for studying delicate systems, and the possibility of several new forms of contrast. To date, neutral helium images have been dominated by topographic contrast, relating to the height and angle of the surface. Here we present data showing contrast resulting from specular reflection and diffraction of helium atoms from an atomic lattice of lithium fluoride. The signature for diffraction is evident by varying the scattering angle and observing sharp features in the scattered distribution. The data indicates the viability of the approach for imaging with diffraction contrast and suggests application to a wide variety of other locally crystalline materials.

A method for constrained optimisation of the design of a scanning helium microscope.

We describe a method for obtaining the optimal design of a normal incidence Scanning Helium Microscope (SHeM). Scanning helium microscopy is a recently developed technique that uses low energy neutral helium atoms as a probe to image the surface of a sample without causing damage. After estimating the variation of source brightness with nozzle size and pressure, we perform a constrained optimisation to determine the optimal geometry of the instrument (i.e. the geometry that maximises intensity) for a given target resolution. For an instrument using a pinhole to form the helium microprobe, the source and atom optics are separable and Lagrange multipliers are used to obtain an analytic expression for the optimal parameters. For an instrument using a zone plate as the focal element, the whole optical system must be considered and a numerical approach has been applied. Unlike previous numerical methods for optimisation, our approach provides insight into the effect and significance of each instrumental parameter, enabling an intuitive understanding of effect of the SHeM geometry. We show that for an instrument with a working distance of 1 mm, a zone plate with a minimum feature size of 25 nm becomes the advantageous focussing element if the desired beam standard deviation is below about 300 nm.

A ray tracing method for predicting contrast in neutral atom beam imaging.

A ray tracing method for predicting contrast in atom beam imaging is presented. Bespoke computational tools have been developed to simulate the classical trajectories of atoms through the key elements of an atom beam microscope, as described using a triangulated surface mesh, using a combination of MATLAB and C code. These tools enable simulated images to be constructed that are directly analogous to the experimental images formed in a real microscope. It is then possible to understand which mechanisms contribute to contrast in images, with only a small number of base assumptions about the physics of the instrument. In particular, a key benefit of ray tracing is that multiple scattering effects can be included, which cannot be incorporated easily in analytic integral models. The approach has been applied to model the sample environment of the Cambridge scanning helium microscope (SHeM), a recently developed neutral atom pinhole microscope. We describe two applications; (i) understanding contrast and shadowing in images; and (ii) investigation of changes in image formation with pinhole-to-sample working distance. More generally the method has a broad range of potential applications with similar instruments, including understanding imaging from different sample topographies, refinement of a particular microscope geometry to enhance specific forms of contrast, and relating scattered intensity distributions to experimental measurements.

The dynamics of benzene on Cu(111): a combined helium spin echo and dispersion-corrected DFT study into the diffusion of physisorbed aromatics on metal surfaces.

We use helium spin-echo spectroscopy (HeSE) to investigate the dynamics of the diffusion of benzene adsorbed on Cu(111). The results of these measurements show that benzene moves on the surface through an activated jump-diffusion process between the adsorption sites on a Bravais lattice. Density Functional Theory (DFT) calculations with van der Waals (vdW) corrections help us understand that the molecule diffuses by jumping through non-degenerate hollow sites. The results of the calculations shed light on the nature of the binding interaction between this prototypical aromatic molecule and the metallic surface. The highly accurate HeSE experimental data provide a quantitatively stringent benchmark for the vdW correction schemes applied to the DFT calculations and we compare the performances of several dispersion interaction schemes.

Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study.

Genome-wide association studies (GWAS) are designed to investigate single nucleotide polymorphisms (SNPs) and the association with a clinical phenotype. A previous GWAS performed in 300 renal transplant recipients identified two SNPs (rs3811321 and rs6565887) associated with serum creatinine and clinical outcome. We sought to validate these findings. Genotyping of the two SNPs was performed using Taqman assays in 1638 Caucasians participating in the Assessment of LEscol in Renal Transplant (ALERT) study. Primary endpoint was death-censored graft loss, and secondary endpoint was all-cause mortality. Applying Cox regression, no crude association to graft loss was found for rs3811321 on chromosome 14 (hazard ratio [HR] 0.87, 95% CI 0.59-1.29, p = 0.50) or rs6565887 on chromosome 18 (HR 0.88, CI 0.62-1.25, p = 0.48). Multivariable adjustments did not change results, nor did evaluation of the number of risk alleles formed by the two SNPs. No association with mortality was detected. In conclusion, an impact of two SNPs on chromosomes 14 and 18 on death-censored graft survival or all-cause mortality was not confirmed. Our results emphasize the importance of validating findings from high-throughput genetics studies and call for large collaborative research initiatives in the field of transplantation outcomes.

Note: A simple sample transfer alignment for ultra-high vacuum systems.

The alignment of ultra-high-vacuum sample transfer systems can be problematic when there is no direct line of sight to assist the user. We present the design of a simple and cheap system which greatly simplifies the alignment of sample transfer devices. Our method is based on the adaptation of a commercial digital camera which provides live views from within the vacuum chamber. The images of the camera are further processed using an image recognition and processing code which determines any misalignments and reports them to the user. Installation has proven to be extremely useful in order to align the sample with respect to the transfer mechanism. Furthermore, the alignment software can be easily adapted for other systems.

Differential visceral blood flow in the hyperdynamic circulation of patients with liver cirrhosis.

BACKGROUND: With advancing liver disease and the development of portal hypertension, there are major alterations in somatic and visceral blood flow. Using phase-contrast magnetic resonance angiography, we characterised alterations in blood flow within the hepatic, splanchnic and extra-splanchnic circulations of patients with established liver cirrhosis. AIM: To compare blood flow in splanchnic and extra-splanchnic circulations in patients with varying degrees of cirrhosis and healthy controls. METHODS: In a single-centre prospective study, 21 healthy volunteers and 19 patients with established liver disease (Child's stage B and C) underwent electrocardiogram-gated phase-contrast-enhanced 3T magnetic resonance angiography of the aorta, hepatic artery, portal vein, superior mesenteric artery, and the renal and common carotid arteries. RESULTS: In comparison to healthy volunteers, resting blood flow in the descending thoracic aorta was increased by 43% in patients with liver disease (4.31 ± 1.47 vs. 3.31 ± 0.80 L/min, P = 0.011). While portal vein flow was similar (0.83 ± 0.38 vs. 0.77 ± 0.35 L/min, P = 0.649), hepatic artery flow doubled (0.50 ± 0.46 vs. 0.25 ± 0.15 L/min, P = 0.021) and consequently total liver blood flow increased by 30% (1.33 ± 0.84 vs. 1.027 ± 0.5 L/min, P = 0.043). In patients with liver disease, superior mesenteric artery flow was threefold higher (0.65 ± 0.35 vs. 0.22 ± 0.13 L/min, P < 0.001), while total renal blood flow was reduced by 40% (0.37 ± 0.14 vs. 0.62 ± 0.22 L/min, P < 0.001) and total carotid blood flow unchanged (0.62 ± 0.20 vs. 0.65 ± 0.13 L/min, P = 0.315). CONCLUSIONS: Rather than a generalised systemic hyperdynamic circulation, liver disease is associated with dysregulated splanchnic vasodilatation and portosystemic shunting that, while inducing a high cardiac output, causes compensatory extra-splanchnic vasoconstriction - the 'splanchnic steal' phenomenon. These circulatory disturbances may underlie many of the manifestations of advanced liver disease.

Unlocking new contrast in a scanning helium microscope.

Delicate structures (such as biological samples, organic films for polymer electronics and adsorbate layers) suffer degradation under the energetic probes of traditional microscopies. Furthermore, the charged nature of these probes presents difficulties when imaging with electric or magnetic fields, or for insulating materials where the addition of a conductive coating is not desirable. Scanning helium microscopy is able to image such structures completely non-destructively by taking advantage of a neutral helium beam as a chemically, electrically and magnetically inert probe of the sample surface. Here we present scanning helium micrographs demonstrating image contrast arising from a range of mechanisms including, for the first time, chemical contrast observed from a series of metal-semiconductor interfaces. The ability of scanning helium microscopy to distinguish between materials without the risk of damage makes it ideal for investigating a wide range of systems.

Combinations of potent topical steroids, mercury and hydroquinone are common in internationally manufactured skin-lightening products: a spectroscopic study.

BACKGROUND: The topical steroids betamethasone (BM) and clobetasol propionate (CP) are illegal in cosmetics. Hydroquinone (HQ) and mercury (Hg) are either illegal or allowed only in limited concentrations (2% and 1 ppm, respectively). AIM: To investigate active ingredients and countries of origin of popular skin-lightening products available in Cape Town, South Africa. METHODS: In total, 29 products were examined; of these, 22 products were purchased from informal vendors, and 2 products (out of a total of 29) were purchased over the counter. HQ, Hg(2+) and steroids were quantified by high-performance liquid chromatography-ultraviolet spectrophotometry, inductively coupled plasma-mass spectrometry and liquid chromatography-mass spectrometry, respectively. RESULTS: Of the 29 products, 22 (75.9%), all imported and bought from informal vendors, contained illegal or banned ingredients: 13 (44.8%) contained steroids (9 CP, 4 BM), 12 (41.4%) contained Hg (30-2300 ppm), and 11 (37.9%) contained HQ. Sequentially, the products originated from Italy (27.3%, n = 6), India (22.7%, n = 5), the Democratic Republic of Congo (DRC) (22.7%, n = 5), Cote d'Ivoire (9.1%, n = 2), USA (9.1%, n = 2), UK (4.5%, n = 1) and France (4.5%, n = 1). Two products, one from India and one from the DRC, contained all four ingredients (HQ, Hg, BM, CP). Of the 12 products containing Hg, 10 also contained HQ and/or a steroid, yet none listed Hg as an ingredient. A significant proportion of the steroid-containing products (76.9%) also contained at least one other skin-lightening agent. Not all internationally available products were tested, which is a limitation of the study. CONCLUSION: In spite of a European Union ban on skin lighteners, a third of the products tested were from Europe. Combinations of Hg and ultrapotent steroids were prominent. International law enforcement and random testing is needed to encourage industry compliance and help protect consumers.

How Atomic Steps Modify Diffusion and Inter-adsorbate Forces: Empirical Evidence from Hopping Dynamics in Na/Cu(115).

We followed the collective atomic-scale motion of Na atoms on a vicinal Cu(115) surface within a time scale of pico- to nanoseconds using helium spin echo spectroscopy. The well-defined stepped structure of Cu(115) allows us to study the effect that atomic steps have on the adsorption properties, the rate for motion parallel and perpendicular to the step edge, and the interaction between the Na atoms. With the support of a molecular dynamics simulation we show that the Na atoms perform strongly anisotropic 1D hopping motion parallel to the step edges. Furthermore, we observe that the spatial and temporal correlations between the Na atoms that lead to collective motion are also anisotropic, suggesting the steps efficiently screen the lateral interaction between Na atoms residing on different terraces.

Cost-effectiveness of breast cancer screening policies using simulation.

In this paper, we study breast cancer screening policies using computer simulation. We developed a multi-state Markov model for breast cancer progression, considering both the screening and treatment stages of breast cancer. The parameters of our model were estimated through data from the Canadian National Breast Cancer Screening Study as well as data in the relevant literature. Using computer simulation, we evaluated various screening policies to study the impact of mammography screening for age-based subpopulations in Canada. We also performed sensitivity analysis to examine the impact of certain parameters on number of deaths and total costs. The analysis comparing screening policies reveals that a policy in which women belonging to the 40-49 age group are not screened, whereas those belonging to the 50-59 and 60-69 age groups are screened once every 5 years, outperforms others with respect to cost per life saved. Our analysis also indicates that increasing the screening frequencies for the 50-59 and 60-69 age groups decrease mortality, and that the average number of deaths generally decreases with an increase in screening frequency. We found that screening annually for all age groups is associated with the highest costs per life saved. Our analysis thus reveals that cost per life saved increases with an increase in screening frequency.

Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions.

A consensus meeting was held in Vienna on September 8-9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new-onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.

Nurses caring for ENT patients in a district general hospital without a dedicated ENT ward score significantly less in a test of knowledge than nurses caring for ENT patients in a dedicated ENT ward in a comparable district general hospital.

OBJECTIVES: To assess whether there is a difference in ENT knowledge amongst nurses caring for patients on a dedicated ENT ward and nurses caring for ENT patients in a similar hospital without a dedicated ENT ward. DESIGN: A test of theoretical knowledge of ENT nursing care was devised and administered to nurses working on a dedicated ENT ward and then to nurses working on generic non-subspecialist wards regularly caring for ENT patients in a hospital without a dedicated ENT ward. The test scores were then compared. SETTING: A single specialist ENT/Maxillo-Facial/Opthalmology ward in hospital A and 3 generic surgical wards in hospital B. Both hospitals are comparable district general hospitals in the south west of England. PARTICIPANTS: Nursing staff working in hospital A and hospital B on the relevant wards were approached during the working day. 11 nurses on ward 1, 10 nurses on ward 2, 11 nurses on ward 3 and 10 nurses on ward 4 (the dedicated ENT ward). MAIN OUTCOME MEASURES: Each individual test score was used to generate an average score per ward and these scores compared to see if there was a significant difference. RESULTS: The average score out of 10 on ward 1 was 6.8 (+/-1.6). The average score on ward two was 4.8 (+/-1.6). The average score on ward three was 5.5 (+/-2.1). The average score on ward 4, which is the dedicated ENT ward, was 9.7 (+/-0.5). The differences in average test score between the dedicated ENT ward and all of the other wards are statistically significant. CONCLUSION: Nurses working on a dedicated ENT ward have an average higher score in a test of knowledge than nurses working on generic surgical wards. This difference is statistically significant and persists despite banding or training.

European perspective on human polyomavirus infection, replication and disease in solid organ transplantation.

Human polyomaviruses (HPyVs) are a growing challenge in immunocompromised patients in view of the increasing number of now 12 HPyV species and their diverse disease potential. Currently, histological evidence of disease is available for BKPyV causing nephropathy and haemorrhagic cystitis, JCPyV causing progressive multifocal leukoencephalopathy and occasionally nephropathy, MCPyV causing Merkel cell carcinoma and TSPyV causing trichodysplasia spinulosa, the last two being proliferative skin diseases. Here, the current role of HPyV in solid organ transplantation (SOT) was reviewed and recommendations regarding screening, monitoring and intervention were made. Pre-transplant screening of SOT donor or recipient for serostatus or active replication is currently not recommended for any HPyV. Post-transplant, however, regular clinical search for skin lesions, including those associated with MCPyV or TSPyV, is recommended in all SOT recipients. Also, regular screening for BKPyV replication (e.g. by plasma viral load) is recommended in kidney transplant recipients. For SOT patients with probable or proven HPyV disease, reducing immunosuppression should be considered to permit regaining of immune control. Antivirals would be desirable for treating proven HPyV disease, but are solely considered as adjunct local treatment of trichodysplasia spinulosa, whereas surgical resection and chemotherapy are key in Merkel cell carcinoma. Overall, the quality of the clinical evidence and the strength of most recommendations are presently limited, but are expected to improve in the coming years.