Correction of EELS dispersion non-uniformities for improved chemical shift analysis.

We outline a simple routine to correct for non-uniformities in the energy dispersion of a post-column electron energy-loss spectrometer for use in scanning transmission electron microscopy. We directly measure the dispersion and its variations by sweeping a spectral feature across the full camera to produce a calibration that can be used to linearize datasets post-acquisition, without the need for reference materials. The improvements are illustrated using core excitation electron energy-loss spectroscopy (EELS) spectra collected from NiO and diamond samples. The calibration is rapid and will be of use in all EELS analysis, particularly in assessments of the chemical states of materials via the chemical shift of core-loss excitations.

The impact of traumatic stress on Pavlovian biases.

BACKGROUND: Disturbances in Pavlovian valuation systems are reported to follow traumatic stress exposure. However, motivated decisions are also guided by instrumental mechanisms, but to date the effect of traumatic stress on these instrumental systems remain poorly investigated. Here, we examine whether a single episode of severe traumatic stress influences flexible instrumental decisions through an impact on a Pavlovian system. METHODS: Twenty-six survivors of the 2011 Norwegian terror attack and 30 matched control subjects performed an instrumental learning task in which Pavlovian and instrumental associations promoted congruent or conflicting responses. We used reinforcement learning models to infer how traumatic stress affected learning and decision-making. Based on the importance of dorsal anterior cingulate cortex (dACC) for cognitive control, we also investigated if individual concentrations of Glx (=glutamate + glutamine) in dACC predicted the Pavlovian bias of choice. RESULTS: Survivors of traumatic stress expressed a greater Pavlovian interference with instrumental action selection and had significantly lower levels of Glx in the dACC. Across subjects, the degree of Pavlovian interference was negatively associated with dACC Glx concentrations. CONCLUSIONS: Experiencing traumatic stress appears to render instrumental decisions less flexible by increasing the susceptibility to Pavlovian influences. An observed association between prefrontal glutamatergic levels and this Pavlovian bias provides novel insight into the neurochemical basis of decision-making, and suggests a mechanism by which traumatic stress can impair flexible instrumental behaviours.

European Headache Federation consensus on technical investigation for primary headache disorders.

The diagnosis of primary headache disorders is clinical and based on the diagnostic criteria of the International Headache Society (ICHD-3-beta). However several brain conditions may mimic primary headache disorders and laboratory investigation may be needed. This necessity occurs when the treating physician doubts for the primary origin of headache. Features that represent a warning for a possible underlying disorder causing the headache are new onset headache, change in previously stable headache pattern, headache that abruptly reaches the peak level, headache that changes with posture, headache awakening the patient, or precipitated by physical activity or Valsalva manoeuvre, first onset of headache ≥50 years of age, neurological symptoms or signs, trauma, fever, seizures, history of malignancy, history of HIV or active infections, and prior history of stroke or intracranial bleeding. All national headache societies and the European Headache Alliance invited to review and comment the consensus before the final draft. The consensus recommends brain MRI for the case of migraine with aura that persists on one side or in brainstem aura. Persistent aura without infarction and migrainous infarction require brain MRI, MRA and MRV. Brain MRI with detailed study of the pituitary area and cavernous sinus, is recommended for all TACs. For primary cough headache, exercise headache, headache associated with sexual activity, thunderclap headache and hypnic headache apart from brain MRI additional tests may be required. Because there is little and no good evidence the committee constructed a consensus based on the opinion of experts, and should be treated as imperfect.

Prevention of early-onset Group B Streptococcal disease - the Northern Ireland experience.

OBJECTIVES: To ascertain guideline adherence for prevention of Group B Streptococcal (GBS) neonatal infection and establish prevalence and outcomes in Northern Ireland (NI). DESIGN: Retrospective observational study. SETTING: Northern Ireland maternity units. POPULATION: Using NI Health Information Systems the following were identified: (1) a cohort of women with one or more risk factors for GBS disease in 2009-2010, (2) all culture-positive cases of GBS in babies aged 0-89 days (2008-2010), (3) stillbirths due to GBS (2009-2010). METHODS: Information was analysed for a 15% randomised sample of the available cases. Maternal and infant case notes were reviewed for confirmed cases of neonatal early onset GBS (EOGBS) during 2008-2010. MAIN OUTCOME MEASURES: Adherence to the 2003 RCOG guideline on prevention of GBS disease (2009-2010). Number of neonatal GBS infections: antenatal risk factors, management and neonatal outcomes (2008-2010). The number of stillbirths related to GBS (2009-2010). RESULTS: Five hundred and seventy-four women had one or more identifiable risk factors for GBS disease; intrapartum antibiotic prophylaxis (IAP) was administered in 42% of cases. Improved administration of IAP was noted in the presence of escalating risk factors. At best, guideline adherence was 50-70%. Forty-three neonates had proven early-onset Group B Streptococcal disease; 55.8% had maternal risk factors. Of the total identified cases, 25.5% received IAP. The total mortality rate was 11.46%. The incidence of EOGBS disease in NI was 0.57/1000 live births. CONCLUSIONS: Prevalence of EOGBS is higher in NI than the UK as a whole. Risk factors are present in 55.8% of mothers; IAP does not prevent all cases of EOGBS.

Enhanced Eshelby twist on thin Wurtzite InP nanowires and measurement of local crystal rotation.

We have performed a detailed study of the lattice distortions of InP wurtzite nanowires containing an axial screw dislocation. Eshelby predicted that this kind of system should show a crystal rotation due to the dislocation induced torque. We have measured the twisting rate and the dislocation Burgers vector on individual wires, revealing that nanowires with a 10-nm radius have a twist up to 100% larger than estimated from elasticity theory. The strain induced by the deformation has a Mexican-hat-like geometry, which may create a tube-like potential well for carriers.

Characterising the surface and interior chemistry of core-shell nanoparticles using scanning transmission electron microscopy.

A method for extracting core and shell spectra from core-shell particles with varying core to shell volume fractions is described. The method extracts the information from a single EELS spectrum image of the particle. The distribution of O and N was correctly reproduced for a nanoparticle with a TiN core and Ti-oxide shell. In addition, the O distribution from a nanoparticle with a Cu core and a Cu-oxide shell was obtained, and the extracted Cu L(2,3)-core and shell spectra showed the required change in EELS near edge fine structure. The extracted spectra can be used for multiple linear least squares fitting to the raw data in the spectrum image. The effect of certain approximations on numerical accuracy, such as treating the nanoparticle as a perfect sphere, as well as the intrinsic detection limits of the technique have also been explored. The technique is most suitable for qualitative, rather than quantitative, work.

Probing magnetic order in EELS of chromite spinels using both multiple scattering (FEFF8.2) and DFT (WIEN2k).

The electron energy loss near edge structure on the O K-edge from chromite spinels contains fine structure from the hybridisation of the O p-orbitals and the Cr d-orbitals. Unlike the aluminates, a non-spin polarised calculation of this fine structure differs significantly from experimental observations. This is due to the large magnetic moment on the Cr. Calculations using simplified collinear ordering of the spins and the local spin density approximation give much improved agreement. A real space multiple scattering formalism and a reciprocal space density functional formalism give results in substantial agreement. In general, the actual spin arrangement of these chromites is not known since they are typically frustrated magnetic systems with ordering temperatures in the 10-20K range. The calculations are based on the hypothesis that dynamic short range order persists to room temperature over the time scale of the interaction with the fast electron. However, it is possible that the observed effects are due to the strong paramagnetism present at room temperatures but which it is not possible to simulate accurately at present.

Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors.

Species specific conversion of the lead PDE4 inhibitor 1 to the quinolone 3 was identified as the major route of metabolism in the cynomolgus monkey. Modification of the template to give the cinnoline 9 retained potency and selectivity, and greatly improved the pharmacokinetic profile in the cynomolgus monkey compared with 1. Additional SAR studies aimed at improving the solubility of 9 are also described.

A new analytical method for characterising the bonding environment at rough interfaces in high-k gate stacks using electron energy loss spectroscopy.

Determining the bonding environment at a rough interface, using for example the near-edge fine structure in electron energy loss spectroscopy (EELS), is problematic since the measurement contains information from the interface and surrounding matrix phase. Here we present a novel analytical method for determining the interfacial EELS difference spectrum (with respect to the matrix phase) from a rough interface of unknown geometry, which, unlike multiple linear least squares (MLLS) fitting, does not require the use of reference spectra from suitable standards. The method is based on analysing a series of EELS spectra with variable interface to matrix volume fraction and, as an example, is applied to a TiN/poly-Si interface containing oxygen in a HfO(2)-based, high-k dielectric gate stack. A silicon oxynitride layer was detected at the interface consistent with previous results based on MLLS fitting.

Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial.

OBJECTIVES: To determine whether self-monitoring of blood glucose (SMBG), either alone or with additional instruction in incorporating the results into self-care, is more effective than usual care in improving glycaemic control in non-insulin-treated diabetes. DESIGN: An open, parallel group randomised controlled trial. SETTING: 24 general practices in Oxfordshire and 24 in South Yorkshire, UK. PARTICIPANTS: Patients with non-insulin-treated type 2 diabetes, aged > or = 25 years and with glycosylated haemoglobin (HbA1c) > or = 6.2%. INTERVENTIONS: A total of 453 patients were individually randomised to one of: (1) standardised usual care with 3-monthly HbA1c (control, n = 152); (2) blood glucose self-testing with patient training focused on clinician interpretation of results in addition to usual care (less intensive self-monitoring, n = 150); (3) SMBG with additional training of patients in interpretation and application of the results to enhance motivation and maintain adherence to a healthy lifestyle (more intensive self-monitoring, n = 151). MAIN OUTCOME MEASURES: The primary outcome was HBA1c at 12 months, and an intention-to-treat analysis, including all patients, was undertaken. Blood pressure, lipids, episodes of hypoglycaemia and quality of life, measured with the EuroQol 5 dimensions (EQ-5D), were secondary measures. An economic analysis was also carried out, and questionnaires were used to measure well-being, beliefs about use of SMBG and self-reports of medication taking, dietary and physical activities, and health-care resource use. RESULTS: The differences in 12-month HbA1c between the three groups (adjusted for baseline HbA1c) were not statistically significant (p = 0.12). The difference in unadjusted mean change in HbA1c from baseline to 12 months between the control and less intensive self-monitoring groups was -0.14% [95% confidence interval (CI) -0.35 to 0.07] and between the control and more intensive self-monitoring groups was -0.17% (95% CI -0.37 to 0.03). There was no evidence of a significantly different impact of self-monitoring on glycaemic control when comparing subgroups of patients defined by duration of diabetes, therapy, diabetes-related complications and EQ-5D score. The economic analysis suggested that SMBG resulted in extra health-care costs and was unlikely to be cost-effective if used routinely. There appeared to be an initial negative impact of SMBG on quality of life measured on the EQ-5D, and the potential additional lifetime gains in quality-adjusted life-years, resulting from the lower levels of risk factors achieved at the end of trial follow-up, were outweighed by these initial impacts for both SMBG groups compared with control. Some patients felt that SMBG was helpful, and there was evidence that those using more intensive self-monitoring perceived diabetes as having more serious consequences. Patients using SMBG were often not clear about the relationship between their behaviour and the test results. CONCLUSIONS: While the data do not exclude the possibility of a clinically important benefit for specific subgroups of patients in initiating good glycaemic control, SMBG by non-insulin-treated patients, with or without instruction in incorporating findings into self-care, did not lead to a significant improvement in glycaemic control compared with usual care monitored by HbA1c levels. There was no convincing evidence to support a recommendation for routine self-monitoring of all patients and no evidence of improved glycaemic control in predefined subgroups of patients.

Near-simultaneous dual energy range EELS spectrum imaging.

A system that allows the collection of the low loss spectrum and the core loss spectrum, covering different energy regions, at each pixel in a spectrum image is described. It makes use of a fast electrostatic shutter with control signals provided by the spectrum imaging software and synchronisation provided by the CCD camera controller. The system also allows simultaneous collection of the X-ray spectrum and the signals from the imaging detectors while allowing the use of the existing features of the spectrum imaging software including drift correction and sub-pixel scanning. The system allows acquisition of high-quality spectra from both the core and the low loss regions, allowing full processing of the EELS data. Examples are given to show the benefits, including deconvolution, absolute thickness mapping and determination of numbers of atoms per unit area and per unit volume. Possible further developments are considered.

Quantitative electron energy-loss spectroscopy (EELS) analyses of lead zirconate titanate.

Electron energy-loss spectroscopy (EELS) analyses have been performed on a sol-gel deposited lead zirconate titanate film, showing that EELS can be used for heavy as well as light element analysis. The elemental distributions within the sol-gel layers are profiled using the Pb N(6,7)-edges, Zr M-edges, Ti L-edges and O K-edge. A multiple linear least squares fitting procedure was used to extract the Zr signal which overlaps with the Pb signal. Excellent qualitative information has been obtained on the distribution of the four elements. The non-uniform and complementary distributions of Ti and Zr within each sol-gel deposited layer are observed. The metal:oxygen elemental ratios are quantified using experimental standards of PbTiO(3), PbZrO(3), ZrO(2) and TiO(2) to provide relevant cross-section ratios. The quantitative results obtained for Ti/O and Pb/O are very good but the Zr/O results are less accurate. Methods of further improving the results are discussed.

Prolactin delays hair regrowth in mice.

Mammalian hair growth is cyclic, with hair-producing follicles alternating between active (anagen) and quiescent (telogen) phases. The timing of hair cycles is advanced in prolactin receptor (PRLR) knockout mice, suggesting that prolactin has a role in regulating follicle cycling. In this study, the relationship between profiles of circulating prolactin and the first post-natal hair growth cycle was examined in female Balb/c mice. Prolactin was found to increase at 3 weeks of age, prior to the onset of anagen 1 week later. Expression of PRLR mRNA in skin increased fourfold during early anagen. This was followed by upregulation of prolactin mRNA, also expressed in the skin. Pharmacological suppression of pituitary prolactin advanced dorsal hair growth by 3.5 days. Normal hair cycling was restored by replacement with exogenous prolactin for 3 days. Increasing the duration of prolactin treatment further retarded entry into anagen. However, prolactin treatments, which began after follicles had entered anagen at 26 days of age, did not alter the subsequent progression of the hair cycle. Skin from PRLR-deficient mice grafted onto endocrine-normal hosts underwent more rapid hair cycling than comparable wild-type grafts, with reduced duration of the telogen phase. These experiments demonstrate that prolactin regulates the timing of hair growth cycles in mice via a direct effect on the skin, rather than solely via the modulation of other endocrine factors.

Bandstructure approach to near edge structure.

We review the current state of the art in EELS fingerprinting by computer simulation, focusing on the bandstructure approach to the problem. Currently calculations are made using a one electron theory, but we describe in principle the way to go beyond this to include final state effects. We include these effects within the one electron framework using the Slater transition state formula and assess the errors involved. Two examples are then given which illustrate the use of the one electron approximation within density functional theory. Our approach is to combine predicted atomic structure with predicted electronic structure to assist in fingerprinting of complex crystal structures.

Improving the analysis of small precipitates in HSLA steels using a plasma cleaner and ELNES.

The change from producing high strength low alloy (HSLA) steel sheet by conventional thick slab casting to producing it by direct charged thin slab casting causes a major change in the evolution of the precipitation. A key area of interest is the composition of the sub-10nm precipitates used to produce dispersion hardening. Carbon extraction replicas are frequently used to study precipitates in steels and other metals. When used with annular dark field imaging, this technique gives high contrast images of the precipitates while the thin carbon film adds little background or additional characteristic signals to either electron energy loss spectra or energy dispersive X-ray spectra. The method has the additional major advantage of removing the ferromagnetic matrix when studying HSLA steels. However, when the precipitates contain carbon, the C K-edge is dominated by the contribution from the amorphous carbon film. A plasma cleaner can be used to thin this carbon film to approximately 0.5 nm or less and then the contribution from the carbon in the precipitate can be separated from that in the carbon film using the electron energy loss near edge structure. A similar approach can be taken to separate the oxygen content of the precipitate from that of oxides formed from low-level impurities in the amorphous carbon during the plasma thinning process. In most cases, the precipitate studied here contained little or no oxygen even for the smallest sizes examined (approximately 4 nm). The precipitates contain mainly nitrogen with little carbon. For some compositions, the precipitates are clearly sub-stoichiometric.

A fast beam switch for controlling the intensity in electron energy loss spectrometry.

The fast deflection system described in this paper is suitable for controlling the intensity reaching the detector of a magnetic sector electron spectrometer mounted below an analytical transmission electron microscope. Amongst other things, this allows the low loss region of the spectrum to be recorded with the same electron probe conditions used to record core losses, something that is essential for high spatial resolution studies. The plate assembly restricts the width of the electron distribution reaching the viewing screen to a strip approximately 17 mm wide in the direction approximately normal to the dispersion direction of the spectrometer. The resulting deflection has no detectable effect on the FWHM of the zero-loss peak for exposure times as short as 1 micros. At incident energies up to 300 keV, positioning the deflection plates in the 35 mm camera port above the viewing chamber allows voltages of < +/- 3 kV to deflect the electrons out of the spectrometer and beyond the edge of the annular detector. When the deflection is switched on, the electrons are deflected out of the spectrometer in << 40 ns and when the deflection is switched off, the electrons return to within 10 microm of the undeflected position within 100 ns. Thus, even at an exposure time of 30 micros, the smallest time likely to be used in practice with a GATAN 666 spectrometer, < 1% of the signal in the spectrum is from electrons whose scattering conditions differ from those in the undeflected position. The performance of the deflection system is such that it will also be suitable for use with the new and much faster GATAN ENFINA spectrometer system. At incident energies up to 200 keV and possibly up to 300 keV, deflection voltages of +/- 3 kV are sufficient to deflect the electrons off a 1 k x 1 k charge coupled device (CCD) camera placed below the photographic camera. Thus the deflection system can be used as a very fast, non-mechanical shutter for such a CCD camera.

Regulation of prolactin receptor expression in ovine skin in relation to circulating prolactin and wool follicle growth status.

Seasonal patterns of hair growth are governed, at least in part, by levels of prolactin in circulation, and although receptors for prolactin (PRLR) have been demonstrated in hair follicles, little is known of their regulation in relation to follicular cycles. In this study, a photoperiod-generated increase in prolactin was used to induce a wool follicle cycle during which changes in PRLR expression in sheep skin were determined by ribonuclease protection assay and in situ hybridisation. mRNA for prolactin and both isoforms of PRLR were also detected in skin by reverse transcription and polymerase chain reaction. As circulating prolactin began to rise from low levels, PRLR mRNA in the skin initially fell. These changes immediately preceded the catagen (regressive) phase of the hair cycle. Further increase in prolactin resulted in up-regulation of PRLR during telogen (dormancy), particularly in the epithelial hair germ, to reach a peak during proanagen (reactivation). In anagen (when follicle growth was fully re-established), PRLR mRNA returned to levels similar to those observed before the induced cycle. Hence, this longer term rise and fall of PRLR expression followed that of plasma prolactin concentration with a lag of 12-14 days. PRLR mRNA was most abundant in the dermal papilla, outer root sheath, hair germ, skin glands and epidermis. Location of PRLR in the dermal papilla and outer root sheath indicates action of prolactin on the growth-controlling centres within wool follicles. These cycle-related patterns of PRLR expression suggest dynamic regulation of PRLR by prolactin, thereby modulating hormonal responsiveness of seasonally growing hair follicles.