Instrumentation and contrast mechanisms in scanning helium microscopy

Scanning helium microscopy (SHeM) is a novel form of microscopy that uses low energy (5-100 meV) helium atoms to image the surface of a sample. Since helium is inert and neutral, it can be used to study delicate and insulating surfaces, but that also means it can be difficult to manipulate for focussing and detection. The first reflection mode helium images were recently demonstrated using a pinhole to form a narrow beam of helium, but without any focussing of the beam the low signal levels pose a significant challenge. This thesis aims to advance the field by describing how to improve the instrumentation for a helium microscope and how both previously observed and novel contrast is formed in images. The thesis begins with an introduction in chapter 1 to motivate the development of a helium microscope. Chapter 2 contains a literature review of beam formation methods and successful implementations of helium microscopy to date. In chapter 3, the design of the scanning helium microscope is explained, with a description of how images of a surface can be formed with an atom beam. The key aspects of the machine are provided, including a new sample stage that uses a magnetically assisted kinematic mount and measurements of the size of the helium source. When using a pinhole to collimate the beam, the quality and resolution of images are largely determined by the performance of the detector. In chapter 4, the design, implementation and properties of a new helium detector that has both a high efficiency and low background are detailed. The detector is comprised of a solenoidal ioniser, magnetic sector for mass selection and finally a conversion dynode and electron multiplier for measuring the ion current. In chapter 5, the origins of the observed contrast in images from a scanning helium microscope are discussed. For rough surfaces, the helium atoms are diffusely scattered from the surface and the resulting contrast mechanisms are investigated. The second half of the chapter focusses on new contrast mechanisms. By using a mixed gas beam, it is possible to simultaneously probe a surface with atoms at different energies and wavelengths, and the first such images are presented. It is well known that atom beams will diffract from well-ordered surfaces, and diffraction contrast on LiF is explicitly shown to be possible for the first time with a scanning helium microscope. Finally, the optimum geometry to maximise the flux using either a pinhole or zone plate to form the beam is investigated by performing a constrained optimisation in chapter 6. The source properties must also be included due to the strong chromatic aberrations present when using a zone plate. It is shown that the pinhole produces the largest flux for large helium spot sizes, but for small spot sizes the zone plate gives the highest flux and therefore the best signal to noise ratio in images, thus indicating the direction for future research

Finite-size scaling in silver nanowire films: design considerations for practical devices

We report the first application of finite-size scaling theory to nanostructured percolating networks, using silver nanowire (AgNW) films as a model system for experiment and simulation. AgNWs have been shown to be a prime candidate for replacing Indium Tin Oxide (ITO) in applications such as capacitive touch sensing. While their performance as large area films is well-studied, the production of working devices involves patterning of the films to produce isolated electrode structures, which exhibit finite-size scaling when these features are sufficiently small. We demonstrate a generalised method for understanding this behaviour in practical rod percolation systems, such as AgNW films, and study the effect of systematic variation of the length distribution of the percolating material. We derive a design rule for the minimum viable feature size in a device pattern, relating it to parameters which can be derived from a transmittance-sheet resistance data series for the material in question. This understanding has direct implications for the industrial adoption of silver nanowire electrodes in applications where small features are required including single-layer capacitive touch sensors, LCD and OLED display panels

The Birth of a Galaxy. II. The Role of Radiation Pressure

Massive stars provide feedback that shapes the interstellar medium of galaxies at all redshifts and their resulting stellar populations. Here we present three adaptive mesh refinement radiation hydrodynamics simulations that illustrate the impact of momentum transfer from ionising radiation to the absorbing gas on star formation in high-redshift dwarf galaxies. Momentum transfer is calculated by solving the radiative transfer equation with a ray tracing algorithm that is adaptive in spatial and angular coordinates. We find that momentum input partially affects star formation by increasing the turbulent support to a three-dimensional rms velocity equal to the circular velocity of early haloes. Compared to a calculation that neglects radiation pressure, the star formation rate is decreased by a factor of five to 1.8 x 10^{-2} Msun/yr in a dwarf galaxy with a dark matter and stellar mass of 2.0 x 10^8 and 4.5 x 10^5 solar masses, respectively, when radiation pressure is included. Its mean metallicity of 10^{-2.1} Z_sun is consistent with the observed dwarf galaxy luminosity-metallicity relation. However, what one may naively expect from the calculation without radiation pressure, the central region of the galaxy overcools and produces a compact, metal-rich stellar population with an average metallicity of 0.3 Z_sun, indicative of an incorrect physical recipe. In addition to photo-heating in HII regions, radiation pressure further drives dense gas from star forming regions, so supernovae feedback occurs in a warmer and more diffuse medium, launching metal-rich outflows. Capturing this aspect and a temporal separation between the start of radiative and supernova feedback are numerically important in the modeling of galaxies to avoid the "overcooling problem". We estimate that dust in early low-mass galaxies is unlikely to aid in momentum transfer from radiation to the gas.Comment: 18 pages, 11 figures, replaced with accepted version, MNRAS. Minor changes with the conclusions unaffecte

PROPHETIC: Prospective Identification of Pneumonia in Hospitalized Patients in the Intensive Care Unit

BACKGROUND: Pneumonia is the leading infection-related cause of death. Using simple clinical criteria and contemporary epidemiology to identify patients at high risk of nosocomial pneumonia should enhance prevention efforts and facilitate development of new treatments in clinical trials. RESEARCH QUESTION: What are the clinical criteria and contemporary epidemiology trends helpful in identifying patients at high risk of nosocomial pneumonia? STUDY DESIGN AND METHODS: Within the intensive care units of 28 United States hospitals, we conducted a prospective cohort study among adults hospitalized more than 48 hours and considered high risk for pneumonia (defined as treatment with invasive or noninvasive ventilatory support or high levels of supplemental oxygen). We estimated the proportion of high-risk patients developing nosocomial pneumonia. Using multivariable logistic regression, we identified patient characteristics and treatment exposures associated with increased risk of pneumonia development during the intensive care unit admission. RESULTS: Between February 6, 2016 and October 7, 2016, 4613 high-risk patients were enrolled. Among 1464/4613 (32%) high-risk patients treated for possible nosocomial pneumonia, 537/1464 (37%) met the study pneumonia definition. Among high-risk patients, a multivariable logistic model was developed to identify key patient characteristics and treatment exposures associated with increased risk of nosocomial pneumonia development (c-statistic 0.709, 95% confidence interval 0.686 to 0.731). Key factors associated with increased odds of nosocomial pneumonia included an admission diagnosis of trauma or cerebrovascular accident, receipt of enteral nutrition, documented aspiration risk, and receipt of systemic antibacterials within the preceding 90 days. INTERPRETATION: Treatment for nosocomial pneumonia is common among intensive care unit patients receiving high levels of respiratory support, yet more than half of patients treated do not fulfill standard diagnostic criteria for pneumonia. Application of simple clinical criteria may improve the feasibility of clinical trials of pneumonia prevention and treatment by facilitating prospective identification of patients at highest risk

PROPHETIC EU: Prospective Identification of Pneumonia in Hospitalized Patients in the Intensive Care Unit in European and United States Cohorts

Background The prospective identification of patients at high risk for hospital-acquired/ventilator-associated bacterial pneumonia may improve clinical trial feasibility and foster antibacterial development. In a prior study conducted in the United States, clinical criteria were used to prospectively identify these patients; however, these criteria have not been applied in a European population. Methods Adults considered high risk for pneumonia (treatment with ventilation or high levels of supplemental oxygen) in the intensive care units of 7 European hospitals were prospectively enrolled from June 12 to December 27, 2017. We estimated the proportion of high-risk patients developing pneumonia according to US Food and Drug Administration guidance and a subset potentially eligible for antibacterial trial enrollment. We compared patient characteristics, treatment exposures, and pneumonia incidence in a European cohort and a previously described US cohort. Results Of 888 high-risk patients, 211/888 (24%) were treated for possible pneumonia, and 150/888 (17%) met the Food and Drug Administration definition for hospital-acquired/ventilator-associated bacterial pneumonia. A higher proportion of European patients treated for possible pneumonia met the pneumonia definition (150/211 [71%] vs 537/1464 [37%]; P < .001). Among patients developing pneumonia, a higher proportion of European patients met antibacterial trial eligibility criteria (124/150 [83%] vs 371/537 [69%]; P < .001). Conclusions Clinical criteria prospectively identified high-risk patients with high rates of pneumonia in the European cohort. Despite higher rates of established risk factors and incident pneumonia, European patients were significantly less likely to receive antibiotics for possible pneumonia than US patients. Different treatment practices may contribute to lower rates of antibacterial trial enrollment in the United States

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

5-benzamidoisoquinolin-1-ones and 5-(ω-carboxyalkyl)isoquinolin-1-ones as isoform-selective inhibitors of poly(ADP-ribose) polymerase 2 (PARP-2)

PARP-2 is a member of the poly(ADP-ribose) polymerase family, with some activities similar to those of PARP-1 but with other distinct roles. Two series of isoquinolin-1-ones were designed, synthesized, and evaluated as selective inhibitors of PARP-2, using the structures of the catalytic sites of the isoforms. A new efficient synthesis of 5-aminoisoquinolin-1-one was developed, and acylation with acyl chlorides gave 5-acylaminoisoquinolin-1-ones. By examination of isoquinolin-1-ones with carboxylates tethered to the 5-position, Heck coupling of 5-iodoisoquinolin-1-one furnished the 5-CH═CHCO2H compound for reduction to the 5-propanoic acid. Alkylation of 5-aminoisoquinolin-1-one under mildly basic conditions, followed by hydrolysis, gave 5-(carboxymethylamino)isoquinolin-1-one, whereas it was alkylated at 2-N with methyl propenoate and strong base. Compounds were assayed in vitro for inhibition of PARP-1 and PARP-2, using FlashPlate and solution-phase assays, respectively. The 5-benzamidoisoquinolin-1-ones were more selective for inhibition of PARP-2, whereas the 5-(ω-carboxyalkyl)isoquinolin-1-ones were less so. 5-Benzamidoisoquinolin-1-one is the most PARP-2-selective compound (IC50(PARP-1)/IC50(PARP-2) = 9.3) to date, in a comparative study

Exome Sequencing Identifies Rare Variants in Multiple Genes in Atrioventricular Septal Defect

Purpose The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of non-syndromic individuals with AVSD. Methods: Whole exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. Results: A significant enrichment of rare and rare/damaging variants was identified in the gene set, compared with controls (odds ratio 1.52, 95% confidence interval 1.35–1.71, p = 4.8 x 10-11). The enrichment was specific to AVSD probands compared with a non-AVSD cohort with tetralogy of Fallot (odds ratio 2.25, 95% confidence interval 1.84-2.76, p = 2.2 x 10-16). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2 and MDM4) were enriched for rare variants in AVSD compared to controls, including three syndrome-associated genes (NIPBL, CHD7, CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. Conclusion: Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort