Multiple scattering for diffraction enhanced X-ray imaging

Materials which multiply scatter X-rays and consisting of weakly absorbing microstructures, such as lung tissue, deliver significant signals and remarkable contrast using the diffraction enhanced imaging (DEI) technique. The DEI technique is investigated with respect to multiple scattering properties and its applicability to soft tissue in order to improve medical diagnostics using phase contrast imaging as a new generation of radiography. Methods and calculation algorithms for extracting multiple scattering information by applying the DEI technique were recently developed considering ultra-small angle X-ray scattering. Algorithms and techniques developed in this work allow (i) extending the DEI technique to small-angle scattering of spherical and cylindrical micro-scattering particles, and (ii) computationally efficient analytical calculation of the scattering power by using the properties of a single scattering microparticle. This method was verified during several experiments at the large-scale facilities ELETTRA and ESRF using (i) synthetic specimens, and (ii) applying the calculations to a cow lung tissue specimen assuming alveolar air. While specimen preparation and deflation of the specimen led to uncertainties, the method was verified in this case by comparing the predicted scattering power of mouse lung tissue with Monte-Carlo simulations of the DEI group of Monash University, Melbourne (AUS). <br />The influence of specimen substructure on multiple scattering is investigated and can be qualitatively reconstructed using the model of scattering elaborated in this work. Calculated scattering angle distributions predict strong influence of substructures on the scattering power. <br />The instrumental effects of the analyser crystal, acting as an angular band-pass filter, on the multiple scattering power are analysed and simulated by calculation. Similar cut-offs by the analyser crystal are expected for soft tissue as for the synthetic specimens: The calculated scattering power of the cow lung tissue specimen as well as an exemplary calculation of the scattering power of a human lung for a frontal thorax exposure demonstrate a similar scattering power as the synthetic specimens.Deutsch <br /> Materialien wie etwa Lungengewebe, die aus schwach absorbierenden, vielfachstreuenden Mikrostrukturen bestehen, zeigen unter Verwendung der „Diffraction Enhanced Imaging“ (DEI) Technik signifikante Signale und bemerkenswerten Bildkontrast. Die DEI Technik wird im Hinblick auf Eigenschaften der Vielfachstreuung und ihre Anwendungsmöglichkeit zur medizinischen Diagnostik als neue Generation phasenkontrastsensitiver Radiografie untersucht. Methoden und Algorithmen zur Bestimmung der Vielfachstreustärke unter Verwendung der DEI Technik sind aktuell nur für besonders kleine Streuwinkel verfügbar. Diese Arbeit zeigt Methoden und Berechnungen (i) zur Erweiterung des Streuwinkelbereiches unter Verwendung von kugel- und zylinderförmigen Streupartikeln, und (ii) die rechentechnisch effektive Bestimmung der Vielfachstreustärke unter Zurückführung auf die Streustärke des einzelnen Partikels. Die vorgestellte Berechnungsmethode wird anhand von Experimenten an den Großforschungseinrichtungen ELETTRA und ESRF unter Benutzung von (i) synthetischen Proben und (ii) der Anwendung der Berechnungen auf eine Probe einer Kuhlunge experimentell verifiziert. Während die Präparation und das Zusammenfallen der Lungenprobe zu Unsicherheiten führt, zeigt die vergleichsweise Berechnung zur Streuwirkung einer Mauslunge, die durch die DEI Gruppe der Monash Universität in Melbourne (AUS) mithilfe der Monte-Carlo Methode simuliert wurde, gute Übereinstimmung. <br /> Der Einfluss von Substrukturen auf die Vielfachstreuwirkung wird untersucht und ist unter Benutzung des in dieser Arbeit vorgestellten Streumodells qualitativ rekonstruierbar. Simulierte Streuwinkelverteilungen prognostizieren einen starken Einfluss von Substrukturen auf die Streustärke. <br /> Der instrumentelle Einfluss des Analysatorkristalls, der als Winkelfilter wirkt, wird im Falle von Vielfachstreuung analysiert und kann rechentechnisch nachgebildet werden. Ähnliche signalverzerrende Eigenschaften, die im Experiment mit den synthetischen Proben beobachtet wurden, werden für Lungengewebe erwartet. Die Probe der Kuhlunge und eine Hochrechnung für die Streustärke der menschlichen Lunge bei einer frontalen Thoraxaufnahme zeigen vergleichbare Streustärken mit den im Experiment verwendeten synthetischen Proben. <br /> <br /> Italiano <br /> Materiali che causano la diffusione multipla di raggi X e che consistono di microstrutture poco assorbenti, come ad esempio il tessuto polmonare, producono segnali significativi e contrasti notevoli utilizzando la tecnica del “Diffraction Enhanced Imaging” (DEI). La tecnica DEI è investigata con particolare riguardo alle proprietà di diffusione multipla ed alle sue applicazioni all’imaging di tessuti molli col fine di migliorare la dignostica medica utilizzando il contrasto di fase come imaging radiografico di nuova generazione. Metodi ed algoritmi di calcolo per estrarre informazioni di diffusione multipla applicando la tecnica DEI sono stati recentemente sviluppati considerando la diffusione di raggi X a piccolissimo angolo. Le tecniche e gli algoritmi sviluppati in questo lavoro di tesi permettono (i) di estendere la tecnica DEI alla diffusione a piccolo angolo da micro particelle sferiche e cilindriche e (ii) di calcolare analiticamente e con un uso efficiente del calcolo numerico la potenza di diffusione utilizzando le proprietà di diffusione da una singola micro-particella. Questo metodo è stato verificato durante diversi esperimenti presso i grandi laboratori internazionali ELETTRA ed ESRF utilizzando (i) campioni sintetici e (ii) applicando i calcoli a campioni di tessuto polmonare di mucca assumendo aria negli alveoli. Poichè la preparazione del campione ed il suo deterioramento hanno portato ad alcune incertezze, il metodo in questo caso è stato verificato confrontando la potenza di scattering prevista nel caso di tessuto polmonare di topo con simulazioni Montecarlo del gruppo DEI dell’Università di Monash, Melbourne (AUS). <br /> L’influenza della sottostruttura del campione sulla diffusione multipla è stata investigata e può essere ricostruita qualitativamente utilizzando il modello di diffusione elaborato in questo lavoro di tesi. Le distribuzioni calcolate per l’angolo di diffusione predicono una forte influenza delle sottostrutture sulla potenza di diffusione. <br /> Si sono analizzati e ricostruiti mediante simulazioni gli effetti strumentali d cristallo analizzatore, che funge da filtro angolare passa-banda, sulla potenza di diffusione multipla. Effetti di taglio simili da parte del cristallo analizzatore sono attesi per i tessuti molli e per i campioni sintetici. La potenza di diffusione calcolata per i campioni di tessuto polmonare di mucca come pure un calcolo dimostrativo della potenza di diffusione di un polmone umano per una esposizione toracica frontale dimostrano una potenza di diffusione simile a quella dei campioni sintetici

X-ray detection of structural orientation in human articular cartilage

AbstractObjective: To determine the feasibility of detecting the structural orientation in cartilage with Diffraction Enhanced X-Ray Imaging.Design: Human tali and femoral head specimens were Diffraction Enhanced X-Ray Imaged (DEI) at the SYRMEP beamline at Elettra at various energy levels to detect the architectural arrangement of collagen within cartilage. DEI utilizes a monochromatic and highly collimated beam, with an analyzer crystal that selectively weights out photons according to the angle they have been deviated with respect to the original direction. This provides images of very high contrast, and with the rejection of X-ray scatter.Results: DEI allowed the visualization of articular cartilage and a structural orientation, resembling arcades, within.Conclusion: Our diffraction enhanced images represent the first radiographic detection of the structural orientation in cartilage. Our data are in line with previous studies on the structural organization of joint cartilage. They confirm the model of a vaulting system of collagen fiber bundles interrupted by proteoglycan aggregates

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

BACKGROUND The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016 -002299-28.)

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used