In laser illuminated dielectric accelerators (DLA) high acceleration gradients can be achieved due to high damage thresholds of the materials at optical frequencies. This is a necessity for ...developing more compact particle accelerator technologies. The Accelerator on a CHip International Program (ACHIP) funded by the Gordon and Betty Moore Foundation is researching such devices. DESY Hamburg is part of the collaboration. The dedicated accelerator research facility SINBAD is particularly well suited for DLA experiments at relativistic electron energies. High quality beams and short bunch lengths are anticipated from the ARES linac which is currently under construction at SINBAD. The aim of the experiment is the injection of a short electron bunch from the ARES linac into a DLA. In this study the results of one of the first possible experiments at the facility are estimated via a combination of particle-in-cell (PIC) and tracking simulations. ASTRA is used to simulate an electron bunch from the ARES linac at a suitable working point. The dielectric part of the setup will be simulated using the PIC code from CST Particle Studio incorporating the retrieved bunch from the ASTRA simulation. The energy spectra of the electron bunches are calculated as would be measured from a spectrometer dipole with and without the laser fields.
In laser illuminated dielectric accelerators (DLA) high acceleration gradients can be achieved, due to high damage thresholds of the materials at optical frequencies. This is a necessity in ...developing more compact particle accelerator technologies. The Accelerator on a CHip International Program funded by the Gordon and Betty Moore Foundation is researching such devices. Means to manipulate the beam, i.e. focusing and deflection, are needed for the proper operation of such devices. These means should rely on the same technologies for manufacturing and powering like the accelerating structures. In this study different concepts for dielectric laser driven deflecting structures are investigated via particle-in-cell (PIC) simulations and compared afterwards. The comparison is conducted with respect to the suitability for beam manipulation. Another interesting application will be investigated as a diagnostic device for ultra short electron bunches from conventional accelerators functioning like a radio frequency transverse deflecting cavity (TDS).
Laser-driven grating type DLA (Dielectric Laser Accelerator) structures have been shown to produce accelerating gradients on the order of GeV/m. In simple \(\beta\)-matched grating structures due to ...the nature of the laser induced steady-state in-channel fields the per period forces on the particles are mostly in longitudinal direction. Even though strong transverse magnetic and electric fields are present, the net focusing effect over one period at maximum energy gain is negligible in the case of relativistic electrons. Stable acceleration of realistic electron beams in a DLA channel however requires the presence of significant net transverse forces. In this work we simulate and study the effect of using the transient temporal shape of short Gaussian drive laser pulses in order to achieve suitable field configurations for potentially stable acceleration of relativistic electrons in the horizontal plane. In order to achieve this, both the laser pulse and the grating geometry are optimized. Simulations conducted with the Particle-In-Cell code VSim 7.2 are shown for both the transient and steady state/long pulse case. Finally we investigate how the drive laser phase dependence of the focusing forces could affect a potential DLA-based focusing lattice.
We will discuss the temporal and spatial challenges for electron acceleration inside dielectric laser accelerators to demonstrate electron acceleration in the relativistic regime and show recent ...acceleration results in 100 MeV electron energy range.
In this work we present the outlines of possible experiments for dielectric laser acceleration (DLA) of ultra-short relativistic electron bunches produced by the ARES linac, currently under ...construction at the SINBAD facility (DESY Hamburg). The experiments are to be performed as part of the Accelerator on a Chip International Program (ACHIP), funded by the Gordon and Betty Moore Foundation. At SINBAD we plan to test the acceleration of already pre-accelerated relativistic electron bunches in laser-illuminated dielectric grating structures. We present outlines of both the acceleration of ultra-short single bunches, as well as the option to accelerate phase-synchronous sub-fs microbunch trains. Here the electron bunch is conditioned prior to the injection by interaction with an external laser field in an undulator. This generates a sinusoidal energy modulation that is transformed into periodic microbunches in a subsequent chicane. The phase synchronization is achieved by driving both the modulation process and the DLA with the same laser pulse. In addition to the conceptual layouts and plans of the experiments we present start-to-end simulation results for different ARES working points.
Short and INnovative Bunches and Accelerators At Desy (SINBAD) at Deutsches Elektronen Synchrotron (DESY) is a dedicated long-term accelerator development and research facility. It is foreseen to ...house several research efforts towards novel high gradient particle acceleration technologies including THz, plasma and dielectric laser based types. A brief overview will be provided. Among the candidates for future applications are dielectric laser accelerators (DLA). Within the Accelerator on a CHip International program (ACHIP) collaboration funded by Gordon and Betty Moore Foundation, grating type DLAs are being investigated with the goal to build a 1 MeV 'shoe box' table top accelerator, only requiring a suitable laser system as input. To achieve this goal, the creation and handling of micro-bunch trains in the regime suitable for DLA has to be researched. The Accelerator Research Experiment at SINBAD (ARES) linear accelerator will to deliver very low-emittance, ultra-short, high-quality electron bunches to be used to investigate these topics. Two experimental approaches towards these goals are presented. One is focused on producing and injecting a phase-synchronous micro-bunch train into a DLA. This experiment is suitable for controlling the phase between electron bunches and the accelerating fields comparable to conventional radiofrequency accelerators. A micro-bunching scheme from seeded free-electron-laser applications using a laser modulator and a magnetic chicane is foreseen to be implemented. The laser for the modulator will also drive the DLA, connecting the spacing in the micro-bunch to the periodicity of the accelerator. An additional approach is focused towards injection of a fs electron bunch into a DLA, probing the accelerating fields and showing different spectra of the particles correlated to the injection phase. The general limitations will be also be discussed. First experiments are planned for spring 2019.
Der demographische Trend zur älteren Gesellschaft wird sich fortsetzen und wird in absehbarer Zeit entscheidenden Einfluss auf die Medizinlandschaft haben. Ältere Menschen leiden öfter an allgemeinen ...Funktionseinschränkungen, zu denen noch spezielle Störungen von Organsystemen kommen, der Gastrointestinaltrakt ist dabei häufig betroffen. Einige gastroenterologische Erkrankungen wie z. B. die Obstipation kommen im Alter häufiger vor, der geriatrische Gesichtspunkt tritt immer mehr in den Vordergrund. Aber auch die Komorbidität (z. B. Herz, Niere) ist zu berücksichtigen. Weitere Einschränkungen sind durch den Verlust der Sehkraft und des Hörvermögens sowie der zunehmenden Gebrechlichkeit mit Fallneigung und der Inkontinenz zu erwarten. Eine altersgerechte Ernährung unter Berücksichtigung der veränderten Funktionen des Gastrointestinaltraktes ist notwendig. Ältere Menschen sind vermehrt auf Medikamente angewiesen. Die medikamentöse Therapie mehrerer Krankheitsentitäten führt dabei häufig zu einer Polypharmazie mit entsprechenden Arzneimittelnebenwirkungen. Arzneimittelnebenwirkungen bei älteren Patienten manifestieren sich häufig als gastroenterologische Symptome. Hier sind z. B. Obstipation, Durchfall, Magengeschwüre mit gastrointestinaler Blutung und Refluxösophagitis zu nennen. Bei älteren Patienten erfordern vielfältige interagierende medizinische Probleme also ein multidimensionales Management, das Gastroenterologen, Geriater, Ernährungsmediziner aber auch Pharmakologen einschließt. Das physiologische Alter und der ,,Funktionszustand" des Patienten müssen mehr als das chronologische Alter berücksichtigt aber auch richtig eingeschätzt werden. Interdisziplinär müssen diagnostische und therapeutische Abläufe unter Berücksichtigung der Physiologie und Pathologie älterer gastroenterologischer Patienten angepasst und optimiert werden. Dazu zählen z. B. auch endoskopische Untersuchungen. Die abgestimmte Zusammenarbeit von Krankenhausärzten und niedergelassenen Kollegen ist zur reibungslosen Überleitung in die häusliche Betreuung der Patienten erforderlich.
BACKGROUND:There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention ...(PCI) in stable single-vessel coronary artery disease.
METHODS:We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling.
RESULTS:Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval CI, –4.0 to 45.5; P=0.100) with no interaction of FFR (Pinteraction=0.318) or iFR (Pinteraction=0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70–1.44; P<0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR (Pinteraction<0.00001) and decreasing iFR (Pinteraction<0.00001). PCI did not improve angina frequency score significantly more than placebo (odds ratio, 1.64; 95% CI, 0.96–2.80; P=0.072) with no detectable evidence of interaction with FFR (Pinteraction=0.849) or iFR (Pinteraction=0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30–4.72; P=0.006) but neither FFR (Pinteraction=0.693) nor iFR (Pinteraction=0.761) modified this effect.
CONCLUSIONS:In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT02062593.
BACKGROUND:Dobutamine stress echocardiography is widely used to test for ischemia in patients with stable coronary artery disease. In this analysis, we studied the ability of the prerandomization ...stress echocardiography score to predict the placebo-controlled efficacy of percutaneous coronary intervention (PCI) within the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina).
METHODS:One hundred eighty-three patients underwent dobutamine stress echocardiography before randomization. The stress echocardiography score is broadly the number of segments abnormal at peak stress, with akinetic segments counting double and dyskinetic segments counting triple. The ability of prerandomization stress echocardiography to predict the placebo-controlled effect of PCI on response variables was tested by using regression modeling.
RESULTS:At prerandomization, the stress echocardiography score was 1.56±1.77 in the PCI arm (n=98) and 1.61±1.73 in the placebo arm (n=85). There was a detectable interaction between prerandomization stress echocardiography score and the effect of PCI on angina frequency score with a larger placebo-controlled effect in patients with the highest stress echocardiography score (Pinteraction=0.031). With our sample size, we were unable to detect an interaction between stress echocardiography score and any other patient-reported response variablesfreedom from angina (Pinteraction=0.116), physical limitation (Pinteraction=0.461), quality of life (Pinteraction=0.689), EuroQOL 5 quality-of-life score (Pinteraction=0.789), or between stress echocardiography score and physician-assessed Canadian Cardiovascular Society angina class (Pinteraction=0.693), and treadmill exercise time (Pinteraction=0.426).
CONCLUSIONS:The degree of ischemia assessed by dobutamine stress echocardiography predicts the placebo-controlled efficacy of PCI on patient-reported angina frequency. The greater the downstream stress echocardiography abnormality caused by a stenosis, the greater the reduction in symptoms from PCI.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT02062593.
6044
Background: More than half of HPV negative HSNCC harbor genomic aberrations (i.e. CDKN2A loss, cyclin D amplification (ampl.)) that activate the cyclin-dependent kinase 4 and 6 (CDK4/6) – ...retinoblastoma protein (Rb) signalling pathway. Hyperactivated CDK4/6-Rb pathway leads to acceleration of G1/S transition of cell cycle and ultimately to uncontrolled cellular proliferation. We hypothesized that abemaciclib, a CDK4/6 inhibitor, could be a potent targeted strategy by inhibiting this commonly dysregulated pathway in HNSCC. Methods: This single arm, multicentre Phase II evaluated the efficacy of abemaciclib (200mg/d orally BID) in molecularly-selected, HPV negative (HPV
-
), RM-HNSCC patients (pts) progressing after at least 1 prior line of platinum and cetuximab. A molecular screening step through centralised CGH-assay was required before treatment start: only pt with tumor harboring CDKN2A loss and/or CCND1 and/or CDK6 ampl. without homozygous deletion of RB1 were eligible to the therapeutic step. The primary endpoint was 8-week non-progression rate (PFR
8W
) as per central imaging review according to RECIST V.1.1. Secondary endpoints included best overall response rate (BORR), progression free survival (PFS), overall survival (OS) and adverse event (AE) according to NCI-CTCAE V5.0. The study used a Fleming A’Hern design with an inefficacy bound of 15% and a target PFR
8W
of 40% (α = 5% one sided, 1-β = 90%). Results: Twenty-six HPV
-
RM-HNSCC pts (M: 23, F: 3, median age: 59 range, 42-78, heavily pre-treated 84.6% ≥ 2 prior lines) received at least one dose of abemaciclib. According to central CGH-assay, molecular alterations were CDKN2A loss + CCND1 ampl. + CDK6 ampl. (n = 1), CDKN2A loss + CCND1 ampl. (n = 10), CDKN2A loss (n = 6) or CCND1 ampl. (n = 9), all with intact Rb. Among the 24 evaluable pts, 7 pts were progression-free at 8 weeks (PFR
8w
:29.2% (95% CI 14.6-)). BORR according to central imaging review was stable disease for 7 pts (31.8%) and progressive disease for 11 pts (50%); no objective response was observed. Median PFS and OS were 7.1 weeks (95% CI: 6.9-10.4) and 4.8 months (95% CI: 2.4-7.3), respectively. Most common related AEs (≥20% of pts, all grade) were diarrhea/nausea/vomiting, fatigue and hematological toxicity (anemia, lymphocyte and neutrophil count decreased). Two fatal serious AE potentially related to abemaciclib according to both investigator and sponsor were reported: a case of pulmonary hemorrhage also possibly related to abemaciclib-induced tumor necrosis and a case of myocardial infarction. Conclusions: Abemaciclib had limited antitumor activity in RM-HNSCC harboring molecular alteration in CDK4/6 pathway. Clinical trial information: NCT03356223 .
PDF
