Angular dependence of the transverse Raman scattering in KDP and DKDP in geometries suitable for beam polarization control.

The angular dependance of the transverse Raman scattering in potassium dihydrogen phosphate (KDP) and its deuterated analogue (DKDP) for the entire range of crystal configurations suitable for laser beam polarization control has been investigated via experimental and modeling tools. This work was made possible by simultaneously rotating a spherical sample and the pump polarization to effectively measure the angular dependance of the transverse Raman signal in 360°. This novel method, which is applicable for the investigation of the Raman scattering in optically anisotropic materials, demonstrates that the spontaneous Raman scattering signal exhibits strong angular dependence that is modulated by depolarization and polarization rotation effects generated as the Raman signal traverses the material due to its birefringence. The results show that the total signal generated by the pump beam is the sum of the signals generated by the two components that have polarization parallel and orthogonal to the optic axis. The peak signal intensity, which is of importance for high-power laser applications, depends on the orientation of the optic axis and can vary by a factor of about 2. The excellent agreement between experimental data and modeling results validates the associated models and enables one to consider optimal crystal cut designs for specific applications.

Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

Magnetization transfer ratio: a quantitative imaging biomarker for 5q spinal muscular atrophy.

BACKGROUND AND PURPOSE: We quantified peripheral nerve lesions in adults with 5q-linked spinal muscular atrophy (SMA) type 3 by analysing the magnetization transfer ratio (MTR) of the sciatic nerve, and tested its potential as a novel biomarker for macromolecular changes. METHODS: Eighteen adults with SMA 3 (50% SMA 3a, 50% SMA 3b) and 18 age-/sex-matched healthy controls prospectively underwent magnetization transfer contrast imaging in a 3-Tesla magnetic resonance scanner. Two axial three-dimensional gradient echo sequences, with and without an off-resonance saturation rapid frequency pulse, were performed at the right distal thigh. Sciatic nerve regions of interest were manually traced on 10 consecutive axial slices in the images generated without off-resonance saturation, and then transferred to corresponding slices generated by the sequence with the off-resonance saturation pulse. Subsequently, MTR and cross-sectional areas (CSAs) of the sciatic nerve were analysed. In addition, detailed neurologic, physiotherapeutic and electrophysiologic examinations were conducted in all patients. RESULTS: Sciatic nerve MTR and CSA reliably differentiated between healthy controls and SMA 3, 3a or 3b. MTR was lower in the SMA 3 (P < 0.0001), SMA 3a (P < 0.0001) and SMA 3b groups (P = 0.0020) than in respective controls. In patients with SMA 3, MTR correlated with all clinical scores, and arm nerve compound motor action potentials (CMAPs). CSA was lower in the SMA 3 (P < 0.0001), SMA 3a (P < 0.0001) and SMA 3b groups (P = 0.0006) than in controls, but did not correlate with clinical scores or electrophysiologic results. CONCLUSIONS: Magnetization transfer ratio is a novel imaging marker that quantifies macromolecular nerve changes in SMA 3, and positively correlates with clinical scores and CMAPs.

Mechanisms of picosecond laser-induced damage in common multilayer dielectric gratings.

The modifications of multilayer dielectric (MLD) gratings arising from laser-induced damage using 0.6-ps and 10-ps laser pulses at 1053 nm are investigated to better understand the damage-initiation mechanisms. Upon damage initiation, sections of the affected grating pillars are removed, thereby erasing the signature of the underlying mechanisms of laser damage. To address this issue, we performed paired studies using macroscopic grating-like features that are 5 mm in width to reveal the laser-damage morphology of the different grating sections: pillar side wall, sole, and pillar top. The results suggest that, similarly to MLD coatings, there are two damage-initiation mechanisms corresponding to the different pulse durations.

Simulation of internal stress waves generated by laser-induced damage in multilayer dielectric gratings.

Multilayer dielectric (MLD) gratings used in ultrahigh-intensity laser systems often exhibit a laser-induced damage performance below that of their constituent materials. Reduced performance may arise from fabrication- and/or design-related issues. Finite element models were developed to simulate stress waves in MLD grating structures generated by laser-induced damage events. These models specifically investigate the influence of geometric and material parameters on how stress waves can lead to degradation of material structural integrity that can have adverse effects on its optical performance under subsequent laser irradiation: closer impedance matching of the layer materials reduces maximum interface stresses by ~20% to 30%; increasing sole thickness from 50 nm to 500 nm reduces maximum interface stresses by ~50%.

Raman Amplification with a Flying Focus.

We propose a new laser amplifier scheme utilizing stimulated Raman scattering in plasma in conjunction with a "flying focus"-a chromatic focusing system combined with a chirped pump beam that provides spatiotemporal control over the pump's focal spot. Pump intensity isosurfaces are made to propagate at v=-c so as to be in sync with the injected counterpropagating seed pulse. By setting the pump intensity in the interaction region to be just above the ionization threshold of the background gas, an ionization wave is produced that travels at a fixed distance ahead of the seed. Simulations show that this will make it possible to optimize the plasma temperature and mitigate many of the issues that are known to have impacted previous Raman amplification experiments, in particular, the growth of precursors.

[Genetic testing in polygenic diseases : Atrial fibrillation, arterial hypertension and coronary artery disease]. / Genetische Diagnostik polygener Erkrankungen : Vorhofflimmern, Hypertonie und koronare Herzerkrankung.

Genetic testing plays an increasing role in cardiovascular medicine. Advances in technology and the development of novel and more affordable (high throughput) methods have led to the identification of genetic risk factors in research and clinical practice. Also, this progress has simplified the screening of patients and individuals at risk. In case of rare monogenic diseases, diagnostics, risk stratification, and, in some cases, treatment decisions have become easier. For common, polygenic cardiovascular diseases, the situation is more complex due to interaction of modifiable external risk factors and nonmodifiable factors like genetic predisposition. Over the last few years, it has been shown that multiple genes are involved in the pathophysiology of these cardiovascular diseases rather than one single gene. In the following article, we give an overview of the genetic risk factors in polygenic cardiovascular diseases as atrial fibrillation, arterial hypertension and coronary artery disease. Furthermore, we aim to illustrate in which cases genetic testing is recommended in these diseases.

Publisher's Note: Demonstration of Fuel Hot-Spot Pressure in Excess of 50 Gbar for Direct-Drive, Layered Deuterium-Tritium Implosions on OMEGA [Phys. Rev. Lett. 117, 025001 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.117.025001.

Demonstration of Fuel Hot-Spot Pressure in Excess of 50 Gbar for Direct-Drive, Layered Deuterium-Tritium Implosions on OMEGA.

A record fuel hot-spot pressure P_{hs}=56±7 Gbar was inferred from x-ray and nuclear diagnostics for direct-drive inertial confinement fusion cryogenic, layered deuterium-tritium implosions on the 60-beam, 30-kJ, 351-nm OMEGA Laser System. When hydrodynamically scaled to the energy of the National Ignition Facility, these implosions achieved a Lawson parameter ∼60% of the value required for ignition [A. Bose et al., Phys. Rev. E 93, 011201(R) (2016)], similar to indirect-drive implosions [R. Betti et al., Phys. Rev. Lett. 114, 255003 (2015)], and nearly half of the direct-drive ignition-threshold pressure. Relative to symmetric, one-dimensional simulations, the inferred hot-spot pressure is approximately 40% lower. Three-dimensional simulations suggest that low-mode distortion of the hot spot seeded by laser-drive nonuniformity and target-positioning error reduces target performance.

Urodynamic investigations in patients with spinal cord injury: should the ice water test follow or precede the standard filling cystometry?

OBJECTIVES: To evaluate whether the ice water test (IWT) should be performed before or after the standard urodynamic investigation (UDI). PATIENTS AND METHODS: Two cohorts of patients suffering from neurogenic lower urinary tract dysfunction (NLUTD) due to spinal cord injury (SCI) were matched by lesion level and age. The patients of cohort A (n=55, retrospective cohort) underwent the IWT before and the patients of cohort B (n=110, prospective cohort) after standard UDI. The IWT effect on urodynamic parameters has been compared between the two groups using the Mann-Whitney U-test for independent samples. UDI was performed according to good urodynamic practices recommended by the International Continence Society. RESULTS: The mean age of both cohorts was 49 years. Performing the IWT before versus after standard UDI resulted in a significantly lower maximum cystometric bladder capacity (P=0.01), lower incidence of detrusor overactivity (P=0.017) and lower maximum detrusor pressure during IWT (P=0.04). All other urodynamic parameters assessed demonstrated no significant difference (P>0.05). CONCLUSIONS: Our results are in line with findings from animal studies demonstrating a bladder cooling-induced gating effect on the micturition reflex volume threshold on the level of sacral interneurons. Since the IWT is an unphysiological investigation that might significantly bias subsequent urodynamics, we suggest that the IWT should not precede more physiological standard UDI.

Electron-beam-deposited distributed polarization rotator for high-power laser applications.

Electron-beam deposition of silica and alumina is used to fabricate distributed polarization rotators suitable for smoothing the intensity of large-aperture, high-peak-power lasers. Low-modulation, low-loss transmittance with a high 351-nm laser-damage threshold is achieved.

[Genetic analyses as basis for a personalized medicine in patients with coronary artery disease]. / Genetische Analysen als Basis einer individualisierten Medizin bei koronarer Herzkrankheit.

Knowledge about the etiology of coronary artery disease (CAD) entered new dimensions using genome-wide association studies. The current situation is that 46 chromosomal loci have been identified to be associated with CAD with genome-wide significance, i.e. p<5×10(-8), in Western Europeans. As the individual DNA sequence remains unchanged after fertilization, the risk variants cannot occur due to confounders, such as secondary disease processes. Thus, it can be proposed that these variants are directly affecting a primary and thereby causal pathophysiological process in CAD. Interestingly, only 20% of the effects mediated by the identified loci can be explained by the influence of traditional risk factors. This implies that yet unknown mechanisms and, as a consequence, new therapeutic targets play an important role in the pathophysiology of CAD. However, the high allele frequency of risk loci was also surprising. In the diploid chromosome set Western European individuals carry on average 30-50 risk variants at the 46 loci. Considering this, every individual in the population carries a larger or smaller genetic predisposition for CAD. On the other hand it is remarkable that many risk allele carriers seem to be able to compensate the genetic risk: even in old age not everyone suffers from CAD. This indicates yet unknown gene-gene and gene-environment interactions and limits the current possibilities in individual risk prediction.

[Importance of modern genome-wide studies for the risk of myocardial infarction]. / Bedeutung moderner Genomstudien für das Herzinfarktrisiko.

The individual genetic susceptibility is a cornerstone in the pathogenesis of coronary artery disease (CAD). The search for the genetic background and the subsequently altered molecular mechanisms has been ineffective for several years. The increase in genome-wide association studies in recent years has changed the scenario and more than 40 variants have so far been identified to be highly significantly associated with CAD and the risk of myocardial infarction (MI). Whereas most of these findings affect frequent polymorphisms, exome-wide sequencing in families with a high prevalence of CAD revealed mutations with a high penetrance and as a consequence a high risk of suffering from MI. The findings allow a deeper insight into functional mechanisms involved in the pathogenesis of atherosclerosis. Furthermore, the data enables validation of the numerous epidemiologically identified risk markers with respect to the causal role in the development of CAD, making the genetic architecture of CAD much more transparent. Nevertheless, individual risk prediction has only made weak progress in the face of the new findings. Every individual without exception carries numerous risk alleles even when the number and effect strength shows individual differences. Thus, a varying degree of genetic susceptibility is shared by all of us. Current research is therefore focusing on the functional integration of genetic information to discover new approaches to prevention and therapy.

Laser-beam zooming to mitigate crossed-beam energy losses in direct-drive implosions.

Spherically symmetric direct-drive-ignition designs driven by laser beams with a focal-spot size nearly equal to the target diameter suffer from energy losses due to crossed-beam energy transfer (CBET). Significant reduction of CBET and improvements in implosion hydrodynamic efficiency can be achieved by reducing the beam diameter. Narrow beams increase low-mode perturbations of the targets because of decreased illumination uniformity that degrades implosion performance. Initiating an implosion with nominal beams (equal in size to the target diameter) and reducing the beam diameter by ∼ 30%-40% after developing a sufficiently thick target corona, which smooths the perturbations, mitigate CBET while maintaining low-mode target uniformity in ignition designs with a fusion gain ≫ 1.

SVEP1 influences monocyte to macrophage differentiation via integrin α4ß1/α9ß1 and Rho/Rac signalling.

BACKGROUND: The large extracellular matrix protein SVEP1 mediates cell adhesion via integrin α9ß1. Recent studies have identified an association between a missense variant in SVEP1 and increased risk of coronary artery disease (CAD) in humans and in mice Svep1 deficiency alters the development of atherosclerotic plaques. However how SVEP1 functionally contributes to CAD pathogenesis is not fully understood. Monocyte recruitment and differentiation to macrophages is a key step in the development of atherosclerosis. Here, we investigated the requirement for SVEP1 in this process. METHODS: SVEP1 expression was measured during monocyte-macrophage differentiation in primary monocytes and THP-1 human monocytic cells. SVEP1 knockout THP-1 cell lines and the dual integrin α4ß1/α9ß1 inhibitor, BOP, were utilised to investigate the effect of these proteins in THP-1 cell adhesion, migration and cell spreading assays. Subsequent activation of downstream integrin signalling intermediaries was quantified by western blotting. RESULTS: SVEP1 gene expression increases in monocyte to macrophage differentiation in human primary monocytes and THP-1 cells. Using two SVEP1 knockout THP-1 cells we observed reduction in monocyte adhesion, migration, and cell spreading compared to control cells. Similar results were found with integrin α4ß1/α9ß1 inhibition. We demonstrate reduced activity of Rho and Rac1 in SVEP1 knockout THP-1 cells. CONCLUSIONS: SVEP1 regulates monocyte recruitment and differentiation phenotypes through an integrin α4ß1/α9ß1 dependent mechanism. GENERAL SIGNIFICANCE: These results describe a novel role for SVEP1 in monocyte behaviour relevant to CAD pathophysiology.

Induction therapy of AML with ara-C plus daunorubicin versus ara-C plus gemtuzumab ozogamicin: a randomized phase II trial in elderly patients.

BACKGROUND: Chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival (OS) of ≤ 1 year. Elderly patients often present with cardiac comorbidity. Gemtuzumab ozogamicin (GO) is active in elderly (≥ 60 years) patients with relapsed AML with low cardiac toxicity. PATIENTS AND METHODS: This randomized phase II study compared a standard combination of ara-C and daunorubicin (DNR; 7+3) versus ara-C plus gemtuzumab ozogamicin (7+GO) as the first course of induction therapy. Primary objectives were comparison of blast clearance on day 16, event-free survival (EFS), and remission duration. OS, complete remission (CR), and tolerability were secondary objectives. RESULTS: One hundred and nineteen patients with de novo AML, treatment-related AML, AML with a history of myelodysplastic syndrome (MDS), or high-risk MDS entered the study. Median age of 115 patients (intent-to-treat population) was 69 years. Protocol outlined a second course 7+3 for patients without blast clearance and two courses of high-dose ara-C consolidation upon CR. Both treatments were equally effective in blast clearance, CR, EFS, remission duration, or OS (median: 7+3, 9 months; 7+GO, 10 months). Induction death rate was higher in the GO group due to veno-occlusive disease. CONCLUSION: The study did not show significant superiority of 7+GO over standard 7+3.

Observation of strong oscillations of areal mass in an unsupported shock wave.

An experimental study of hydrodynamic perturbation evolution in a strong unsupported shock wave, which is immediately followed by an expansion wave, is reported. A planar solid plastic target rippled on the front side is irradiated with a 350-450 ps long laser pulse. The perturbation evolution in the target is observed using face-on monochromatic x-ray radiography during and for up to 4 ns after the laser pulse. The theoretically predicted large oscillations of the areal mass in the target are observed for the first time. Multiple phase reversals of the areal mass modulation are detected.

Purification and characterization of Haemophilus influenzae pili, and their structural and serological relatedness to Escherichia coli P and mannose-sensitive pili.

Haemophilus influenzae pili were purified, and their physical and serological properties were examined. The solution properties of the pili were determined, and then a purification scheme involving repeated cycles of precipitation and solubilization was developed. The purified pili from one type b isolate (A02) were found to consist of multiple copies of a 25,000 mol wt subunit. Amino-terminal sequence analysis of A02 pili was carried out to 40 amino acid residues, and a remarkable degree of sequence homology was found with E. coli P and mannose-sensitive (MS) pili (27.5 and 25% homology, respectively). Purified A02 pili were found to be highly immunogenic, and serological analysis by enzyme-linked immunosorbent assay and whole piliated cell agglutination revealed significant cross-reactivity between A02 pilus antiserum and the pili of seven other H. influenzae strains tested (heterologous titers = 2-100% of the homologous titer). Cross-reactivity was also observed between the H. influenzae pili (five of eight strains tested) and the P pili from E. coli strains HU849 and 3669; no cross-reactivity was detected with MS pili from E. coli strain H10407 and C94. The structural similarities between H. influenzae and E. coli P and MS pili suggest a common gene ancestry.

Reactor decay heat in 239Pu: solving the γ discrepancy in the 4-3000-s cooling period.

The ß feeding probability of (102,104,105,106,107)Tc, 105Mo, and 101Nb nuclei, which are important contributors to the decay heat in nuclear reactors, has been measured using the total absorption technique. We have coupled for the first time a total absorption spectrometer to a Penning trap in order to obtain sources of very high isobaric purity. Our results solve a significant part of a long-standing discrepancy in the γ component of the decay heat for 239Pu in the 4-3000 s range.

Determination of the Raman polarizability tensor in the optically anisotropic crystal potassium dihydrogen phosphate and its deuterated analog.

The Raman tensor of the dominant A1 modes of the nonlinear optical crystalline material potassium dihydrogen phosphate and its 70% deuterated analog have been ascertained. Challenges in determining the A1 mode tensor element values based on previous reports have been resolved using a specially designed experimental setup that makes use of spherical crystal samples. This novel experimental design enabled the determination of measurement artifacts, including polarization rotation of the pump and/or scattered light propagating through the sample and the contribution of additional overlapping phonon modes, which have hindered previous efforts. Results confirmed that the polarization tensor is diagonal, and matrix elements were determined with high accuracy.