Laser-accelerated electron beams at 1 GeV using optically-induced shock injection.

In recent years, significant progress has been made in laser wakefield acceleration (LWFA), both regarding the increase in electron energy, charge and stability as well as the reduction of bandwidth of electron bunches. Simultaneous optimization of these parameters is, however, still the subject of an ongoing effort in the community to reach sufficient beam quality for next generation's compact accelerators. In this report, we show the design of slit-shaped gas nozzles providing centimeter-long supersonic gas jets that can be used as targets for the acceleration of electrons to the GeV regime. In LWFA experiments at the Centre for Advanced Laser Applications, we show that electron bunches are accelerated to [Formula: see text] using these nozzles. The electron bunches were injected into the laser wakefield via a laser-machined density down-ramp using hydrodynamic optical-field-ionization and subsequent plasma expansion on a ns-timescale. This injection method provides highly controllable quasi-monoenergetic electron beams with high charge around [Formula: see text], low divergence of [Formula: see text], and a relatively small energy spread of around [Formula: see text] at [Formula: see text]. In contrast to capillaries and gas cells, the scheme allows full plasma access for injection, probing or guiding in order to further improve the energy and quality of LWFA beams.

Measuring spatio-temporal couplings using modal spatio-spectral wavefront retrieval.

Knowledge of spatio-temporal couplings such as pulse-front tilt or curvature is important to determine the focused intensity of high-power lasers. Common techniques to diagnose these couplings are either qualitative or require hundreds of measurements. Here we present both a new algorithm for retrieving spatio-temporal couplings, as well as novel experimental implementations. Our method is based on the expression of the spatio-spectral phase in terms of a Zernike-Taylor basis, allowing us to directly quantify the coefficients for common spatio-temporal couplings. We take advantage of this method to perform quantitative measurements using a simple experimental setup, consisting of different bandpass filters in front of a Shack-Hartmann wavefront sensor. This fast acquisition of laser couplings using narrowband filters, abbreviated FALCON, is easy and cheap to implement in existing facilities. To this end, we present a measurement of spatio-temporal couplings at the ATLAS-3000 petawatt laser using our technique.

Soft Reconstruction Kernels Improve HCC Imaging on a Photon-Counting Detector CT.

RATIONALE AND OBJECTIVES: Hepatocellular carcinoma (HCC) is the only tumor entity that allows non-invasive diagnosis based on imaging without further histological proof. Therefore, excellent image quality is of utmost importance for HCC diagnosis. Novel photon-counting detector (PCD) CT improves image quality via noise reduction and higher spatial resolution, inherently providing spectral information. The aim of this study was to investigate these improvements for HCC imaging with triple-phase liver PCD-CT in a phantom and patient population study focusing on identification of the optimal reconstruction kernel. MATERIALS AND METHODS: Phantom experiments were performed to analyze objective quality characteristics of the regular body and quantitative reconstruction kernels, each with four sharpness levels (36-40-44-48). For 24 patients with viable HCC lesions on PCD-CT, virtual monoenergetic images at 50 keV were reconstructed using these kernels. Quantitative image analysis included contrast-to-noise ratio (CNR) and edge sharpness. Three raters performed qualitative analyses evaluating noise, contrast, lesion conspicuity, and overall image quality. RESULTS: In all contrast phases, the CNR was highest using the kernels with a sharpness level of 36 (all p < 0.05), with no significant influence on lesion sharpness. Softer reconstruction kernels were also rated better regarding noise and image quality (all p < 0.05). No significant differences were found in image contrast and lesion conspicuity. Comparing body and quantitative kernels with equal sharpness levels, there was no difference in image quality criteria, neither regarding in vitro nor in vivo analysis. CONCLUSION: Soft reconstruction kernels yield the best overall quality for the evaluation of HCC in PCD-CT. As the image quality of quantitative kernels with potential for spectral post-processing is not restricted compared to regular body kernels, they should be preferred.

Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555.

Sorafenib in combination with docetaxel as first-line therapy for HER2-negative metastatic breast cancer: Final results of the randomized, double-blind, placebo-controlled phase II MADONNA study.

BACKGROUND: This multicenter, double-blind phase II study assessed the antitumor activity and toxicity profile of docetaxel with the antiangiogenic multikinase inhibitor sorafenib or matching placebo as a first-line treatment in patients with metastatic or locally advanced HER2-negative breast cancer. PATIENTS AND METHODS: Patients were randomized 1:1 to receive docetaxel 100 mg/m2 on day 1 every 3 weeks in combination with sorafenib 400 mg bid or placebo on days 2-18 of each cycle until tumor progression, or unacceptable toxicity. Sorafenib/placebo could be continued at the investigator's discretion if docetaxel was stopped due to toxicity. Primary endpoint was progression free survival (PFS). RESULTS: From October 2008 to December 2013, 102 patients were randomized; 98 patients were evaluable. The trial was prematurely terminated due to slow accrual. Due to increased toxicity the dose of docetaxel was reduced to 75 mg/m2 and an increasing sorafenib dosing schedule was implemented as part of a protocol amendment. The addition of sorafenib to docetaxel did not improve PFS (8.2 vs. 7.3 months for docetaxel/placebo; HR 0.84, log rank p = 0.43), but led to higher rates of early treatment discontinuation. There were no statistically significant differences between sorafenib dosing schedules. CONCLUSIONS: Addition of sorafenib to taxane-based first-line chemotherapy in patients with metastatic breast cancer failed to improve PFS and resulted in increased toxicity.

[Cost-effective medical therapy of hepatitis C employing novel compensation models - pay for cure]. / Kosteneffiziente medikamentöse Therapie der Hepatitis C durch neue Vergütungsmodelle - pay for cure.

Direct acting antivirals (DAAs) have increased cure rates for chronic hepatitis C infection up to nearly 100 %. At the same time treatment costs have risen significantly. Treating all HCV infected patients in Germany with DAAs would generate medication costs ranging between 19 and 37 billion EUR depending on the drug regimen used. Expenses in patients who fail to respond to treatment would amount to approximately 0.9 to 2.15 billion EUR. In difficult to treat patient populations that are characterized by prior failure to treatment or advanced liver disease, lost drug expenses are particularly high due to lower cure rates and longer treatment duration. Outcome-based reimbursement schemes are used to improve the quality of care and to reduce costs in the health care system. In Germany, disease management programs have been implemented for defined chronic diseases. However, drug reimbursement is still based on packages sold (pay for pill). In this context, it would be appealing to link reimbursement and treatment success (pay for cure) in order to reward successful treatment, limit lost drug spending and develop a shared risk environment that would involve all concerned parties. Under the assumption that 20,000 patients with HCV are treated each year in Germany and that cure rates are 95.4 %, the saved treatment costs would amount up to 45 and 107 million EUR per year. By this approach, economic incentives to withhold therapy from difficult to treat patients could be avoided.

Targeting the actin cytoskeleton: selective antitumor action via trapping PKCɛ.

Targeting the actin cytoskeleton (CSK) of cancer cells offers a valuable strategy in cancer therapy. There are a number of natural compounds that interfere with the actin CSK, but the mode of their cytotoxic action and, moreover, their tumor-specific mechanisms are quite elusive. We used the myxobacterial compound Chondramide as a tool to first elucidate the mechanisms of cytotoxicity of actin targeting in breast cancer cells (MCF7, MDA-MB-231). Chondramide inhibits cellular actin filament dynamics shown by a fluorescence-based analysis (fluorescence recovery after photobleaching (FRAP)) and leads to apoptosis characterized by phosphatidylserine exposure, release of cytochrome C from mitochondria and finally activation of caspases. Chondramide enhances the occurrence of mitochondrial permeability transition (MPT) by affecting known MPT modulators: Hexokinase II bound to the voltage-dependent anion channel (VDAC) translocated from the outer mitochondrial membrane to the cytosol and the proapoptotic protein Bad were recruited to the mitochondria. Importantly, protein kinase C-ɛ (PKCɛ), a prosurvival kinase possessing an actin-binding site and known to regulate the hexokinase/VDAC interaction as well as Bad phosphorylation was identified as the link between actin CSK and apoptosis induction. PKCɛ, which was found overexpressed in breast cancer cells, accumulated in actin bundles induced by Chondramide and lost its activity. Our second goal was to characterize the potential tumor-specific action of actin-binding agents. As the nontumor breast epithelial cell line MCF-10A in fact shows resistance to Chondramide-induced apoptosis and notably express low level of PKCɛ, we suggest that trapping PKCɛ via Chondramide-induced actin hyperpolymerization displays tumor cell specificity. Our work provides a link between targeting the ubiquitously occurring actin CSK and selective inhibition of pro-tumorigenic PKCɛ, thus setting the stage for actin-stabilizing agents as innovative cancer drugs. This is moreover supported by the in vivo efficacy of Chondramide triggered by abrogation of PKCɛ signaling shown in a xenograft breast cancer model.

Tremor in Parkinson's disease: 24-hr monitoring with calibrated accelerometry.

Monitoring systems enable the long-term registration of tremor in patients with Parkinson's disease This method is useful in the objective measurement of tremor during the course of treatments. Indeed, the symptoms of tremor as well as the aggravating and attenuating influences can be observed under real-life conditions. The methodology of data recording and analysis, described in previous investigations, was extended to automatically detect body position and certain movement patterns with calibrated 4-channel accelerometry. The main purpose of the present investigation was to apply this refined and extended methodology to patients in a clinical rehabilitation program, and to examine its practability with respect to the results of the treatment and the patients' compliance. The methodology was tested on 30 patients (17 male, 13 female) with Parkinson's disease. The mean age was 64.8 years (s = 8.9). The Hoehn-Yahr index ranged from 1 to 3 (m = 2.3, s = 0.7) and the overall UPDRS scale between 10 and 74 (m = 42.9, s = 18.1). The data recording included: (1) the registration of tremor under standardised conditions of rest and postural tremor test with and without distraction; (2) a standard protocol to obtain reference values for body position and movement; and (3) the 24-hr monitoring. 21 patients could be recorded a second time, on average 18 days after the first recording. Between the two registrations, patients received individually tailored drug treatment supplemented with specific activating physiotherapy, ergotherapy measures, and individual psychotherapeutic counseling. Changes between first and second recording were evident for the three tremor variables, but significant only for the 24-hr ambulatory monitoring. The between and within-subjects correlations of the tremor variables were rather low except the correlations between occurrence and amplitude (between-subjects. 87; within-subjects. 67). Conditions of rest and postural tremor test showed a correlation with corresponding segments of the ambulatory monitoring of about. 50 for the tremor occurrence. The best prediction of the day-time monitoring was made by the tremor tests with distraction, whereas the night segment was best predicted by the standard protocol.

Development of prosaccade and antisaccade task performance in participants aged 6 to 26 years.

There are few studies on the development of oculomotor functions during childhood. B. Fischer, M. Biscaldi, and S. Gezeck (1997) reported improvement of antisaccade task performance between ages 6 and 16 years. The present study is a replication and extension of those results. In three age groups (6-7, 10-11, 18-26 years), saccades during pro- and antisaccade tasks with 200-ms gap and overlap and during a fixation task were measured. Adults exhibited faster saccades and less prosaccades during the antisaccade tasks than 10-11-year-old children; these two groups had faster saccades during all tasks and less prosaccades during the anti- and the fixation task than 6-7-year-old subjects. Both children groups made more express saccades than adults. Results suggest different degrees of age-related improvement for different saccadic parameters, the effects being greatest for prosaccade inhibition during the antisaccade task and in line with the assumed protracted development of prefrontal functions.

The gap effect in pro-saccades and anti-saccades in psychometric schizotypes.

Schizophrenic patients and their first-degree relatives exhibit deficits in the anti-saccade task. In the present study, anti-saccade task performance was examined in subjects with 'high' and 'low' expressions of the schizotypal personality trait. For that purpose, the SPQ-G, the German adaptation of the Schizotypal Personality Questionnaire (SPQ; Raine, 1991), was filled in by 489 university students. Twenty and 21 participants with 'high' and 'low' SPQ-G scores, respectively, were compared with respect to saccadic eye movements elicited under the overlap and 200 ms gap conditions of the pro- and anti-saccade tasks. Each task block comprised 150 trials, 75 to either side in random order. The order of presentation of the task blocks was counterbalanced across the participants of each group. Saccadic reaction times were slower during the anti- as compared to the pro-saccade task and under the overlap as compared to the gap condition. Direction errors occurred almost exclusively during the anti-saccade task, express saccades mainly under the pro-saccadic gap condition. High-schizotypal participants did not differ significantly from low-schizotypal participants in any of these measures. While these results might suggest normal anti-saccade task performance in schizotypal personality as defined by the SPQ-G, the sampling strategy adopted in the present study is the more plausible explanation for the lack of group differences.

Motion pattern and posture: correctly assessed by calibrated accelerometers.

Basic motion patterns and posture can be distinguished by multichannel accelerometry, as recently shown. A refinement of this method appeared to be desirable to further increase its effectiveness, especially to distinguish walking and climbing stairs, and body rotation during sleep. Recordings were made of 31 subjects, according to a standard protocol comprising 13 motions and postures. This recording was repeated three times with appropriate permutation. Five uni-axial sensors and three sites of placement (sternum with three axes, right and left thigh) were selected. A hierarchical classification strategy used a standard protocol (i.e., individual reference patterns) to distinguish subtypes of moving behaviors and posture. The analysis method of the actometer signals reliably detected 13 different postural and activity conditions (only 3.2% misclassifications). A minimum set of sensors can be found for a given application; for example, a two-sensor configuration would clearly suffice to differentiate between four basic classes (sitting, standing, lying, moving) in ambulatory monitoring.

Joint amplitude and frequency analysis of tremor activity.

Clinical tremor analysis mostly is used for the measurement of tremor frequency. The analysis is based on short segments of EMG recordings and on clinical ratings of tremor intensity. Accelerometry appears to have some practical advantages. The present study was concerned with the development of a methodology for assessing tremor activity using the three parameters, frequency (Hz), amplitude (g), and occurrence of tremor (in per cent of time). These parameters were derived from joint amplitude frequency analysis of the calibrated accelerometer raw signal and from appropriate decision rules. This methodology was used in connection with 27 patients with Parkinson's disease, to investigate the aforesaid parameters of tremor activity. Postural tremor had a higher occurrence time (right-hand only) and higher frequency (left-hand only) than resting tremor, however, the average amplitudes did not differ. The correlations between right-hand and left-hand measures were higher during postural tremor test. Frequency was not correlated to amplitude or occurrence time, however, moderate correlations did exist between amplitude and occurrence time. In addition to the assessment of tremor activity, multi-channel accelerometry may be used for the detection of posture and motion. Further applications of this methodology, for example, in 24 hr ambulatory monitoring of tremor, are discussed.

Assessment of posture and motion by multichannel piezoresistive accelerometer recordings.

Modern assessment of posture and motion involves the use of wide bandwidth piezoresistive accelerometers. The direct current (DC) component allows for assessment of slow motion and change in position referring to the gravitational axis: the alternating current (AC) component, calibrated in g. represents acceleration along the sensitive axis of the device. A method study was designed to evaluate the division in DC and AC components, reliabilities, discrimination between conditions, and detection of types of physical activities. Recordings were made in 26 student participants for eight conditions: sitting, standing, lying supine, sitting and typing on a PC keyboard, walking, climbing stairs, walking downstairs, and cycling. This procedure was repeated in reversed order. A classification of physical activities according to the eight conditions (first trial) and based on four parameters, that is DC components trunk, thigh, and lower leg and AC component trunk, was correct in almost 100% of patterns, when applied to the second trial.

Non-invasive estimations of ventricular ejection time and stroke volume: comparison of impedance cardiography and the Portapres 2.

Stroke volume estimates and left ventricular ejection time (1) derived from calibrated finger pulse pressure recordings (Portapres 2, TNO-BMI, Amsterdam) based on the Model Flow method and (2) derived from impedance cardiography were compared in 20 student subjects. The recordings were made for seven conditions: supine rest, standing, mental arithmetic, ergometer exercise 50 W, motor performance test, reading aloud, and walking. Findings indicated that caution is required in assuming concurrent validity for both methods in tracking haemodynamic changes. Within-subject correlations were low or even negligible. Basic discrepancies were evident regarding the estimation of left ventricular ejection time but obviously more sources of measurement error exist which necessitate further research.

Task analysis exemplified: the process of resolving unfinished business.

The steps of a task-analytic research program designed to identify the in-session performances involved in resolving lingering bad feelings toward a significant other are described. A rational-empirical methodology of repeatedly cycling between rational conjecture and empirical observations is demonstrated as a method of developing an intervention manual and the components of client processes of resolution. A refined model of the change process developed by these procedures is validated by comparing 11 successful and 11 unsuccessful performances. Four performance components-intense expression of feeling, expression of need, shift in representation of other, and self-validation or understanding of the other-were found to discriminate between resolution and nonresolution performances. These components were measured on 4 process measures: the Structural Analysis of Social Behavior, the Experiencing Scale, the Client's Emotional Arousal Scale, and a need scale.

Is elevated blood pressure level associated with higher cardiovascular responsiveness in laboratory tasks and with response specificity?

Cardiovascular responsiveness and response specificity were investigated in male students, 48 with moderately elevated blood pressure (systolic blood pressure [SBP] > 140 mmHg and/or diastolic blood pressure [DBP] > 90 mmHg), 31 with mildly elevated blood pressure, and 57 with normal blood pressure. The behavioral tests and physically demanding tasks in the laboratory included mental arithmetic, free speech condition, cold pressor test, upright tilt, and ergometer exercise. Subjects with elevated blood pressure differed in baseline, task, and recovery levels of SBP, DBP, and heart rate. There were no significant effects in task-baseline differences or in residualized change scores. However, a positive initial-value dependency (LIV) in blood pressure responses was found: elevated blood pressure is associated with a larger increase under task conditions. Response scaling that employed reliability estimates and true difference scores indicated higher responsiveness in subjects with moderately elevated blood pressure and, thus, are in accordance with the positive LIV as compared with response measures based on task-baseline differences or residualized change scores. Findings from the specificity analysis indicated a higher incidence of SBP responders, that is, subjects with maximum response in SBP, among subjects with elevated blood pressure. Some of the inconsistencies in the literature with respect to blood pressure responsiveness and heart rate level in individuals with borderline hypertension may be attributed to the specific method of response scaling and to insufficient habituation to the setting and measurement.

Covariation of physiological sleep parameters in coronary patients and their relationships to sleep quality.

Relationships between the time series of five physiological sleep parameters were examined and related to sleep quality. Twenty-eight male coronary patients participated in the investigation. Recordings were carried out with a mobile device consisting of two Medilog 4-24 recorders and one DMI-recorder assessing five biosignals: EEG, EOG, EMG, ECG and body movements. Relationships between the time series of physiological sleep parameters were obtained by partitioning of covariance. The investigation showed that substantial relationships exist between the time series of the EEG, the number of eye movements and heart rate. Moreover, the time series of body movements showed substantial relationships to the time series of the EMG and heart rate. High correlations between the time series of the EEG and heart rate were related to a better sleep quality.

Development of a new dynamic method for quantitative evaluation of in vitro hemocompatibility of biomedical materials.

In this study a new dynamic method is introduced allowing the estimation of blood cell adhesion on flat test surfaces by measuring the cell loss in the bulk phase of surface contacting test blood under defined rheological conditions. This was achieved by constructing a novel test chamber permitting the contact of small amounts of blood with a large geometrical test surface. The construction consists of a spiral-shaped flow channel of 0.3 cm width, 0.02 cm height and 78 cm length covered with the biomaterials to be tested from both sides. Laminarity of blood flow in the conduit was confirmed theoretically by the calculation of an equivalent to the Reynolds number for curved systems the so-called Dean number. Furthermore, flow laminarity was proved experimentally finding that the flow rate of blood with different hematocrit values was proportional to the hydrostatic pressure applied. The applicability of the novel 'spiral method' for the estimation of hemocompatibility was demonstrated by evaluation of platelet adhesion onto different polymers in comparison to siliconized and fibrinogen coated glass as reference surfaces. Additionally, it was possible under distinct conditions to determine the adhesion of leucocytes and the detachment of platelet aggregates. Therefore, it was concluded that the spiral method can be used for the assessment of the hemocompatibility of flat biomedical polymers. As main advantages of the new method can be considered the high time efficiency and accuracy without labelling or optical detection of adherent cells.

A model of cardiovascular activation components for studies using autonomic receptor antagonists.

Alpha-adrenergic, beta-adrenergic, and cholinergic responses are often considered important activation components when conceptual and empirical analyses are made of single physiological variables and of patterns of cardiovascular reactivity; these autonomic distinctions are also of particular significance in autonomic blockade studies. A Model of Cardiovascular Activation Components is introduced that relates these components to both the measured cardiovascular variables and the protocol of autonomic blockade studies. It is pointed out that a restricted form of the complete model is often implicitly used in cardiovascular psychophysiology. The differential consequences of an erroneous employment of the restricted model are discussed for single and dual blockade protocols. Critical evaluations of autonomic blockade as a tool in cardiovascular psychophysiology are examined and are proposed to be often the consequence of the restricted model assumptions. Lastly, the utility of the Activation Components Model for a componential description of tasks and for componential intertask relationships is illustrated with data from the literature.