Feasibility of azacitidine added to standard chemotherapy in older patients with acute myeloid leukemia - a randomised SAL pilot study

INTRODUCTION: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML. TRIAL DESIGN: Prospective, randomised, open, phase II trial with parallel group design and fixed sample size. PATIENTS AND METHODS: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/µl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint. RESULTS: Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days. CONCLUSIONS: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm

Invasive Pressure Monitoring Saves from Tuberculous Meningitis with Fulminant Generalized Brain Edema

We report a 57-year old female patient with a rapid and dramatic dynamic of whole brain edema caused by tuberculous meningitis. After initiation of tuberculostatic medication, general condition of the patient worsened and finally she was intubated due to a progredient loss of consciousness and respiratory insufficiency. Repeated cerebral computer tomography (CCT) revealed a global brain edema with slit ventricles and a dramatic progress of generalized brain swelling. Highly interesting, a rapid expanded regime of brain pressure monitoring and treatment according to a neurosurgical intensive standard ICP/CPP management protocol, which was complemented by the tuberculostatic therapy and high dose steroid application, dramatically improved the general conditions, so that the patient is now in a general condition which corresponds that before the occurrence of tuberculous meningitis. Thus, it is mandatory in situations with a rapid progressive brain swelling caused by bacterial meningitis to consider an intensified cerebral monitoring and stratified treatment protocol in order to avoid the devasting effects of a long lasting increase in intracranical pressure

Towards in-line real-time characterization of roll-to-roll produced ZTO/Ag/ITO thin films by hyperspectral imaging

Large area manufacturing processes of thin films such as large-area vacuum roll-to-roll coating of dielectric and gas permeation barrier layers in industry require a precise control of e.g. film thickness, homogeneity, chemical compositions, crystallinity and surface roughness. In order to determine these properties in real time, hyperspectral imaging is a novel, cost-efficient, and fast tool as in-line technology for large-area quality control. We demonstrate the application of hyperspectral imaging to characterize the thickness of thin films of the multilayer system ZTO/Ag/ITO produced by roll-to-roll magnetron sputtering on 220 mm wide polyethylene terephthalate substrate. X-ray reflectivity measurements are used to determine the thickness gradients of roll-to-roll produced foils with sub nanometer accuracy that serve as ground truth data to train a machine learning model for the interpretation of the hyperspectral imaging spectra. Based on the model, the sub-layer thicknesses on the complete substrate foil area were predicted which demonstrates the capabilities of this approach for large-scale in-line real-time quality control for industrial applications

Projection of young-old and old-old with functional disability: Does accounting for the changing educational composition of the elderly population make a difference?

10.1371/journal.pone.0126471PLoS ONE105e012647

A Logic with Reverse Modalities for History-preserving Bisimulations

We introduce event identifier logic (EIL) which extends Hennessy-Milner logic by the addition of (1) reverse as well as forward modalities, and (2) identifiers to keep track of events. We show that this logic corresponds to hereditary history-preserving (HH) bisimulation equivalence within a particular true-concurrency model, namely stable configuration structures. We furthermore show how natural sublogics of EIL correspond to coarser equivalences. In particular we provide logical characterisations of weak history-preserving (WH) and history-preserving (H) bisimulation. Logics corresponding to HH and H bisimulation have been given previously, but not to WH bisimulation (when autoconcurrency is allowed), as far as we are aware. We also present characteristic formulas which characterise individual structures with respect to history-preserving equivalences.Comment: In Proceedings EXPRESS 2011, arXiv:1108.407

Coherent States for Particle Beams in the Thermal Wave Model

In this paper, by using an analogy among {\it quantum mechanics}, {\it electromagnetic beam optics in optical fibers}, and {\it charge particle beam dynamics}, we introduce the concept of {\it coherent states} for charged particle beams in the framework of the {\it Thermal Wave Model} (TWM). We give a physical meaning of the Gaussian-like coherent structures of charged particle distribution that are both naturally and artificially produced in an accelerating machine in terms of the concept of coherent states widely used in quantum mechanics and in quantum optics. According to TWM, this can be done by using a Schr\"{o}dinger-like equation for a complex function, the so-called {\it beam wave function} (BWF), whose squared modulus is proportional to the transverse beam density profile, where Planck's constant and the time are replaced by the transverse beam emittance and by the propagation coordinate, respectively. The evolution of the particle beam, whose initial BWF is assumed to be the simplest coherent state (ground-like state) associated with the beam, in an infinite 1-D quadrupole-like device with small sextupole and octupole aberrations, is analytically and numerically investigated.Comment: 21 pages, Late

Diffusion-weighted magnetic resonance imaging using a preclinical 1 T PET/MRI in healthy and tumor-bearing rats

Background: Hybrid positron emission tomography and magnetic resonance imaging (PET/MRI) scanners are increasingly used for both clinical and preclinical imaging. Especially functional MRI sequences such as diffusionweighted imaging (DWI) are of great interest as they provide information on a molecular level, thus, can be used as surrogate biomarkers. Due to technical restrictions, MR sequences need to be adapted for each system to perform reliable imaging. There is, to our knowledge, no suitable DWI protocol for 1 Tesla PET/MRI scanners. We aimed to establish such DWI protocol with focus on the choice of b values, suitable for longitudinal monitoring of tumor characteristics in a rat liver tumor model. Material and methods: DWI was first performed in 18 healthy rat livers using the scanner-dependent maximum of 4 b values (0, 100, 200, 300 s/mm2). Apparent diffusion coefficients (ADC) were calculated from different b value combinations and compared to the reference measurement with four b values. T2-weighted MRI and optimized DWI with best agreement between accuracy, scanning time, and system performance stability were used to monitor orthotopic hepatocellular carcinomas (HCC) in five rats of which three underwent additional 2-deoxy-2-(18F)fluoro-D-glucose(FDG)-PET imaging. ADCs were calculated for the tumor and the surrounding liver parenchyma and verified by histopathological analysis. Results: Compared to the reference measurements, the combination b = 0, 200, 300 s/mm2 showed the highest correlation coefficient (rs = 0.92) and agreement while reducing the acquisition time. However, measurements with less than four b values yielded significantly higher ADCs (p < 0.001). When monitoring the HCC, an expected drop of the ADC was observed over time. These findings were paralleled by FDG-PET showing both an increase in tumor size and uptake heterogeneity. Interestingly, surrounding liver parenchyma also showed a change in ADC values revealing varying levels of inflammation by immunohistochemistry. Conclusion: We established a respiratory-gated DWI protocol for a preclinical 1 T PET/MRI scanner allowing to monitor growth-related changes in ADC values of orthotopic HCC liver tumors. By monitoring the changes in tumor ADCs over time, different cellular stages were described. However, each study needs to adapt the protocol further according to their question to generate best possible results

Direct evidence of a prey depletion "halo" surrounding a pelagic predator colony

Colonially breeding birds and mammals form some of the largest gatherings of apex predators in the natural world and have provided model systems for studying mechanisms of population regulation in animals. According to one influential hypothesis, intense competition for food among large numbers of spatially constrained foragers should result in a zone of prey depletion surrounding such colonies, ultimately limiting their size. However, while indirect and theoretical support for this phenomenon, known as "Ashmole's halo," has steadily accumulated, direct evidence remains exceptionally scarce. Using a combination of vesselbased surveys and Global Positioning System tracking, we show that pelagic seabirds breeding at the tropical island that first inspired Ashmole's hypothesis do indeed deplete their primary prey species (flying fish; Exocoetidae spp.) over a considerable area, with reduced prey density detectable >150 km from the colony. The observed prey gradient was mirrored by an opposing trend in seabird foraging effort, could not be explained by confounding environmental variability, and can be approximated using a mechanistic consumption-dispersion model, incorporating realistic rates of seabird predation and random prey dispersal. Our results provide a rare view of the resource footprint of a pelagic seabird colony and reveal how aggregations of these central-place foraging, marine top predators profoundly influence the oceans that surround them

Future requirements for and supply of ophthalmologists for an aging population in Singapore

#### Background Singapore’s population, as that of many other countries, is aging; this is likely to lead to an increase in eye diseases and the demand for eye care. Since ophthalmologist training is long and expensive, early planning is essential. This paper forecasts workforce and training requirements for Singapore up to the year 2040 under several plausible future scenarios. #### Methods The Singapore Eye Care Workforce Model was created as a continuous time compartment model with explicit workforce stocks using system dynamics. The model has three modules: prevalence of eye disease, demand, and workforce requirements. The model is used to simulate the prevalence of eye diseases, patient visits, and workforce requirements for the public sector under different scenarios in order to determine training requirements. #### Results Four scenarios were constructed. Under the baseline business-as-usual scenario, the required number of ophthalmologists is projected to increase by 117% from 2015 to 2040. Under the current policy scenario (assuming an increase of service uptake due to increased awareness, availability, and accessibility of eye care services), the increase will be 175%, while under the new model of care scenario (considering the additional effect of providing some services by non-ophthalmologists) the increase will only be 150%. The moderated workload scenario (assuming in addition a reduction of the clinical workload) projects an increase in the required number of ophthalmologists of 192% by 2040. Considering the uncertainties in the projected demand for eye care services, under the business-as-usual scenario, a residency intake of 8–22 residents per year is required, 17–21 under the current policy scenario, 14–18 under the new model of care scenario, and, under the moderated workload scenario, an intake of 18–23 residents per year is required. #### Conclusions The results show that under all scenarios considered, Singapore’s aging and growing population will result in an almost doubling of the number of Singaporeans with eye conditions, a significant increase in public sector eye care demand and, consequently, a greater requirement for ophthalmologists

An online international comparison of palliative care identification in primary care using the Surprise Question.

BACKGROUND The Surprise Question ('Would I be surprised if this patient died within 12 months?') identifies patients in the last year of life. It is unclear if 'surprised' means the same for each clinician, and whether their responses are internally consistent. AIM To determine the consistency with which the Surprise Question is used. DESIGN A cross-sectional online study of participants located in Belgium, Germany, Italy, The Netherlands, Switzerland and UK. Participants completed 20 hypothetical patient summaries ('vignettes'). Primary outcome measure: continuous estimate of probability of death within 12 months (0% [certain survival]-100% [certain death]). A threshold (probability estimate above which Surprise Question responses were consistently 'no') and an inconsistency range (range of probability estimates where respondents vacillated between responses) were calculated. Univariable and multivariable linear regression explored differences in consistency. Trial registration: NCT03697213. SETTING/PARTICIPANTS Registered General Practitioners (GPs). Of the 307 GPs who started the study, 250 completed 15 or more vignettes. RESULTS Participants had a consistency threshold of 49.8% (SD 22.7) and inconsistency range of 17% (SD 22.4). Italy had a significantly higher threshold than other countries (p = 0.002). There was also a difference in threshold levels depending on age of clinician, for every yearly increase, participants had a higher threshold. There was no difference in inconsistency between countries (p = 0.53). CONCLUSIONS There is variation between clinicians regarding the use of the Surprise Question. Over half of GPs were not internally consistent in their responses to the Surprise Question. Future research with standardised terms and real patients is warranted