5-year results of accelerated partial breast irradiation (APBI) with SBRT (stereotactic body radiation therapy) and exactrac adaptive gating (Novalis®) for very early breast cancer patients: was it all worth it?

Purpose To explore the feasibility of image-guided and respiratory-gated Stereotactic Body Radiation Therapy (SBRT) for Accelerated Partial Breast Irradiation (APBI) in patients with very early breast cancer. Material and methods Selected patients with early breast carcinoma after breast-conserving surgery were enrolled in this phase II trial. A fiducial marker was percutaneously placed close to surgical bed and five external fiducials were set on the skin. A CT scan for planning was acquired at free breathing. The treatment was planned and DVH were assessed according to international recommendations. Prescription dose was 30 Gy in five consecutive fractions of 6 Gy. A 6MV monoenergetic LINAC (linear accelerator) that combines stereoscopic X-ray imaging system and ExacTrac Adaptive Gating technique was used. PTV (planning target volume) intrafraction motion was controlled and PTV was irradiated in a selected gated area of the respiratory cycle. Shifts for a correct, gated set-up were calculated and automatically applied. Results Between April 2013 and October 2015, a total of 23 patients were included. The median tumor size was 12 mm. The mean PTV volume was 114 cc. The mean ipsilateral lung V9 Gy was 2.2% and for left-sided breast cancers, the volume of the heart receiving 1.5 Gy was 11.5%. Maximum skin dose was 30.8 Gy. Acute toxicity was grade1 in all the patients and 100% experienced excellent/good breast cosmesis outcomes. With a median follow-up of 66 months (range 8–99 months) local-relapse-free-survival reaches 100%. One patient developed a second breast cancer outside the treated quadrant after 25.1 months. Conclusion APBI with SBRT and ExacTrac Adaptive Gating System was feasible. The acute and late toxicities were almost null and cosmesis was excellent. We also found that the margins of 5 mm applied from CTV to PTV were sufficient to compensate for geometric uncertainties (AU)

Bistability in the synchronization of identical neurons.

We investigate the role of bistability in the synchronization of a network of identical bursting neurons coupled through an generic electrical mean-field scheme. These neurons can exhibit distinct multistable states and, in particular, bistable behavior is observed when their sodium conductance is varied. With this, we consider three different initialization compositions: (i) the whole network is in the same periodic state; (ii) half of the network periodic, half chaotic; (iii) half periodic, and half in a different periodic state. We show that (i) and (ii) reach phase synchronization (PS) for all coupling strengths, while for (iii) small coupling regimes do not induce PS, and instead, there is a coexistence of different frequencies. For stronger coupling, case (iii) synchronizes, but after (i) and (ii). Since PS requires all neurons being in the same state (same frequencies), these different behaviors are governed by transitions between the states. We find that, during these transitions, (ii) and (iii) have transient chimera states and that (iii) has breathing chimeras. By studying the stability of each state, we explain the observed transitions. Therefore, bistability of neurons can play a major role in the synchronization of generic networks, with the simple initialization of the system being capable of drastically changing its asymptotic space.

Phase-locking intermittency induced by dynamical heterogeneity in networks of thermosensitive neurons.

In this work, we study the phase synchronization of a neural network and explore how the heterogeneity in the neurons' dynamics can lead their phases to intermittently phase-lock and unlock. The neurons are connected through chemical excitatory connections in a sparse random topology, feel no noise or external inputs, and have identical parameters except for different in-degrees. They follow a modification of the Hodgkin-Huxley model, which adds details like temperature dependence, and can burst either periodically or chaotically when uncoupled. Coupling makes them chaotic in all cases but each individual mode leads to different transitions to phase synchronization in the networks due to increasing synaptic strength. In almost all cases, neurons' inter-burst intervals differ among themselves, which indicates their dynamical heterogeneity and leads to their intermittent phase-locking. We argue then that this behavior occurs here because of their chaotic dynamics and their differing initial conditions. We also investigate how this intermittency affects the formation of clusters of neurons in the network and show that the clusters' compositions change at a rate following the degree of intermittency. Finally, we discuss how these results relate to studies in the neuroscience literature, especially regarding metastability.

Discriminating chaotic and stochastic time series using permutation entropy and artificial neural networks.

Extracting relevant properties of empirical signals generated by nonlinear, stochastic, and high-dimensional systems is a challenge of complex systems research. Open questions are how to differentiate chaotic signals from stochastic ones, and how to quantify nonlinear and/or high-order temporal correlations. Here we propose a new technique to reliably address both problems. Our approach follows two steps: first, we train an artificial neural network (ANN) with flicker (colored) noise to predict the value of the parameter, [Formula: see text], that determines the strength of the correlation of the noise. To predict [Formula: see text] the ANN input features are a set of probabilities that are extracted from the time series by using symbolic ordinal analysis. Then, we input to the trained ANN the probabilities extracted from the time series of interest, and analyze the ANN output. We find that the [Formula: see text] value returned by the ANN is informative of the temporal correlations present in the time series. To distinguish between stochastic and chaotic signals, we exploit the fact that the difference between the permutation entropy (PE) of a given time series and the PE of flicker noise with the same [Formula: see text] parameter is small when the time series is stochastic, but it is large when the time series is chaotic. We validate our technique by analysing synthetic and empirical time series whose nature is well established. We also demonstrate the robustness of our approach with respect to the length of the time series and to the level of noise. We expect that our algorithm, which is freely available, will be very useful to the community.

5-year results of accelerated partial breast irradiation (APBI) with SBRT (stereotactic body radiation therapy) and exactrac adaptive gating (Novalis®) for very early breast cancer patients: was it all worth it?

PURPOSE: To explore the feasibility of image-guided and respiratory-gated Stereotactic Body Radiation Therapy (SBRT) for Accelerated Partial Breast Irradiation (APBI) in patients with very early breast cancer. MATERIAL AND METHODS: Selected patients with early breast carcinoma after breast-conserving surgery were enrolled in this phase II trial. A fiducial marker was percutaneously placed close to surgical bed and five external fiducials were set on the skin. A CT scan for planning was acquired at free breathing. The treatment was planned and DVH were assessed according to international recommendations. Prescription dose was 30 Gy in five consecutive fractions of 6 Gy. A 6MV monoenergetic LINAC (linear accelerator) that combines stereoscopic X-ray imaging system and ExacTrac Adaptive Gating technique was used. PTV (planning target volume) intrafraction motion was controlled and PTV was irradiated in a selected gated area of the respiratory cycle. Shifts for a correct, gated set-up were calculated and automatically applied. RESULTS: Between April 2013 and October 2015, a total of 23 patients were included. The median tumor size was 12 mm. The mean PTV volume was 114 cc. The mean ipsilateral lung V9 Gy was 2.2% and for left-sided breast cancers, the volume of the heart receiving 1.5 Gy was 11.5%. Maximum skin dose was 30.8 Gy. Acute toxicity was grade1 in all the patients and 100% experienced excellent/good breast cosmesis outcomes. With a median follow-up of 66 months (range 8-99 months) local-relapse-free-survival reaches 100%. One patient developed a second breast cancer outside the treated quadrant after 25.1 months. CONCLUSION: APBI with SBRT and ExacTrac Adaptive Gating System was feasible. The acute and late toxicities were almost null and cosmesis was excellent. We also found that the margins of 5 mm applied from CTV to PTV were sufficient to compensate for geometric uncertainties.

Author Correction: Thermodynamics of CuPt nanoalloys.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Thermodynamics of CuPt nanoalloys.

The control of structural and chemical transitions in bimetallic nanoalloys at finite temperatures is one of the challenges for their use in advanced applications. Comparing Nested Sampling and Molecular Dynamics simulations, we investigate the phase changes of CuPt nanoalloys with the aim to elucidate the role of kinetic effects during their solidification and melting processes. We find that the quasi-thermodynamic limit for the nucleation of (CuPt)309 is 965 ± 10 K, but its prediction is increasingly underestimated when the system is cooled faster than 109 K/s. The solidified nanoparticles, classified following a novel tool based on Steinhardt parameters and the relative orientation of characteristic atomic environments, are then heated back to their liquid phase. We demonstrate the kinetic origin of the hysteresis in the caloric curve as (i) it closes for rates slower than 108 K/s, with a phase change temperature of 970 K ± 25 K, in very good agreement with its quasi-thermodynamic limit; (ii) the process happens simultaneously in the inner and outer layers; (iii) an onion-shell chemical order - Cu-rich surface, Pt-rich sub-surface, and mixed core - is always preserved.

Point of Care Testing (POCT) to assess drug concentration in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs).

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) do not need routine laboratory monitoring but measurement of drug concentration is important in emergency conditions. Specific laboratory tests are not readily available or not implemented in every hospital. Point-of-Care Tests (POCT) may bridge this gap and be used as a bedside solution. OBJECTIVES: Feasibility of POCT to assess plasma levels of dabigatran, rivaroxaban and apixaban. PATIENTS/METHODS: Activated Coagulation Time-Low Range (ACT - LR) using a portable Hemochron Signature Elite for dabigatran and prothrombin time (expressed as INR) by Coaguchek XS Pro for rivaroxaban and apixaban were obtained at trough and peak in 136 consecutive patients taking NOACs (70 on dabigatran, 45 on rivaroxaban and 20 on apixaban). Using a paired study design, drug concentrations were concurrently determined by functional specific tests. RESULTS AND CONCLUSIONS: The correlation between NOACs concentration and the values obtained using the POCTs was high for dabigatran and rivaroxaban (r = 0.80 and r = 0.82, respectively) and low for apixaban (r = 0.21). ACT-LR ≤ 188 s better detected dabigatran levels ≤ 50 ng/ml, with a sensitivity of 87.5% and a specificity of 84.1%. ACT-LR values > 217 s better discriminated value of dabigatran > 200 ng/ml, with a sensitivity of 86.7% and a specificity of 81.4%. INR Coaguchek values ≤ 1.2 better identified patients with rivaroxaban values < 100 ng/ml, with sensitivity of 90%, specificity of 88.5%. This analysis was not possible for apixaban. CONCLUSION: In emergency situations POCT use may provide useful immediate information on dabigatran and rivaroxaban concentration.

Melting of large Pt@MgO(1 0 0) icosahedra.

On the basis of ab initio calculations, we present a new parametrisation of the Vervisch-Mottet-Goniakowski (VMG) potential (Vervisch et al 2002 Phys. Rev. B 24 245411) for modelling the oxide-metal interaction. Applying this model to mimic the finite temperature behaviour of large platinum icosahedra deposited on the pristine MgO(1 0 0), we find the nanoparticle undergoes two solid-solid transitions. At 650 K the 'squarisation' of the interface layer, while a full reshaping towards a fcc architecture takes place above 950 K. In between, a quite long-lived intermediate state with a (1 0 0) interface but with an icosahedral cap is observed. Our approach reproduces experimental observations, including wetting behaviour and the lack of surface diffusion.

Reasons for and consequences of vitamin K antagonist discontinuation in very elderly patients with non-valvular atrial fibrillation.

Essentials Anticoagulation in the elderly is still a challenge and suspension of warfarin is common. This is an observational study reporting reasons and consequences of warfarin suspension. Vascular disease, age, time in therapeutic range, and bleedings are associated with suspension. After suspension for bleeding or frailty, patients remain at high-risk of death or complications. SUMMARY: Background Anticoagulation in elderly patients with non-valvular atrial fibrillation (NVAF) is still a challenge, and discontinuation of warfarin is common. The aim of this study was to analyze the aspects related to warfarin discontinuation in a real-world population. Methods This was an observational cohort study on very elderly NVAF patients naive to warfarin therapy (VENPAF). The included subjects were aged at least 80 years, and started using warfarin after a diagnosis of NVAF. Warfarin discontinuation was assessed, and the reason reported for discontinuation, the person who decided to stop treatment, subsequent antithrombotic therapy and mortality, ischemic and bleeding events were collected. Results Over a period of 5 years, warfarin was discontinued in 148 of 798 patients. Despite similar CHA2 DS2 -VASc scores, the frequencies of thromboembolic and major bleeding events were significantly higher (P = 0.01 and P = 0.001, respectively) and the time in therapeutic range (TTR) was significantly lower (P < 0.001) in patients who discontinued warfarin. Independent risk factors for warfarin discontinuation were vascular disease (hazard ratio [HR] 2.5, P < 0.001), age ≥ 85 years (HR 1.4, P = 0.04), TTR < 60% (HR 1.8, P = 0.001), and bleeding events (HR 2.3, P < 0.001). The main reasons for warfarin discontinuation were physician-perceived frailty or low life-expectancy (45.9%), bleeding complications (19.6%), and sinus rhythm restoration (16.9%). Event and death rates were very high, especially in frail patients and in those with bleeding complications. Conclusions Warfarin discontinuation is frequent in very elderly patients, and is associated with increased risks of death and adverse events. Identification of elderly patients who are at high risk of bleeding and the poor quality of anticoagulation during warfarin are still unsolved clinical problems.

Metallic nanoparticles meet metadynamics.

Metadynamics coupled with classical molecular dynamics has been successfully applied to sample the configuration space of metallic and bimetallic nanoclusters. We implement a new set of collective variables related to the pair distance distribution function of the nanoparticle to achieve an exhaustive isomer sampling. As paradigmatic examples, we apply our methodology to Ag147, Pt147, and their alloy Ag(shell)Pt(core) at 2:1 and 1:1 chemical compositions. The proposed scheme is able to reproduce the known solid-solid structural transformation pathways, based on the Lipscomb's diamond-square-diamond mechanisms, both in mono and bimetallic nanoparticles. A discussion of the free energy barriers involved in these processes is provided.

[Prophylaxis of group B streptococcal infections in the birth centers of Emilia Romagna]. / La profilassi dell'infezione da streptococco di gruppo B nei punti nascita della regione Emilia Romagna.

OBJECTIVES: In the last decade several guidelines for prevention of neonatal group B streptococcal invasive disease have been published, mainly based on administration of intrapartum antibiotics. The spread of such recommendations yielded a reduction of the early-onset disease. The aim of the study was to investigate the practices for prophylaxis of neonatal infection in our region during the 2000 and to standardize them according to the new available evidence. METHODS: We conducted a multicenter study in Emilia Romagna, sending by mail a detailed questionnaire to the 28 birth centers of our region. RESULTS: Fifteen centers answered to the questionnaire. The practices were often differing from the recommendations of scientific societies. The most sensitive methods to identify colonized women were not widely used. Colonized infants were frequently treated with antibiotics and discharged later from the nursery. The incidence of neonatal invasive diseases was low, but most centers did not regularly collect a blood culture before antibiotic treatment is started. CONCLUSIONS: Repeated meetings among centers promoted the diffusion of information, the implementation of a shared protocol and the spread of the practices. The results of such meetings will be evalued in the next months.

Amnioreduction versus septostomy in twin-twin transfusion syndrome.

OBJECTIVE: The purpose of this study was to compare treatment outcomes in pregnancies affected with twin-twin transfusion syndrome. Treatment consisted of serial amnioreduction or septostomy. STUDY DESIGN: A retrospective review of patients who were diagnosed with twin-twin transfusion syndrome from June 1998 to June 2000 was conducted. Diagnosis was based on polyhydramnios (maximal vertical pocket, >8 cm) in conjunction with an enlarged fetal bladder, oligohydramnios (maximal vertical pocket, <2 cm) with nonvisualization of the fetal bladder, and documentation of a single placenta. Data evaluated were gestational age at enrollment and delivery, prolongation of gestation, and number of surviving fetuses by treatment modality. RESULTS: There were 7 patients in the amnioreduction group and 7 patients in the septostomy group. The mean gestational age at enrollment for amnioreduction was 21.0 weeks and for septostomy was 18.0 weeks (P =.01). There were 67% 2-twin survivors in the septostomy group (P = not significant), but an overall equal number of survivors (78%) in both treatment groups. The rate of no surviving twins was equal (14%) in both groups. Pregnancy was prolonged an average of 12 weeks in the septostomy group and 6.5 weeks in the amnioreduction group (P =.007). The average gestational age at delivery was 27.5 weeks for the amnioreduction group and 30.0 weeks for the septostomy group (P =.08). CONCLUSION: The prolongation of pregnancy from diagnosis to delivery was statistically significant for septostomy when compared to amnioreduction. Although not statistically significant, there appears to be a trend toward increasing gestational age at delivery with septostomy. Further randomized studies are warranted for septostomy as a treatment modality in twin-twin transfusion syndrome.

A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy.

Guanylyl cyclase-A (NPR-A; GC-A) is the major and possibly the only receptor for atrial natriuretic peptide (ANP) or B-type natriuretic peptide. Although mice deficient in GC-A display an elevated blood pressure, the resultant cardiac hypertrophy is much greater than in other mouse models of hypertension. Here we overproduce GC-A in the cardiac myocytes of wild-type or GC-A null animals. Introduction of the GC-A transgene did not alter blood pressure or heart rate as a function of genotype. Cardiac myocyte size was larger (approximately 20%) in GC-A null than in wild-type animals. However, introduction of the GC-A transgene reduced cardiac myocyte size in both wild-type and null mice. Coincident with the reduction in myocyte size, both ANP mRNA and ANP content were significantly reduced by overexpression of GC-A, and this reduction was independent of genotype. This genetic model, therefore, separates a regulation of cardiac myocyte size by blood pressure from local regulation by a GC-mediated pathway.

Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa.

Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.

Design, synthesis, and biological evaluation of potent and selective amidino bicyclic factor Xa inhibitors.

Thrombotic diseases are a major cause of death and morbidity. Factor Xa (fXa) plays a vital role in the regulation of normal homeostasis and abnormal intravascular thrombus development in the blood coagulation cascade. A novel series of fXa inhibitors incorporating an amidino 6,5-fused bicyclic moiety at the P1 position has been designed and synthesized based on molecular modeling studies. Structure-activity relationship (SAR) studies have led to selective subnanomolar fXa inhibitors. The most potent fXa inhibitor in this series (72, SE170) has a potent inhibition constant (K(i) = 0.3 nM), is 350-fold selective for fXa over trypsin, and also shows good in vivo efficacy in a rabbit arterio-venous thrombosis model (ID(50) = 0.14 micromol/kg/h). An X-ray crystal structure of 72 complexed to bovine trypsin was completed, and a binding mode of 72 with fXa has been proposed based on modeling with human des-Gla-fXa.

Factors affecting the work of an occupational health nurse.

Society, economies, work-life and work are undergoing changes that will have global impact on occupational health services (OHS) and the work of occupational health nurses (OHNs) during the next 5-10 years. These changes will bring new challenges to both occupational health services and representatives of specialist groups within those services. The changes will require new ways of working, work methods, performance monitoring, and evaluation of impacts. These developments will also call for changes in the education of occupational health nurses.

Metabolic and respiratory effects of theophylline in the preterm infant.

BACKGROUND: Methylxanthines are often administered to preterm infants for the treatment of apnoea. AIMS: To study the effects of theophylline on energy metabolism, physical activity, and lung mechanics in preterm infants. METHODS: Indirect calorimetry was performed for six hours before and after administration of a bolus of theophylline (5 mg/kg) in 18 preterm infants while physical activity was recorded with a video camera. Lung mechanics measurements were performed at baseline and 12 and 24 hours after theophylline treatment. RESULTS: Theophylline increased mean (SEM) energy expenditure by 15 (5) kJ/kg/day and augmented carbohydrate utilisation from 6.8 to 8.0 g/kg/day, but fat oxidation was unchanged. After theophylline treatment, preterm infants had faster respiration, lower transcutaneous CO2, and improved static respiratory compliance without increased physical activity. CONCLUSIONS: A bolus of 5 mg/kg theophylline increased energy expenditure independently of physical activity, increased carbohydrate utilisation, and improved respiratory compliance. The increased energy expenditure could be detrimental to the growth of the preterm infant.