Two-year outcome of an observe-and-plan regimen for neovascular age-related macular degeneration treated with Aflibercept.

The purpose of our study was to investigate the two-year outcome of Aflibercept treatment for neovascular age-related macular degeneration (nAMD), using the Observe-and-Plan regimen, an individually planned treatment regimen, based on the predictability of an individual's need for retreatment, aiming to reduce the clinical burden. Our prospective study used the Observe-and-Plan regimen with Aflibercept to treat nAMD: Three loading doses, followed by monthly observation visits until the disease-recurrence interval was determined, which then was shortened by 2 weeks in a treatment plan for the next three injections without intermediate monitoring visits. The subsequent treatment plans were adjusted according to periodically assessed disease activity. The primary outcome measures were visual acuity changes, number of injections, and number of monitoring visits. The study included 112 eyes of 102 patients with a mean age of 80.7 years (SD 7.6). Mean visual acuity (VA) improved from 61.8 ETDRS letters (20/60(+2)) at baseline, by 8.5, 8.0, and 6.2 letters at months 3, 12 and 24, respectively. Mean central retinal thickness was 438um at baseline, and reduced by 152um, 155um, and 150um at months 3, 12 and 24, respectively. The mean number of injections was 8.7 and 6.5 in the first and second year, respectively. The mean number of monitoring visits after baseline was 3.8 and 2.8 during the first and second year, respectively. The Observe-and-Plan regimen significantly improved VA, while fewer monitoring visits were needed as compared to other variable dosing regimens, thus reducing the workload for chronic care management of nAMD

Spin injection in a single metallic nanoparticle: a step towards nanospintronics

We have fabricated nanometer sized magnetic tunnel junctions using a new nanoindentation technique in order to study the transport properties of a single metallic nanoparticle. Coulomb blockade effects show clear evidence for single electron tunneling through a single 2.5 nm Au cluster. The observed magnetoresistance is the signature of spin conservation during the transport process through a non magnetic cluster.Comment: 3 page

Electric-field control of domain wall nucleation and pinning in a metallic ferromagnet

The electric (E) field control of magnetic properties opens the prospects of an alternative to magnetic field or electric current activation to control magnetization. Multilayers with perpendicular magnetic anisotropy (PMA) have proven to be particularly sensitive to the influence of an E-field due to the interfacial origin of their anisotropy. In these systems, E-field effects have been recently applied to assist magnetization switching and control domain wall (DW) velocity. Here we report on two new applications of the E-field in a similar material : controlling DW nucleation and stopping DW propagation at the edge of the electrode

Testing Conditional Independence of Discrete Distributions

We study the problem of testing \emph{conditional independence} for discrete distributions. Specifically, given samples from a discrete random variable $(X, Y, Z)$ on domain $[\ell_1]\times[\ell_2] \times [n]$, we want to distinguish, with probability at least $2/3$, between the case that $X$ and $Y$ are conditionally independent given $Z$ from the case that $(X, Y, Z)$ is $\epsilon$-far, in $\ell_1$-distance, from every distribution that has this property. Conditional independence is a concept of central importance in probability and statistics with a range of applications in various scientific domains. As such, the statistical task of testing conditional independence has been extensively studied in various forms within the statistics and econometrics communities for nearly a century. Perhaps surprisingly, this problem has not been previously considered in the framework of distribution property testing and in particular no tester with sublinear sample complexity is known, even for the important special case that the domains of $X$ and $Y$ are binary. The main algorithmic result of this work is the first conditional independence tester with {\em sublinear} sample complexity for discrete distributions over $[\ell_1]\times[\ell_2] \times [n]$. To complement our upper bounds, we prove information-theoretic lower bounds establishing that the sample complexity of our algorithm is optimal, up to constant factors, for a number of settings. Specifically, for the prototypical setting when $\ell_1, \ell_2 = O(1)$, we show that the sample complexity of testing conditional independence (upper bound and matching lower bound) is \[ \Theta\left({\max\left(n^{1/2}/\epsilon^2,\min\left(n^{7/8}/\epsilon,n^{6/7}/\epsilon^{8/7}\right)\right)}\right)\,. \

Chloroplast microsatellites: measures of genetic diversity and the effect of homoplasy

Chloroplast microsatellites have been widely used in population genetic studies of conifers in recent years. However, their haplotype configurations suggest that they could have high levels of homoplasy, thus limiting the power of these molecular markers. A coalescent-based computer simulation was used to explore the influence of homoplasy on measures of genetic diversity based on chloroplast microsatellites. The conditions of the simulation were defined to fit isolated populations originating from the colonization of one single haplotype into an area left available after a glacial retreat. Simulated data were compared with empirical data available from the literature for a species of Pinus that has expanded north after the Last Glacial Maximum. In the evaluation of genetic diversity, homoplasy was found to have little influence on Nei's unbiased haplotype diversity (H(E)) while Goldstein's genetic distance estimates (D2sh) were much more affected. The effect of the number of chloroplast microsatellite loci for evaluation of genetic diversity is also discussed

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m−2d−1on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m−2d−1, experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m−2d−1) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m−2d−1). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m−2d−1in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose. © 2001 Cancer Research Campaign  http://www.bjcancer.co

Variability in spine radiosurgery treatment planning - results of an international multi-institutional study

Background: The aim of this study was to quantify the variability in spinal radiosurgery (SRS) planning practices between five international institutions, all member of the Elekta Spine Radiosurgery Research Consortium. Methods: Four institutions provided one representative patient case each consisting of the medical history, CT and MR imaging. A step-wise planning approach was used where, after each planning step a consensus was generated that formed the basis for the next planning step. This allowed independent analysis of all planning steps of CT-MR image registration, GTV definition, CTV definition, PTV definition and SRS treatment planning. In addition, each institution generated one additional SRS plan for each case based on intra-institutional image registration and contouring, independent of consensus results. Results: Averaged over the four cases, image registration variability ranged between translational 1.1 mm and 2.4 mm and rotational 1.1° and 2.0° in all three directions. GTV delineation variability was 1.5 mm in axial and 1.6 mm in longitudinal direction averaged for the four cases. CTV delineation variability was 0.8 mm in axial and 1.2 mm in longitudinal direction. CTV-to-PTV margins ranged between 0 mm and 2 mm according to institutional protocol. Delineation variability was 1 mm in axial directions for the spinal cord. Average PTV coverage for a single fraction18 Gy prescription was 87 ± 5 %; Dmin to the PTV was 7.5 ± 1.8 Gy averaged over all cases and institutions. Average Dmax to the PRV_SC (spinal cord + 1 mm) was 10.5 ± 1.6 Gy and the average Paddick conformity index was 0.69 ± 0.06. Conclusions: Results of this study reflect the variability in current practice of spine radiosurgery in large and highly experienced academic centers. Despite close methodical agreement in the daily workflow, clinically significant variability in all steps of the treatment planning process was demonstrated. This may translate into differences in patient clinical outcome and highlights the need for consensus and established delineation and planning criteria

HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis

Background: Statins [3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors] and antiplatelet therapy reduce the risk of atherosclerotic disease. Besides a reduction of lipid levels, statins might also have antithrombotic and anti-inflammatory properties, and anti-platelet therapy reduces clot formation. We have studied the risk of venous thrombosis with use of statins, other lipid-lowering medication, and antiplatelet therapy. Materials and methods: Patients with a first episode of deep vein thrombosis in the leg or pulmonary embolism between March 1999 and September 2004 were included in a large population-based case–control study (MEGA study). Control subjects were partners of patients (53%) or recruited via a random-digit-dialing method (47%). Participants reported different all-medication use in a questionnaire. Results: Of 4538 patients, 154 used statins (3.3%), as did 354 of 5914 control subjects (5.7%). The use of statins [odds ratio (OR) 0.45; 95% confidence interval (CI) 0.36–0.56] but not other lipid-lowering medications (OR 1.22; 95% CI 0.62–2.43), was associated with a reduced venous thrombosis risk as compared with individuals who did not use any lipid-lowering medication, after adjustment for age, sex, body mass index, atherosclerotic disease, antiplatelet therapy and use of vitamin K antagonists. Different types and various durations of statin therapy were all associated with a decreased venous thrombosis risk. Antiplatelet therapy also reduced venous thrombosis risk (OR 0.56; 95% CI 0.42–0.74). However, sensitivity analyses suggested that this effect is most likely explained by a so-called ‘healthy user effect’. Simultaneous use of medication most strongly reduced venous thrombosis risk. Conclusion: These results suggest that the use of various types of statins is associated with a reduced risk of venous thrombosis, whereas antiplatelet therapy and other lipid-lowering medications are not.\u

A multiscale analysis of gene flow for the New England cottontail, an imperiled habitat specialist in a fragmented landscape

Landscape features of anthropogenic or natural origin can influence organisms\u27 dispersal patterns and the connectivity of populations. Understanding these relationships is of broad interest in ecology and evolutionary biology and provides key insights for habitat conservation planning at the landscape scale. This knowledge is germane to restoration efforts for the New England cottontail (Sylvilagus transitionalis), an early successional habitat specialist of conservation concern. We evaluated local population structure and measures of genetic diversity of a geographically isolated population of cottontails in the northeastern United States. We also conducted a multiscale landscape genetic analysis, in which we assessed genetic discontinuities relative to the landscape and developed several resistance models to test hypotheses about landscape features that promote or inhibit cottontail dispersal within and across the local populations. Bayesian clustering identified four genetically distinct populations, with very little migration among them, and additional substructure within one of those populations. These populations had private alleles, low genetic diversity, critically low effective population sizes (3.2-36.7), and evidence of recent genetic bottlenecks. Major highways and a river were found to limit cottontail dispersal and to separate populations. The habitat along roadsides, railroad beds, and utility corridors, on the other hand, was found to facilitate cottontail movement among patches. The relative importance of dispersal barriers and facilitators on gene flow varied among populations in relation to landscape composition, demonstrating the complexity and context dependency of factors influencing gene flow and highlighting the importance of replication and scale in landscape genetic studies. Our findings provide information for the design of restoration landscapes for the New England cottontail and also highlight the dual influence of roads, as both barriers and facilitators of dispersal for an early successional habitat specialist in a fragmented landscape