Effects of rf Current on Spin Transfer Torque Induced Dynamics

The impact of radiofrequency (rf) currents on the direct current (dc) driven switching dynamics in current-perpendicular-to-plane nanoscale spin valves is demonstrated. The rf currents dramatically alter the dc driven free layer magnetization reversal dynamics as well as the dc switching level. This occurs when the frequency of the rf current is tuned to a frequency range around the dc driven magnetization precession frequencies. For these frequencies, interactions between the dc driven precession and the injected rf induce frequency locking and frequency pulling effects that lead to a measurable dependence of the critical switching current on the frequency of the injected rf. Based on macrospin simulations, including dc as well as rf spin torque currents, we explain the origin of the observed effects.Comment: 5 pages, 4 figure

Practice patterns and outcomes of equivocal bone scans for patients with castration-resistant prostate cancer: Results from SEARCH.

ObjectiveTo review follow-up imaging after equivocal bone scans in men with castration resistant prostate cancer (CRPC) and examine the characteristics of equivocal bone scans that are associated with positive follow-up imaging.MethodsWe identified 639 men from five Veterans Affairs Hospitals with a technetium-99m bone scan after CRPC diagnosis, of whom 99 (15%) had equivocal scans. Men with equivocal scans were segregated into "high-risk" and "low-risk" subcategories based upon wording in the bone scan report. All follow-up imaging (bone scans, computed tomography [CT], magnetic resonance imaging [MRI], and X-rays) in the 3 months after the equivocal scan were reviewed. Variables were compared between patients with a positive vs. negative follow-up imaging after an equivocal bone scan.ResultsOf 99 men with an equivocal bone scan, 43 (43%) received at least one follow-up imaging test, including 32/82 (39%) with low-risk scans and 11/17 (65%) with high-risk scans (p = 0.052). Of follow-up tests, 67% were negative, 14% were equivocal, and 19% were positive. Among those who underwent follow-up imaging, 3/32 (9%) low-risk men had metastases vs. 5/11 (45%) high-risk men (p = 0.015).ConclusionWhile 19% of all men who received follow-up imaging had positive follow-up imaging, only 9% of those with a low-risk equivocal bone scan had metastases versus 45% of those with high-risk. These preliminary findings, if confirmed in larger studies, suggest follow-up imaging tests for low-risk equivocal scans can be delayed while high-risk equivocal scans should receive follow-up imaging

Financing essential HIV services: a new economic agenda.

Anna Vassall and colleagues discuss the need for, and challenges facing, innovative and sustainable financing of the HIV response. Please see later in the article for the Editors' Summary

Informing targeted HIV self-testing: a protocol for discrete choice experiments in Malawi, Zambia and Zimbabwe

Introduction HIV self-testing (HIVST) is a new approach to HIV testing where a person collects his or her own specimen, performs an HIV test and interprets the result, either alone or with someone he or she trusts. It is becoming increasingly relevant as a complement to standard-of-care HIV testing and is now recommended by the World Health Organization. Few studies have explored user preferences around HIVST service delivery and optimal models for increasing uptake and linkage to care, particularly among hard-to-reach populations. This paper describes an ongoing study that uses discrete choice experiments (DCE) to identify key HIVST service characteristics that drive people’s willingness to self-test for HIV and link to care, measure the relative strength of user preferences, and explore preference heterogeneity in Southern Africa. Method and Analysis Two DCEs – one on HIVST delivery and one on linkage to care after a positive self-test – are being administered in Malawi, Zambia and Zimbabwe. The designs in each country were informed by a qualitative study, which identified key HIVST service characteristics that influence user decision-making and refined scenario presentations and illustrations. Following data collection, DCE data will be analysed using a multinomial logit model as well as latent class, nested logit and generalised mixed models to examine heterogeneity in preferences by sociodemographic background, HIV testing experience and sexual behaviour. Ethics and dissemination The study has been approved by the College of Medicine Research Ethics Committee in Malawi, the Biomedical Ethics Committee of the University of Zambia, the Medical Research Council of Zimbabwe and the Research Ethics Committee of the London School of Hygiene and Tropical Medicine. Findings from the study will be presented at international conferences and in peer-reviewed journals. The results will help inform the HIVST implementation strategy in Southern Africa, particularly among populations underserved by standard-of-care services, such as men and young women

Cost-effectiveness of tenofovir gel in urban South Africa: model projections of HIV impact and threshold product prices.

BACKGROUND: There is urgent need for effective HIV prevention methods that women can initiate. The CAPRISA 004 trial showed that a tenofovir-based vaginal microbicide had significant impact on HIV incidence among women. This study uses the trial findings to estimate the population-level impact of the gel on HIV and HSV-2 transmission, and price thresholds at which widespread product introduction would be as cost-effective as male circumcision in urban South Africa. METHODS: The estimated 'per sex-act' HIV and HSV-2 efficacies were imputed from CAPRISA 004. A dynamic HIV/STI transmission model, parameterised and fitted to Gauteng (HIV prevalence of 16.9% in 2008), South Africa, was used to estimate the impact of gel use over 15 years. Uptake was assumed to increase linearly to 30% over 10 years, with gel use in 72% of sex-acts. Full economic programme and averted HIV treatment costs were modelled. Cost per DALY averted is estimated and a microbicide price that equalises its cost-effectiveness to that of male circumcision is estimated. RESULTS: Using plausible assumptions about product introduction, we predict that tenofovir gel use could lead to a 12.5% and 4.9% reduction in HIV and HSV-2 incidence respectively, by year 15. Microbicide introduction is predicted to be highly cost-effective (under $300 per DALY averted), though the dose price would need to be just$0.12 to be equally cost-effective as male circumcision. A single dose or highly effective (83% HIV efficacy per sex-act) regimen would allow for more realistic threshold prices ($0.25 and$0.33 per dose, respectively). CONCLUSIONS: These findings show that an effective coitally-dependent microbicide could reduce HIV incidence by 12.5% in this setting, if current condom use is maintained. For microbicides to be in the range of the most cost-effective HIV prevention interventions, product costs will need to decrease substantially

An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs. METHODS: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1–5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan–Meier and Cox regression methods. RESULTS: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16–82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006). CONCLUSION: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up

Universal Vectorial and Ultrasensitive Nanomechanical Force Field Sensor

Miniaturization of force probes into nanomechanical oscillators enables ultrasensitive investigations of forces on dimensions smaller than their characteristic length scale. Meanwhile it also unravels the force field vectorial character and how its topology impacts the measurement. Here we expose an ultrasensitive method to image 2D vectorial force fields by optomechanically following the bidimensional Brownian motion of a singly clamped nanowire. This novel approach relies on angular and spectral tomography of its quasi frequency-degenerated transverse mechanical polarizations: immersing the nanoresonator in a vectorial force field does not only shift its eigenfrequencies but also rotate eigenmodes orientation as a nano-compass. This universal method is employed to map a tunable electrostatic force field whose spatial gradients can even take precedence over the intrinsic nanowire properties. Enabling vectorial force fields imaging with demonstrated sensitivities of attonewton variations over the nanoprobe Brownian trajectory will have strong impact on scientific exploration at the nanoscale

Modelling the impact and cost-effectiveness of combination prevention amongst HIV serodiscordant couples in Nigeria.

OBJECTIVE: To estimate the impact and cost-effectiveness of treatment as prevention (TasP), pre-exposure prophylaxis (PrEP) and condom promotion for serodiscordant couples in Nigeria. DESIGN: Mathematical and cost modelling. METHODS: A deterministic model of HIV-1 transmission within a cohort of serodiscordant couples and to/from external partners was parameterized using data from Nigeria and other African settings. The impact and cost-effectiveness were estimated for condom promotion, PrEP and/or TasP, compared with a baseline where antiretroviral therapy (ART) was offered according to 2010 national guidelines (CD4 <350 cells/μl) to all HIV-positive partners. The impact was additionally compared with a baseline of current ART coverage (35% of those with CD4 <350 cells/μl). Full costs (in US $2012) of programme introduction and implementation were estimated from a provider perspective. RESULTS: Substantial benefits came from scaling up ART to all HIV-positive partners according to 2010 national guidelines, with additional smaller benefits of providing TasP, PrEP or condom promotion. Compared with a baseline of offering ART to all HIV-positive partners at the 2010 national guidelines, condom promotion was the most cost-effective strategy [US$1206/disability-adjusted-life-year (DALY)], the next most cost-effective intervention was to additionally give TasP to HIV-positive partners (incremental cost-effectiveness ratio US $1607/DALY), followed by additionally giving PrEP to HIV-negative partners until their HIV-positive partners initiate ART (US$7870/DALY). When impact was measured in terms of infections averted, PrEP with condom promotion prevented double the number of infections as condom promotion alone. CONCLUSIONS: The first priority intervention for serodiscordant couples in Nigeria should be scaled up ART access for HIV-positive partners. Subsequent incremental benefits are greatest with condom promotion and TasP, followed by PrEP

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

Transgressing the moral economy: Wheelerism and management of the nationalised coal industry in Scotland

This article illuminates the links between managerial style and political economy in post-1945 Britain, and explores the origins of the 1984–1985 miners' strike, by examining in longer historical context the abrasive attitudes and policies of Albert Wheeler, Scottish Area Director of the National Coal Board (NCB). Wheeler built on an earlier emphasis on production and economic criteria, and his micro-management reflected pre-existing centralising tendencies in the industries. But he was innovative in one crucial aspect, transgressing the moral economy of the Scottish coalfield, which emphasised the value of economic security and changes by joint industrial agreement