bluuebunny/crossref_metadata_2025 huggingface dataset:
Noninvasive Skin Fluorescence Spectroscopy for Diabetes Screening
Authors: Stirban Alin
Published: June 2016

The development of cost-effective, simple, and reproducible tests for diabetes screening represents a priority of modern medicine in light of the increasing prevalence of diabetes mellitus. Besides fasting plasma glucose, the oral glucose tolerance test, and glycated hemoglobin A1c, several tests have been proposed, among them the assessment of skin fluorescence spectroscopy (SFS). This article comments on the article by Olson and coauthors published in this issue of Journal of Diabetes Science and Technology and comprehensively reviews related available information. Overall, SFS seems to represent an easy-to-use, noninvasive tool that adds value to existing tests for diabetes screening.
Analysis and Perspective of Dosing Accuracy and Insulin Flow Rate Characteristics of a New Disposable Insulin Pen, FlexTouch, Compared with SoloSTAR
Authors: Yeager Harold K. , Ignaut Debra A.
Published: June 2016

Pen injectors for the administration of insulin have been available since the 1980s. The first insulin pen, NovoPen®, was introduced by Novo in 1985 ( http://www.novonordisk.com/about_us/history/step-by-step.asp ). In the years since, insulin pens have seen innovation in both features and functionality, and many more manufacturers have entered the market. This analysis discusses several features and design alternatives of insulin pens and comments on a new study by Bohnet and coauthors in this issue of Journal of Diabetes Science and Technology that compared the dosing accuracy of the spring-driven FlexTouch® (FT; Novo Nordisk; insulin aspart) with that of the manually operated SoloSTAR® (Sanofi; insulin glulisine). The volumetric flow rate of insulin delivery with FT was also evaluated.
Advancement of the Artificial Pancreas through the Development of Interoperability Standards
Authors: Picton Peter E. , Yeung Melanie , Hamming Nathaniel , Desborough Lane , Dassau Eyal , Cafazzo Joseph A.
Published: June 2016

Despite advancements in the development of the artificial pancreas, barriers in the form of proprietary data and communication protocols of diabetes devices have made the integration of these components challenging. The Artificial Pancreas Standards and Technical Platform Project is an initiative funded by the JDRF Canadian Clinical Trial Network with the goal of developing device communication standards for the interoperability of diabetes devices. Stakeholders from academia, industry, regulatory agencies, and medical and patient communities have been engaged in advancing this effort. In this article, we describe this initiative along with the process involved in working with the standards organizations and stakeholders that are key to ensuring effective standards are developed and adopted. Discussion from a special session of the 12th Annual Diabetes Technology Meeting is also provided.

Conclusion

This session provided the project team an excellent opportunity to interact with a diverse group of stakeholders and brought a number of new collaborators to the table who will contribute to the initiative. Starting in January 2013, the project team has convened regular meetings with collaborating researchers and industry representatives to discuss the direction of the standards development, focusing on the IEEE-11073 PHD standards for the insulin pump and CGM. Through this ongoing collaboration, the barriers to the interoperability of diabetes devices will eventually be eliminated, fostering greater innovation in the development of the AP and other diabetes management tools.
The impact of the DoH Commissioning for Quality and Innovation incentive on the success of venous thromboembolism risk assessment in hospitalised patients. A single institution experience in a quality outcome improvement over a 4-year cycle
Authors: Shlebak Abdul , Sandhu Polly , Ali Vernisha , Jones Garth , Baker Christopher
Published: June 2016

Objectives

To i) demonstrate compliance with the Commissioning for Quality and Innovation for venous thromboembolism risk assessment ii) to undertake root cause analysis of Hospital Acquired Thrombosis and to investigate its impact on quality of care.

Design

Prospective monitoring of all admissions.

Setting

Imperial College Healthcare Hospitals, London.

Participants

All Hospital Provider Spells as defined on the NHS Data Model and Dictionary.

Main outcome measures

i) Percentage of patients undergoing Venous Thromboembolism Risk Assessment (VTE-RA) at and 24-hours after admission ii) root cause analysis of Hospital Acquired Thrombosis up to 90 days following discharge.

Results

Over a 48-month cycle 83% were overall VTE-RA assessed with 36% in the first 12 months but with significant improvement to ≥95% between April 2013 and April 2015, achieving compliance target since April 2012 involving a massive 633, 850 Spells over the 4 year period. We undertook root cause analysis of all VTE episodes from April 2013 to March 2014, to ascertain Hospital Acquired Thrombosis (HAT), we analysed 433, 174 inpatient days and found a HAT rate of 1 per 1000 with 23% and 24% for DVTs and PEs potentially avoidable respectively. We further analysed VTE risk stratification (n = 1000) and found 37.0% at high risk, 44.4% at medium risk and 18.6 % at low risk, indicating the need of thromboprophylaxis in 81.4% (high and medium) of whom 33.6% were excluded.

Conclusions

We achieved 95% RA compliance which has favourably impacted on our daily practice and improved the quality of the clinical care.
Lungworm Eucoleus aerophilus (Capillaria aerophila) infection in a feline immunodeficiency virus-positive cat in France
Authors: Elhamiani Khatat Sarah , Rosenberg Dan , Benchekroun Ghita , Polack Bruno
Published: June 2016

Case summary

A 2-year-old domestic shorthair female outdoor cat living in France was diagnosed with a lungworm infection due to Eucoleus aerophilus. The history and clinical signs, in association with bronchoscopic examination, suggested chronic upper respiratory disease. Cytological examination of bronchoalveolar lavage fluid (BALF) was consistent with suppurative bronchitis. Direct microscopic examination of BALF enabled the identification of E aerophilus ova.

Relevance and novel information

The cat was positive for feline immunodeficiency virus and had been treated with steroids for a suspected allergic bronchitis, suggesting that immunodeficiency was probably a facilitating factor for E aerophilus infection, as described in previous cases. This case report emphasises the importance of considering eucoleosis (capillariosis) in the differential diagnosis of respiratory disease in cats. To our knowledge, this is the first clinical case of E aerophilus infection described in a domestic cat in France.
The Legacy of Luella Miner
Authors: Wong Mary Shepard
Published: June 2016

Luella Miner, missionary to China from 1887 to 1935, was the founder and president of the first college for women in China. Her many writings, including letters, journals, articles, and books, are a window into China’s changing political scene in the early twentieth century and into the life of an educational missionary in north China who helped launch basic education for girls and higher education for women. While one should be cautious not to overstate Luella Miner’s legacy, it is hard to deny the influence she had in China as a teacher, author, activist, president, and scholar.
Influence of phyllosilicates and fluid–rock interaction on the deformation style and mechanical behaviour of quartz-rich rocks in the Carboneras and Palomares fault areas (SE Spain)
Authors: Jiménez-Millán J. , Abad I. , Hernández-Puentes P. , Jiménez-Espinosa R.
Published: June 2016

Deformed quartzitic rocks from the Carboneras and Palomares fault areas (SE Spain) are enriched in phyllosilicates compared to their respective protoliths. Deformation is mainly localized in highly foliated chlorite-rich bands. Quartz-rich bands show brittle deformation developing dolomite-rich cross-cutting veins re-cementing microcataclasite areas. Undamaged lenses within the cataclastic rocks contain patches of phyllosilicates with randomly oriented chlorite and mica. Mg, Fe, water, As and Zn enrichment of the damaged rocks suggests a process of hydrothermal chloritization associated with the Cabo de Gata volcanism. Petrographic characteristics indicate that hydrothermal alteration that produced chlorite and mica-enrichment occurred before faulting. Phyllosilicates provided lubricating properties to the quartzitic rocks, favouring the predominance of creep over seismic stick-slip and reducing the possibility of large seismogenic events. Dolomite cementation as a consequence of fluid–rock interaction processes would have a limited effect, due to the presence of weak phyllosilicate surfaces.
High-altitude alpine therapy and lung function in asthma: systematic review and meta-analysis
Authors: Vinnikov Denis , Khafagy Abdullah , Blanc Paul D. , Brimkulov Nurlan , Steinmaus Craig
Published: June 2016

We used meta-analysis to measure the effect of high-altitude climate therapy (HACT) on lung function outcomes in asthma, and systematically searched PubMed, Embase andwww.elibrary.rufor publications appearing from 1970 to mid-2015. We included studies carried out with children or adults with an exposure of up to 12 weeks at an altitude of ≥1500 m above sea level. Changes in forced expiratory volume in 1 s (FEV1), FEV1/vital capacity ratio or peak expiratory flow rate as the HACT intervention outcomes were analysed. We included data for 907 participants (age range 4–58 years) from 21 studies, altogether including 28 substrata based on asthma type or severity. Only three of 21 included studies had high quality, whereas 93% of substudies reported lung function improvement with an overall pooled standardised mean difference (SMD) of 0.53 (95% CI 0.43–0.62). The measured effect of HACT was greater in adults (SMD 0.75, 95% CI 0.63–0.88, n=14) than in children (SMD 0.24, 95% CI 0.09–0.38, n=14). Studies at altitude >2000 m above sea level yielded the same effect as those at lower altitude. Based on a cut-point of a 0.50 change in SMD to define a meaningful clinical difference, HACT appears to have efficacy as an intervention. This extent of benefit appears to be limited to adults with asthma.
If the shoe fits: development of an on‐line tool to aid practitioner/patient discussions about ‘healthy footwear’
Authors: Farndon Lisa , Robinson Victoria , Nicholls Emily , Vernon Wesley
Published: June 2016

Background

A previous study highlighted the importance of footwear to individuals' sense of their identity, demonstrating that shoes must ‘fit’ someone socially, as well as functionally. However, unhealthy shoes can have a detrimental effect on both foot health and mobility. This project utilises qualitative social science methods to enable podiatrists to understand the broader contribution of footwear to patients' sense of themselves and from this an online toolkit was developed to aid footwear education.

Method

Semi‐structured interviews were conducted with six podiatrists/shoe‐fitters and 13 people with foot pathologies, some of whom also completed shoe diaries. These were supplemented with some follow‐up interviews and photographs of participants' own shoes were taken to allow in‐depth discussions.

Results

Four areas related to ‘fit’ were identified; practicalities, personal, purpose and pressures, all of which need to be considered when discussing changes in footwear. These were incorporated into an online toolkit which was further validated by service users and practitioners in a focus group.

Conclusion

This toolkit can support podiatrists in partnership with patients to identify and address possible barriers to changing footwear towards a more suitable shoe. Enabling patients to make healthier shoe choices will help contribute to improvements in their foot health and mobility.
Gigwa—Genotype investigator for genome-wide analyses
Authors: Sempéré Guilhem , Philippe Florian , Dereeper Alexis , Ruiz Manuel , Sarah Gautier , Larmande Pierre
Published: June 2016

Background

Exploring the structure of genomes and analyzing their evolution is essential to understanding the ecological adaptation of organisms. However, with the large amounts of data being produced by next-generation sequencing, computational challenges arise in terms of storage, search, sharing, analysis and visualization. This is particularly true with regards to studies of genomic variation, which are currently lacking scalable and user-friendly data exploration solutions.

Description

Here we present Gigwa, a web-based tool that provides an easy and intuitive way to explore large amounts of genotyping data by filtering it not only on the basis of variant features, including functional annotations, but also on genotype patterns. The data storage relies on MongoDB, which offers good scalability properties. Gigwa can handle multiple databases and may be deployed in either single- or multi-user mode. In addition, it provides a wide range of popular export formats.

Conclusions

The Gigwa application is suitable for managing large amounts of genomic variation data. Its user-friendly web interface makes such processing widely accessible. It can either be simply deployed on a workstation or be used to provide a shared data portal for a given community of researchers.
Macroscopic framework for viscoelasticity, poroelasticity, and wave-induced fluid flows — Part 2: Effective media
Authors: Morozov Igor B. , Deng Wubing
Published: June 2016

Sedimentary rocks possess complex microstructures and require simplified descriptions in terms of averaged, or effective mechanical properties. Most conventional approaches to effective media use the concept of viscoelastic moduli to describe the frequency-dependent wave velocities and attenuation. However, for rock containing pore fluids, a single pair of bulk and shear moduli does not account for slow P- and S-waves and for reflections and conversions in heterogeneous media. To overcome these limitations, we use the general linear solid (GLS) theoretical framework to derive multiphase models of effective media. Two types of models are considered. First, for sandstone containing thin layers saturated with brine and gas, two-phase effective-medium relations are derived in a (relatively) closed form for the density and elasticity, and the parameters of internal friction are inferred by fitting the dispersion spectra of both fast and slow P-waves. In the second application, we consider the generalized standard linear solid (GSLS) medium, which is broadly used in numerical simulations of seismic wavefields. The GLS point of view suggests that (petro)physical significance should always be sought for the mathematical variables usually assumed in GSLS models. Inertial effects and interactions between internal variables cause additional wave modes in a GSLS medium. Contrary to what is often thought, with inertial effects and fuller interactions between the internal variables, near-zero or negative velocity dispersion can occur in a medium with band-limited attenuation.
Intelligent meshing technique for 2D resistivity inverse problems
Authors: Chou Ting-Kuei , Chouteau Michel , Dubé Jean-Sébastien
Published: June 2016

In geophysical inverse problems, an a priori structured mesh is often used for inversion and mesh refinement is applied if needed by the user after observation of inversion results. We have developed a new intelligent self-adaptive unstructured finite-element meshing technique for electrical resistivity tomography inverse problems. This new approach uses Harris corner-and-edge detectors that are based on the local autocorrelation function of 2D distribution of pixels. This meshing technique optimizes the size of the inverse problem by refining areas where variations in the physical property structure are sensed to be important. The meshing technique also generates a more appropriate and optimum mesh for the inverse problem that is dependent on the problem itself. Tests on modeled data have demonstrated that the proposed intelligent meshing technique can reduce data misfit, produce a better reconstruction of the true physical properties, and minimize the size of the inverse problem. The synthetic model consists of a conductive dike in a resistive medium. By applying the proposed intelligent meshing technique, the inverse model of the dike is very similar to the inverse model produced using fine meshes, and it is also better reconstructed than the inverse model produced using conventional meshes. We have also applied the intelligent meshing technique to survey data collected for groundwater-saltwater mapping and characterizing the subsurface conductive structure with topography included. Our results indicate that the new meshing technique can produce solutions that are comparable with standard meshing and fine meshing techniques, while optimizing the size of the inverse problem.
Monte Carlo data-driven tight frame for seismic data recovery
Authors: Yu Siwei , Ma Jianwei , Osher Stanley
Published: June 2016

Seismic data denoising and interpolation are essential preprocessing steps in any seismic data processing chain. Sparse transforms with a fixed basis are often used in these two steps. Recently, we have developed an adaptive learning method, the data-driven tight frame (DDTF) method, for seismic data denoising and interpolation. With its adaptability to seismic data, the DDTF method achieves high-quality recovery. For 2D seismic data, the DDTF method is much more efficient than traditional dictionary learning methods. But for 3D or 5D seismic data, the DDTF method results in a high computational expense. The motivation behind this work is to accelerate the filter bank training process in DDTF, while doing less damage to the recovery quality. The most frequently used method involves only a randomly selective subset of the training set. However, this random selection method uses no prior information of the data. We have designed a new patch selection method for DDTF seismic data recovery. We suppose that patches with higher variance contain more information related to complex structures, and should be selected into the training set with higher probability. First, we calculate the variance of all available patches. Then for each patch, a uniformly distributed random number is generated and the patch is preserved if its variance is greater than the random number. Finally, all selected patches are used for filter bank training. We call this procedure the Monte Carlo DDTF method. We have tested the trained filter bank on seismic data denoising and interpolation. Numerical results using this Monte Carlo DDTF method surpass random or regular patch selection DDTF when the sizes of the training sets are the same. We have also used state-of-the-art methods based on the curvelet transform, block matching 4D, and multichannel singular spectrum analysis as comparisons when dealing with field data.
P- and S-wave velocity models of shallow dry sand formations from surface wave multimodal inversion
Authors: Bergamo Paolo , Socco Laura Valentina
Published: June 2016

Surficial formations composed of loose, dry granular materials constitute a challenging target for seismic characterization. They exhibit a peculiar seismic behavior, characterized by a nonlinear seismic velocity gradient with depth that follows a power-law relationship, which is a function of the effective stress. The P- and S-wave velocity profiles are then characterized by a power-law trend, and they can be defined by two power-law exponents [Formula: see text] and two power-law coefficients [Formula: see text]. In case of depth-independent Poisson’s ratio, the P-wave velocity profile can be defined using the [Formula: see text] power-law parameters and Poisson’s ratio. Because body wave investigation techniques (e.g., P-wave tomography) may perform ineffectively on such materials because of high attenuation, we addressed the potential of surface-wave method for a reliable seismic characterization of shallow formations of dry, uncompacted granular materials. We took into account the dependence of seismic wave velocity on effective pressure and performed a multimodal inversion of surface-wave data, which allowed the [Formula: see text] and [Formula: see text] profiles to be retrieved. The method requires the selection of multimodal dispersion curve points referring to surface-wave frequency components traveling within the granular media formation and their inversion for the S-wave power-law parameters and Poisson’s ratio. We have tested our method on a synthetic dispersion curve and applied it to a real data set. In both cases, the surficial layer was made of loose dry sand. The test on the synthetic data set confirmed the reliability of the proposed procedure because the thickness and the [Formula: see text], [Formula: see text] profiles of the sand layer were correctly estimated. For the real data, the outcomes were validated by other geophysical measurements conducted at the same site and they were in agreement with similar studies regarding loose sand formations.
Approximate semianalytical solutions for the electromagnetic response of a dipping-sphere interacting with conductive overburden
Authors: Desmarais Jacques K. , Smith Richard S.
Published: June 2016

Electromagnetic exploration methods have important applications for geologic mapping and mineral exploration in igneous and metamorphic terranes. In such cases, the earth is often largely resistive and the most important interaction is between a conductor of interest and a shallow, thin, horizontal sheet representing glacial tills and clays or the conductive weathering products of the basement rocks (both of which are here termed the “conductive overburden”). To this end, we have developed a theory from which the step and impulse responses of a sphere interacting with conductive overburden can be quickly and efficiently approximated. The sphere model can also be extended to restrict the currents to flow in a specific orientation (termed the dipping-sphere model). The resulting expressions are called semianalytical because all relevant relations are developed analytically, with the exception of the time-convolution integrals. The overburden is assumed to not be touching the sphere, so there is no galvanic interactions between the bodies. We make use of the dipole sphere in a uniform field and thin sheet approximations; however, expressions could be obtained for a sphere in a dipolar (or nondipolar) field using a similar methodology. We have found that there is no term related to the first zero of the relevant Bessel function in the response of the sphere alone. However, there are terms for all other zeros. A test on a synthetic model shows that the combined sphere-overburden response can be reasonably approximated using the first-order perturbation of the overburden field. Minor discrepancies between the approximate and more elaborate numerical responses are believed to be the result of numerical errors. This means that in practice, the proposed approach consists of evaluating one convolution integral over a sum of exponentials multiplied by a polynomial function. This results in an extremely simple algorithmic implementation that is simple to program and easy to run. The proposed approach also provides a simple method that can be used to validate more complex algorithms. A test on field data obtained at the Reid Mahaffy site in Northern Ontario shows that our approximate method is useful for interpreting electromagnetic data even when the background is thick. We use our approach to obtain a better estimate of the geometry and physical properties of the conductor and evaluate the conductance of the overburden.
Elastic wave propagation in fractured media using the discontinuous Galerkin method
Authors: De Basabe Jonás D. , Sen Mrinal K. , Wheeler Mary F.
Published: June 2016

We have formulated and implemented a discontinuous Galerkin method (DGM) for elastic wave propagation that allows for discontinuities in the displacement field to simulate fractures or faults. The approach is based on the interior-penalty formulation of DGM, and the fractures are simulated using the linear-slip model, which is incorporated into the weak formulation by including an additional term that is similar to the penalty term but uses the fracture compliance instead of an arbitrary penalty parameter. We have calibrated our results against an analytic solution of fracture-induced anisotropy for a set of elongated horizontal fractures, and we have evaluated numerical examples that simulate the reflection and transmission of waves at a fracture and at fracture interface waves. This method can further be used with models containing intersecting fractures and multiple fracture sets in 2D or 3D domains.
Fully automated near-surface analysis by surface-consistent refraction method
Authors: Colombo Daniele , Miorelli Federico , Sandoval Ernesto , Erickson Kevin
Published: June 2016

Industry practices for near-surface analysis indicate difficulties in coping with the increased number of channels in seismic acquisition systems, and new approaches are needed to fully exploit the resolution embedded in modern seismic data sets. To achieve this goal, we have developed a novel surface-consistent refraction analysis method for low-relief geology to automatically derive near-surface corrections for seismic data processing. The method uses concepts from surface-consistent analysis applied to refracted arrivals. The key aspects of the method consist of the use of common midpoint (CMP)-offset-azimuth binning, evaluation of mean traveltime and standard deviation for each bin, rejection of anomalous first-break (FB) picks, derivation of CMP-based traveltime-offset functions, conversion to velocity-depth functions, evaluation of long-wavelength statics, and calculation of surface-consistent residual statics through waveform crosscorrelation. Residual time lags are evaluated in multiple CMP-offset-azimuth bins by crosscorrelating a pilot trace with all the other traces in the gather in which the correlation window is centered at the refracted arrival. The residuals are then used to build a system of linear equations that is simultaneously inverted for surface-consistent shot and receiver time shift corrections plus a possible subsurface residual term. All the steps are completely automated and require a fraction of the time needed for conventional near-surface analysis. The developed methodology was successfully performed on a complex 3D land data set from Central Saudi Arabia where it was benchmarked against a conventional tomographic work flow. The results indicate that the new surface-consistent refraction statics method enhances seismic imaging especially in portions of the survey dominated by noise.
Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group
Authors: Pieters Rob , de Groot-Kruseman Hester , Van der Velden Vincent , Fiocco Marta , van den Berg Henk , de Bont Evelien , Egeler R. Maarten , Hoogerbrugge Peter , Kaspers Gertjan , Van der Schoot Ellen , De Haas Valerie , Van Dongen Jacques
Published: June 2016

Purpose

Outcome of childhood acute lymphoblastic leukemia (ALL) improved greatly by intensifying chemotherapy for all patients. Minimal residual disease (MRD) levels during the first months predict outcome and may select patients for therapy reduction or intensification.

Methods

Patients 1 to 18 years old with ALL were stratified on the basis of MRD levels after the first and second course of chemotherapy. Thereafter, therapy was substantially reduced in patients with undetectable MRD (standard risk) and intensified in patients with intermediate (medium risk) and high (high risk) levels of MRD. Seven hundred seventy-eight consecutive patients were enrolled. The method of analysis was intention-to-treat. Outcome was compared with historical controls.

Results

In MRD-based standard-risk patients, the 5-year event-free survival (EFS) rate was 93% (SE 2%), the 5-year survival rate was 99% (SE 1%), and the 5-year cumulative incidence of relapse rate was 6% (SE 2%). The safety upper limit of number of observation years was reached and therapy reduction was declared safe. MRD-based medium-risk patients had a significantly higher 5-year EFS rate (88%, SE 2%) with therapy intensification (including 30 weeks of asparaginase exposure and dexamethasone/vincristine pulses) compared with historical controls (76%, SE 6%). Intensive chemotherapy and stem cell transplantation in MRD-based high-risk patients resulted in a significantly better 5-year EFS rate (78%, SE 8% v 16%, SE 8% in controls). Overall outcome improved significantly (5-year EFS rate 87%, 5-year survival rate 92%, and 5-year cumulative incidence of relapse rate 8%) compared with preceding Dutch Childhood Oncology Group protocols.

Conclusion

Chemotherapy was substantially reduced safely in one-quarter of children with ALL who were selected on the basis of undetectable MRD levels, without jeopardizing the survival rate. Outcomes of patients with intermediate and high levels of MRD improved with therapy intensification.
Evaluation of the Risk of Relapse in Classical Hodgkin Lymphoma at Event-Free Survival Time Points and Survival Comparison With the General Population in British Columbia
Authors: Hapgood Greg , Zheng Yvonne , Sehn Laurie H. , Villa Diego , Klasa Richard , Gerrie Alina S. , Shenkier Tamara , Scott David W. , Gascoyne Randy D. , Slack Graham W. , Parsons Christina , Morris James , Pickles Tom , Connors Joseph M. , Savage Kerry J.
Published: June 2016

Purpose

Studies in classical Hodgkin lymphoma (cHL) typically measure the time to events from diagnosis. We evaluated the risk of relapse at event-free survival time points in cHL and compared the risk of death to expected mortality rates in British Columbia (BC).

Methods

The BC Cancer Agency Lymphoid Cancer Database was screened to identify all patients age 16 to 69 years diagnosed with cHL between 1989 and 2012 treated with the chemotherapy regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (or equivalent). We compared the observed mortality to the general population using age-, sex-, and calendar period–generated expected mortality rates from BC life-tables. Relative survival was calculated using a conditional approach and expressed as a standardized mortality ratio of observed-to-expected deaths.

Results

One thousand four hundred two patients were identified; 749 patients were male (53%), the median age was 32 years, and 68% had advanced-stage disease. The median follow-up time was 8.4 years. Seventy-two percent of relapses occurred within the first 2 years of diagnosis. For all patients, the 5-year risk of relapse from diagnosis was 18.1% but diminished to 5.6% for patients remaining event free at 2 years. For advanced-stage patients who were event free at 2 years, the 5-year risk of relapse was only 7.6%, and for those who were event free at 3 years, it was comparable to that of limited-stage patients (4.1% v 2.5%, respectively; P = .07). Furthermore, international prognostic score ≥ 4 and bulky disease were no longer prognostic in patients who were event free at 1 year. Although the relative survival improved as patients remained in remission, it did not normalize compared with the general population.

Conclusion

Patients with cHL who are event free at 2 years have an excellent outcome regardless of baseline prognostic factors. All patients with cHL had an enduring increased risk of death compared with the general population.
Double-Blind, Placebo-Controlled, Randomized Phase III Trial Evaluating Pertuzumab Combined With Chemotherapy for Low Tumor Human Epidermal Growth Factor Receptor 3 mRNA–Expressing Platinum-Resistant Ovarian Cancer (PENELOPE)
Authors: Kurzeder Christian , Bover Isabel , Marmé Frederik , Rau Joern , Pautier Patricia , Colombo Nicoletta , Lorusso Domenica , Ottevanger Petronella , Bjurberg Maria , Marth Christian , Barretina-Ginesta Pilar , Vergote Ignace , Floquet Anne , del Campo Josep M. , Mahner Sven , Bastière-Truchot Lydie , Martin Nicolas , Oestergaard Mikkel Z. , Kiermaier Astrid , Schade-Brittinger Carmen , Polleis Sandra , du Bois Andreas , Gonzalez-Martin Antonio
Published: June 2016

Purpose

The AGO-OVAR 2.29/ENGOT-ov14/PENELOPE prospectively randomized phase III trial evaluated the addition of pertuzumab to chemotherapy in patients with platinum-resistant ovarian carcinoma with low tumor human epidermal growth factor receptor 3 (HER3) mRNA expression. We report the results of the primary efficacy analysis.

Patients and Methods

Eligible patients had ovarian carcinoma that progressed during or within 6 months of completing four or more platinum cycles, centrally tested low tumor HER3 mRNA expression (concentration ratio ≤ 2.81 by quantitative reverse transcriptase polymerase chain reaction on cobas z480 [Roche Molecular Diagnostics, Pleasanton, CA]), and no more than two prior lines of chemotherapy. After investigators’ selection of the chemotherapy backbone (single-agent topotecan, weekly paclitaxel, or gemcitabine), patients were randomly assigned to also receive either placebo or pertuzumab (840-mg loading dose followed by 420 mg every 3 weeks). Stratification factors were selected chemotherapy, prior antiangiogenic therapy, and platinum-free interval. The primary end point was independent review committee–assessed progression-free survival (PFS). Additional end points included overall survival, investigator-assessed PFS, objective response rate, safety, patient-reported outcomes, and translational research.

Results

Overall, 156 patients were randomly assigned. Adding pertuzumab to chemotherapy did not significantly improve independent review committee–assessed PFS for the primary analysis (stratified hazard ratio, 0.74; 95% CI, 0.50 to 1.11; P = .14; median PFS, 4.3 months for pertuzumab plus chemotherapy v 2.6 months for placebo plus chemotherapy). Sensitivity analyses and secondary efficacy end point results were consistent with the primary analysis. The effect on PFS favoring pertuzumab was more pronounced in the gemcitabine and paclitaxel cohorts. No new safety signals were seen.

Conclusion

Although the primary objective was not met, subgroup analyses showed trends in PFS favoring pertuzumab in the gemcitabine and paclitaxel cohorts, meriting further exploration of pertuzumab in ovarian cancer.
Lack of Effectiveness of Neutropenic Diet and Social Restrictions as Anti-Infective Measures in Children With Acute Myeloid Leukemia: An Analysis of the AML-BFM 2004 Trial
Authors: Tramsen Lars , Salzmann-Manrique Emilia , Bochennek Konrad , Klingebiel Thomas , Reinhardt Dirk , Creutzig Ursula , Sung Lillian , Lehrnbecher Thomas
Published: June 2016

Purpose

Although nonpharmacologic anti-infective measures are widely used in children treated for acute myeloid leukemia (AML), there is little evidence of their effectiveness.

Patients and Methods

We analyzed infectious complications in children during intensive treatment of AML according to the AML-BFM 2004 trial and surveyed sites on institutional standards regarding recommended restrictions of social contacts (six items), pets (five items), and food (eight items). A scoring system was developed with a restriction score for each item. Multivariable Poisson regression adjusted for sex, age, weight group, risk stratification, and prophylactic antibiotics was used to estimate the impact of the restrictions on the incidence ratios of fever of unknown origin, bacteremia, pneumonia, and gastroenteritis.

Results

Data on recommendations of nonpharmacologic anti-infective measures and infectious complications were available in 339 patients treated in 37 institutions. Analyses did not demonstrate a significant benefit of any of the restrictions regarding food, social contacts, and pets on the risk of fever, bacteremia, pneumonia, and gastroenteritis. In contrast, age, weight group, risk stratification, and nonabsorbable antibiotics had some influence on infections complications.

Conclusion

The lack of effectiveness of dietary restrictions and restrictions regarding social contacts and pets should result in reconsideration of anti-infective policies.
Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer
Authors: Fribbens Charlotte , O’Leary Ben , Kilburn Lucy , Hrebien Sarah , Garcia-Murillas Isaac , Beaney Matthew , Cristofanilli Massimo , Andre Fabrice , Loi Sherene , Loibl Sibylle , Jiang John , Bartlett Cynthia Huang , Koehler Maria , Dowsett Mitch , Bliss Judith M. , Johnston Stephen R.D. , Turner Nicholas C.
Published: June 2016

Purpose

ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor–positive advanced breast cancer.

Materials and Methods

In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction.

Results

In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001).

Conclusion

ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.
Comparative Effectiveness of Treatment Strategies for Bladder Cancer With Clinical Evidence of Regional Lymph Node Involvement
Authors: Galsky Matthew D. , Stensland Kristian , Sfakianos John P. , Mehrazin Reza , Diefenbach Michael , Mohamed Nihal , Tsao Che-Kai , Boffetta Paolo , Wiklund Peter , Oh William K. , Mazumdar Madhu , Ferket Bart
Published: June 2016

Purpose

Patients with bladder cancer with clinical lymph node involvement (cN+) are at high risk for distant metastases, but are potentially curable. Such patients are excluded from neoadjuvant chemotherapy trials and pooled with patients with distant metastases in first-line chemotherapy trials not suited to define the role of combined-modality therapy. To address this evidence void, we performed a comparative effectiveness analysis.

Methods

We included cTanyN1-3M0 bladder cancer patients from the National Cancer Data Base (2003-2012) treated with chemotherapy and/or cystectomy. We used multistate survival analysis, allowing for delayed entry, to assess overall survival (OS) according to various treatment strategies. Effectiveness was estimated with multivariable adjustment for tumor-, patient-, and facility-level characteristics.

Results

Among 1,739 patients (cN1, 48%; cN2, 45%; cN3, 7%), 1,104 underwent cystectomy and 635 were treated with chemotherapy alone. Of the cystectomy patients, 363 received preoperative and 328 received adjuvant chemotherapy. The crude 5-year OS for chemotherapy alone, cystectomy alone, preoperative chemotherapy followed by cystectomy, and cystectomy followed by adjuvant chemotherapy was 14% (95% CI, 11% to 17%), 19% (95% CI, 15% to 24%), 31% (95% CI, 25% to 38%), and 26% (95% CI, 21% to 34%), respectively. Compared with cystectomy alone, preoperative chemotherapy was associated with a significant improvement in OS (hazard ratio, 0.80; 95% CI, 0.66 to 0.97). Adjuvant chemotherapy was also associated with a significant improvement in survival compared with cystectomy alone. The survival of patients treated with chemotherapy alone was worse than those treated with cystectomy alone.

Conclusion

A subset of patients with cN+ bladder cancer achieves long-term survival. Combined-modality therapy, with chemotherapy and cystectomy, is associated with the best outcomes.
PRKACA Somatic Mutations Are Rare Findings in Aldosterone-Producing Adenomas
Authors: Rhayem Yara , Perez-Rivas Luis G. , Dietz Anna , Bathon Kerstin , Gebhard Christian , Riester Anna , Mauracher Brigitte , Gomez-Sanchez Celso , Eisenhofer Graeme , Schwarzmayr Thomas , Calebiro Davide , Strom Tim M. , Reincke Martin , Beuschlein Felix
Published: June 2016

Context:

Somatic mutations have been found causative for endocrine autonomy in aldosterone-producing adenomas (APAs). Whereas mutations of PRKACA (catalytic subunit of protein kinase A) have been identified in cortisol-producing adenomas, the presence of PRKACA variants in APAs is unknown, especially in those that display cosecretion of cortisol.

Objective:

The objective of the study was to investigate PRKACA somatic variants identified in APA cases.

Design:

Identification of PRKACA somatic variants in APAs by whole-exome sequencing followed by in vitro analysis of the enzymatic activity of PRKACA variants and functional characterization by double immunofluorescence of CYP11B2 and CYP11B1 expression in the corresponding tumor tissues.

Setting and Patients:

APA tissues were collected from 122 patients who underwent unilateral adrenalectomy for primary aldosteronism between 2005 and 2015 at a single institution.

Results:

PRKACA somatic mutations were identified in two APA cases (1.6%). One APA carried a newly identified p.His88Asp variant, whereas in a second case, a p.Leu206Arg mutation was found, previously described only in cortisol-producing adenomas with overt Cushing's syndrome. Functional analysis showed that the p.His88Asp variant was not associated with gain of function. Although CYP11B2 was strongly expressed in the p.His88Asp-mutated APA, the p.Leu206Arg carrying APA predominantly expressed CYP11B1. Accordingly, biochemical Cushing's syndrome was present only in the patient with the p.Leu206Arg mutation. After adrenalectomy, both patients improved with a reduced number of antihypertensive medications and normalized serum potassium levels.

Conclusions:

We describe for the first time PRKACA mutations as rare findings associated with unilateral primary aldosteronism. As cortisol cosecretion occurs in a subgroup of APAs, other molecular mechanisms are likely to exist.
Signaling pathways controlling activity-dependent local translation of BDNF and their localization in dendritic arbors
Authors: Baj Gabriele , Pinhero Vera , Vaghi Valentina , Tongiorgi Enrico
Published: June 2016

Brain-derived neurotrophic factor (BDNF) is encoded by multiple mRNA variants whose differential subcellular distribution constitutes a ‘spatial code’ for local translation of BDNF and selective morphological remodeling of dendrites. Here, we investigated where BDNF translation takes place and what are the signaling pathways involved. Cultured hippocampal neurons treated with KCl showed increased BDNF in the soma, proximal and distal dendrites, even in quaternary branches. This activity-dependent increase of BDNF was abolished by cycloheximide, suggesting local translation, and required activation of glutamate and Trk receptors. Our data showed that BDNF translation was regulated by multiple signaling cascades including RAS–Erk and mTOR pathways, and CaMKII–CPEB1, Aurora-A–CPEB1 and Src–ZBP1 pathways. Aurora-A, CPEB1, ZBP1 (also known as IGF2BP1), eiF4E, S6 (also known as rpS6) were present throughout the dendritic arbor. Neuronal activity increased the levels of Aurora-A, CPEB1 and ZBP1 in distal dendrites whereas those of eiF4E and S6 were unaffected. BDNF-6, the main dendritic BDNF transcript, was translated in the same subcellular domains and in response to the same pathways as total BDNF. In conclusion, we identified the signaling cascades controlling BDNF translation and we describe how the translational machinery localization is modulated in response to electrical activity.
Unique Approach for Transforming Glucose to C3 Platform Chemicals Using Metallic Iron and a Pd/C Catalyst in Water
Authors: Hirano Yoshiaki , Kasai Yuka , Sagata Kunimasa , Kita Yuichi
Published: June 2016

In the utilization of biomass for fuels and chemicals, the key reactions involved are hydrogenolysis and deoxygenation using hydrogen. Unfortunately, the industrial use of molecular hydrogen is limited because of various drawbacks, such as high cost and considerable hazards associated with high-pressure operation. In this study, a unique chemical manufacturing process was proposed for inducing the hydrogenolysis and deoxygenation of biomass carbohydrates using hydrogen generated in situ from the reaction between metallic iron and water. From the results obtained, hydrogen generated in situ by metallic iron particles (hydrogen-generating agent) combined with a carbon-supported palladium catalyst (hydrogenation catalyst) transforms glucose to C3 platform chemicals, such as propylene glycol, hydroxyacetone, and lactic acid. Moreover, reaction conditions and mechanism were also evaluated. With the use of the proposed system, value-added chemicals were produced from biomass carbohydrates by using renewable sources of energy (such as hydrogen generated from the reaction between iron and water) without the complete dependence on fossil resources.
Bi- and Multilayered Assembly of Amphiphilic Pd(II) and Pt(II) Complexes with N-Alkyl-4,4′-bipyridinium Ligands
Authors: Endo Hirotaka , Suzaki Yuji , Komura Motonori , Osakada Kohtaro
Published: June 2016

Alternating transition metal-organic bi- and multilayers composed of dicationic (ethylenediamine)palladium(II) and platinum(II) complexes and N-alkyl-4,4′-bipyridinium, [(η3–C3H5)Pd{4,4′-bpy-N-(CH2)12OC6H3-3,5-(OMe)2}(OAc)]NO3 and [M{4,4′-bpy-N-(CH2)12OC6H3-3,5-(OMe)2}2(en)](NO3)4 (M = Pd, Pt, en = 1,2-ethylenediamine), were synthesized on mica surface by simple casting method from aqueous solution.