bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetes Device Reimbursement in the EU-5
Authors: Schäfer Elmar , Schnell Gerald , Bobáková Tamara
Published: June 2016

The reimbursement landscape for new and innovative diabetes devices in Europe is very heterogeneous and nontransparent, with each country employing different mechanisms, pathways, and requirements. This article provides an overview of how diabetes device reimbursement works in the outpatient setting in the five major European Union markets (France, Germany, Italy, Spain, and the United Kingdom; the EU-5). It will be of particular interest to manufacturers of innovative devices. Markets are first categorized as either a centralized or a regionalized reimbursement decision-making system, and implications for device reimbursement are explored. In the second part, specific requirements and success factors for wide reimbursement in the EU-5 are analyzed in detail. Gaining early acceptance by the main influencers (key opinion leaders and payers) is the first step. Equally important is the provision of convincing evidence, be this clinical, health-economic (cost-effectiveness), or a demonstration of cost savings (budget impact). In some countries, local usage data may be a requirement as well. Lastly, as payers' willingness to pay stems directly from their perceived value of a device, a key success factor and a necessary precondition for manufacturers is to set the right price.
Dexcom G4AP: An Advanced Continuous Glucose Monitor for the Artificial Pancreas
Authors: Garcia Arturo , Rack-Gomer Anna Leigh , Bhavaraju Naresh C. , Hampapuram Haripriyan , Kamath Apurv , Peyser Thomas , Facchinetti Andrea , Zecchin Chiara , Sparacino Giovanni , Cobelli Claudio
Published: June 2016

Input from continuous glucose monitors (CGMs) is a critical component of artificial pancreas (AP) systems, but CGM performance issues continue to limit progress in AP research. While G4 PLATINUM has been integrated into AP systems around the world and used in many successful AP controller feasibility studies, this system was designed to address the needs of ambulatory CGM users as an adjunctive use system. Dexcom and the University of Padova have developed an advanced CGM, called G4AP, to specifically address the heightened performance requirements for future AP studies. The G4AP employs the same sensor and transmitter as the G4 PLATINUM but contains updated denoising and calibration algorithms for improved accuracy and reliability. These algorithms were applied to raw data from an existing G4 PLATINUM clinical study using a simulated prospective procedure. The results show that mean absolute relative difference (MARD) compared with venous plasma glucose was improved from 13.2% with the G4 PLATINUM to 11.7% with the G4AP. Accuracy improvements were seen over all days of sensor wear and across the plasma glucose range (40–400 mg/dl). The greatest improvements occurred in the low glucose range (40–80 mg/dl), in euglycemia (80–120 mg/dl), and on the first day of sensor use. The percentage of sensors with a MARD <15% increased from 69% to 80%. Metrics proposed by the AP research community for addressing specific AP requirements were also computed. The G4AP consistently exhibited improved sensor performance compared with the G4 PLATINUM. These improvements are expected to enable further advances in AP research.
Pharmacokinetics of Insulin Aspart and Glucagon in Type 1 Diabetes during Closed-Loop Operation
Authors: Haidar Ahmad , Duval Claire , Legault Laurent , Rabasa-Lhoret Rémi
Published: June 2016

Background:

We assessed the pharmacokinetics of subcutaneous insulin aspart and glucagon during closed-loop operation and their relationship with body composition variables.

Methods:

We retrospectively analyzed data collected from closed-loop experiments in 15 type 1 diabetes patients (age 47.1 ± 12.3 years, body mass index 25.9 ± 4.6 kg/m2, glycated hemoglobin 7.9% ± 0.7%). Patients received an evening meal accompanied with prandial insulin bolus and stayed in the clinical facility until the next morning. Glucose levels were regulated by dual-hormone closed-loop delivery. Insulin and glucagon were delivered using two subcutaneous infusion pumps installed on the abdominal wall. Plasma insulin and glucagon were measured every 10–30 min. Percentage of body fat, percentage of fat in the abdominal area, and mass of abdominal fat were measured by dual X-ray absorptiometry.

Results:

A pharmacokinetic model estimated time-to-peak plasma concentrations [ tmax insulin 51 (19) min, tmax glucagon 19 (4) min, mean (standard deviation)], metabolic clearance rate [ MCR insulin 0.019 (0.015–0.026) liter/kg/min, MCR glucagon 0.012 (0.010–0.014) liter/kg/min, median (interquartile range)], and the background plasma concentrations [ Ib insulin 10.2 (6.3–15.2) mU/liter, Ib glucagon 50 (45–56) pg/ml, median (interquartile range)]. tmax correlated positively between insulin and glucagon ( r = 0.7; p = .007) while MCR correlated negatively ( r = –0.7; p = .015). In this small sample size, tmax, MCR, and Ib of insulin and glucagon did not correlate with percentage of body fat, percentage of fat in the abdominal area, or total mass of abdominal fat.

Conclusions:

Insulin and glucagon pharmacokinetics might be related during closed-loop operation. Our data suggest that slower absorption of insulin is associated with slower absorption of glucagon. Body composition does not seem to influence insulin and glucagon pharmacokinetics.
Influence of Partial Pressure of Oxygen in Blood Samples on Measurement Performance in Glucose-Oxidase-Based Systems for Self-Monitoring of Blood Glucose
Authors: Baumstark Annette , Schmid Christina , Pleus Stefan , Haug Cornelia , Freckmann Guido
Published: June 2016

Background:

Partial pressure of oxygen (pO2) in blood samples can affect blood glucose (BG) measurements, particularly in systems that employ the glucose oxidase (GOx) enzyme reaction on test strips. In this study, we assessed the impact of different pO2 values on the performance of five GOx systems and one glucose dehydrogenase (GDH) system. Two of the GOx systems are labeled by the manufacturers to be sensitive to increased blood oxygen content, while the other three GOx systems are not.

Methods:

Aliquots of 20 venous samples were adjusted to the following pO2 values: <45, ∼70, and ≥150 mmHg. For each system, five consecutive measurements on each sample aliquot were performed using the same test strip lot. Relative differences between the mean BG results at pO2 ∼70 mmHg, which is considered to be similar to pO2 in capillary blood samples, and the mean BG result at pO2 <45 and ≥150 mmHg were calculated.

Results:

For all tested GOx systems, mean relative differences in the BG measurement results were between 6.1% and 22.6% at pO2 <45 mmHg and between −7.9% and −14.9% at pO2 ≥150 mmHg. For both pO2 levels, relative differences of all tested GOx systems were significant ( p < .0001). The GDH system showed mean relative differences of −1.0% and −0.4% at pO2 values <45 and ≥150 mmHg, respectively, which were not significant.

Conclusions:

These data suggest that capillary blood pO2 variations lead to clinically relevant BG measurement deviations in GOx systems, even in GOx systems that are not labeled as being oxygen sensitive.
Role of Interleukin-1/Interleukin-1 Receptor Antagonist Family of Cytokines in Long-Term Continuous Glucose Monitoring In Vivo
Authors: Klueh Ulrike , Antar Omar , Qiao Yi , Kreutzer Donald L.
Published: June 2016

Background:

Glucose-sensor-induced tissue reactions (e.g., inflammation and wound healing) are known to negatively impact sensor function in vivo. The roles of cytokine networks in controlling these tissue reactions (i.e., sensor biofouling) is not understood. In the present study, we investigated the role of interleukin-1 receptor antagonist (IL-1Ra), a key anti-inflammatory antagonist of the proinflammatory interleukin-1 cytokines [i.e. interleukin-1 (IL-1) alpha and IL-1 beta] in controlling continuous glucose monitoring (CGM).

Methods:

To investigate the role of IL-1Ra in long-term CGM in vivo, we compared CGM in transgenic mice that overexpress IL-1Ra [interleukin-1 receptor antagonist overexpresser (IL-1Ra∼OE), B6.Cg-Tg (IL1rn)1Dih/J] or are deficient in IL-1Ra [interleukin-1 receptor antagonist knockout (IL-1Ra∼KO), B6.129S- IL1rntm1Dih/J] with mice that have normal levels of IL-1Ra (C57BL/6) over a 28-day time period.

Results:

Mean absolute relative difference (MARD) analysis of CGM results among the mice of varying IL-1Ra levels demonstrated that during the first 21 days, IL-1∼KO mice had the greatest tissue inflammation and the poorest sensor performance (i.e., higher MARD values) when compared with normal or IL-1Ra∼OE mice. By 28 days post-sensor implantation, the inflammatory reactions had subsided and were replaced by varying degrees of fibrosis.

Conclusions:

These data support our hypothesis on the importance of the IL-1 family of agonists and antagonists in controlling tissue reactions and sensor function in vivo. These data also suggest that local delivery of IL-1Ra genes or recombinant proteins (anakinra) or other IL-1 antagonists such as antibodies or soluble IL-1 receptors would suppress sensor-induced tissue reactions and likely enhance glucose sensor function by inhibiting inflammation and wound healing at sensor implantation sites.
The Evidence Base for Diabetes Technology: Appropriate and Inappropriate Meta-Analysis
Authors: Pickup John C.
Published: June 2016

When we are interested in making decisions about best use, comparative therapeutic efficacy, or cost-effectiveness of diabetes technologies such as insulin pump therapy [continuous subcutaneous insulin infusion (CSII)] or continuous glucose monitoring, meta-analysis for the purpose of literature summary is inappropriate and may be misleading. Instead, “decision-making meta-analysis” is more appropriate and should involve either preselection of trials based on intended use [e.g., elevated baseline hemoglobin A1c or hypoglycemia rate for trials of multiple daily injections (MDI) versus CSII] or metaregression of summary effect sizes in different trials against potential effect-modifying covariates such as baseline risk, or models of the covariates that determine effect size using individual patient data. Appropriate meta-analysis should also only include trials that are of sufficient duration to accurately measure outcomes such as severe hypoglycemia, and they should not use obsolete technology that is of proven inferiority to current technology. The use of appropriate decision-making meta-analysis is illustrated by the change in the rate ratio for severe hypoglycemia in randomized controlled trials of MDI versus CSII in type 1 diabetes from 1.56 (95% confidence interval 0.96–2.55; p = .074) for literature-summary meta-analysis to 2.0 (1.08–3.69; p = .027) for decision-making meta-analysis of all patients and 3.91 (1.35–11.36; p = .01) for trials in children.
Algorithms for a Closed-Loop Artificial Pancreas: The Case for Proportional-Integral-Derivative Control
Authors: Steil Garry M.
Published: June 2016

Closed-loop insulin delivery continues to be one of most promising strategies for achieving near-normal control of blood glucose levels in individuals with diabetes. Of the many components that need to work well for the artificial pancreas to be advanced into routine use, the algorithm used to calculate insulin delivery has received a substantial amount of attention. Most of that attention has focused on the relative merits of proportional-integral-derivative versus model-predictive control. A meta-analysis of the clinical data obtained in studies performed to date with these approaches is conducted here, with the objective of determining if there is a trend for one approach to be performing better than the other approach. Challenges associated with implementing each approach are reviewed with the objective of determining how these approaches might be improved. Results of the meta-analysis, which focused predominantly on the breakfast meal response, suggest that to date, the two approaches have performed similarly. However, uncontrolled variables among the various studies, and the possibility that future improvements could still be effected in either approach, limit the validity of this conclusion. It is suggested that a more detailed examination of the challenges associated with implementing each approach be conducted.
Culture, Fixed-World Beliefs, Relationships, and Perceptions of Identity Change
Authors: Kung Franki Y. H. , Eibach Richard P. , Grossmann Igor
Published: June 2016

Personal identity continuity has been a focus of much philosophical inquiry, yet lay perceptions of identity continuity and their psychological bases are not well understood. We hypothesize that cultural differences in lay beliefs about the fixedness of the world promote different intuitions about identity continuity: People from a society with rigid social systems should perceive more identity discontinuity when a person’s social relationships (vs. internal traits) change, whereas those from a society with more flexible social systems should perceive the reverse. We tested this hypothesis by comparing fixed-world beliefs and perceptions of identity discontinuity in India and the United States. Results of two studies ( N = 863) showed that Indians perceived more identity discontinuity than Americans when relationships (vs. internal traits) changed, which was explained by Indians’ stronger fixed-world beliefs. Moreover, in Study 2, cultural differences in perceived identity discontinuity mediated cultural differences in trust when a target’s relationships (vs. internal traits) changed.
Progressive myoclonic epilepsy with Fanconi syndrome
Authors: Seaby Eleanor G , Gilbert Rodney D , Pengelly Reuben J , Andreoletti Gaia , Clarke Antonia , Ennis Sarah
Published: June 2016

This report illustrates the difficulties in diagnosing complex cases and demonstrates how whole exome sequencing can resolve complex phenotypes.
Comparing UK and 20 Western countries' efficiency in reducing adult (55–74) cancer and total mortality rates 1989–2010: Cause for cautious celebration? A population-based study
Authors: Pritchard Colin , Hickish Tamas , Rosenorn-Lanng Emily , Wallace Mark
Published: June 2016

Objective

Every Western nation expends vast sums on health, especially for cancer; thus, the question is how efficient is the UK in reducing adult (55–74) cancer mortality rates and total mortality rates (TMR) compared to the other Western nations in the context of economic-input to health, the percentage of Gross-Domestic-Product-expenditure-on-Health.

Design

WHO mortality rates for baseline 3 years 1989–1991 and 2008–2010 were analysed, and confidence intervals determine any significant differences between the UK and other countries in reducing the mortalities. Efficiency ratios are calculated by dividing reduced mortality over the period by the average % of national income.

Setting

Twenty-one similar socio-economic Western countries.

Participants

The 21 countries’ general population.

Main outcome measures

Cancer mortality rates, total mortality rates Gross Domestic Product and Efficiency Ratios.

Results

Economic Input: In 1980, UK national income was 5.6% and the European average was 7.1%. By 2010, UK national income was 9.4% being equal 17th of 21 averaging 7.1% over the period. Europe’s 1980–2010 average of 8.4% yields a UK to Europe ratio of 1:1.18. Clinical output 1989–2010: UK Cancer Mortality Rates was the sixth highest, but equal sixth biggest fall, significantly greater than 14 other countries. UK Total Mortality Rates was the fifth highest but third biggest decline, significantly greater than 17 countries. UK’s cancer Efficiency Ratios is largest at 1:301 and second biggest for Total Mortality Rates at 1.1341; the USA ratios were 1:152 and 1:525, respectively.

Conclusions

UK reduced mortalities indicate that the NHS achieves proportionally more with relatively less, but UK needs to match European average Gross-Domestic-Product-expenditure-on-Health to meet future challenges.
Who Looks Suspicious? Racialized Surveillance in a Predominantly White Neighborhood
Authors: Lowe Maria R. , Stroud Angela , Nguyen Alice
Published: June 2016

In recent decades, neighborhoods across the United States have begun to employ digital media to monitor their communities for outsiders who are seen as suspicious. Yet, little is known about these surveillance practices and their consequences at the individual and neighborhood levels. Such monitoring behaviors are important to analyze not only because of the ways that perceptions of criminal threat are often racialized but also because of the role that private citizens play in initiating contact between strangers and the police. Based on an analysis of e-mails submitted to a listserv in a liberal, predominantly white neighborhood from September 2008 through August 2009, this article explores how residents identify, discuss, and respond to people whom they define as suspicious. Findings show that most suspicious person e-mails focus on black men who are also more likely to be portrayed as unique threats to neighborhood safety. These results suggest that listserv surveillance practices foster racialized notions of criminal threat that both reinforce the boundaries of predominantly white neighborhoods and reproduce the perception of black men as criminals.
My Pilgrimage in Mission
Authors: Boyd Robin
Published: June 2016

Born in Belfast, Robin Boyd studied there and in Dublin, Edinburgh, and Basel. Ordained in the Irish Presbyterian Church, he served the Student Christian Movement and in 1954 went to India (Gujarat), becoming a presbyter of the nascent (1970) Church of North India. In 1974 he moved to Melbourne, Australia, and ministered in a parish of the Uniting Church (1977). From 1980–87 he was director of the Irish School of Ecumenics (Dublin). His writing includes An Introduction to Indian Christian Theology (1969), and recent work on the eschatology of interfaith relations. Twice happily married, he lives in Edinburgh.
Mineralogical and physico-chemical characteristics of Cameroonian smectitic clays after treatment with weakly sulfuric acid
Authors: Mache J.R. , Signing P. , Mbey J.A. , Razafitianamaharavo A. , Njopwouo D. , Fagel N.
Published: June 2016

Smectitic clays from the Sabga and Bana areas, western Cameroon were treated with sulfuric-acid solutions of various concentrations – 0.5, 0.7, 1.0 and 4.0 N – at 80°C for 2 h. The mineralogical, physicochemical and morphological characteristics of the samples treated were analysed using several techniques. The sulfuric acid caused structural modification of the dioctahedral smectite. The accessory minerals such as cristobalite, quartz, feldspars and anatase remained unaltered by the acid attack. The supernatant solutions after acid treatment contain Mg, Ca, K, Na, Si, Al and Fe as a result of partial dissolution of octahedral and tetrahedral cations. The activated clay samples exhibited a smaller cation exchange capacity (CEC) and the specific surface area (SSA) increased with increasing concentration of sulfuric acid, ranging from 65 to 134 m2/g for the sample from Bana and from 74 to 84 m2/g for the sample from Sabga. The different SSAvalues were affected by the relative abundance of smectite and cristobalite (SiO2/Al2O3 = 2.2 and 6.5, respectively, from Bana and Sabga). The activated clays from Bana and Sabga displayed interesting physicochemical and textural properties and can be considered as promising adsorbents for the bleaching of vegetable oils.
Synthesis of sodalite from Brazilian kaolin wastes
Authors: Maia Ana Áurea B. , Neves Roberto F. , Angélica Rômulo S. , Pöllmann Herbert
Published: June 2016

Kaolin wastes from the Capim and Jari regions (Brazil) were used to produce sodalite under the same conditions used in the Bayer process, in order to control its formation when necessary. Of the two kaolin source materials, the kaolinite from the Jari region was more reactive in the synthesis of sodalite, which is attributed to the low degree of structural order of this clay mineral which increased its reactivity. At a temperature of 150°C and with a Na/Al ratio of 2, although the kaolinite did not react completely, sodalitewas the primary reaction product. An increase in the temperature to 200°C provoked the complete reaction of the kaolinite only for the products in which carbonate and sulfate were used. With a Na/Al ratio >2 and for both of the temperatures, the kaolinite reacted completely to form sodalite.
Bagging survival tree procedure for variable selection and prediction in the presence of nonsusceptible patients
Authors: Mbogning Cyprien , Broët Philippe
Published: June 2016

Background

For clinical genomic studies with high-dimensional datasets, tree-based ensemble methods offer a powerful solution for variable selection and prediction taking into account the complex interrelationships between explanatory variables. One of the key component of the tree-building process is the splitting criterion. For survival data, the classical splitting criterion is the Logrank statistic. However, the presence of a fraction of nonsusceptible patients in the studied population advocates for considering a criterion tailored to this peculiar situation.

Results

We propose a bagging survival tree procedure for variable selection and prediction where the survival tree-building process relies on a splitting criterion that explicitly focuses on time-to-event survival distribution among susceptible patients.

A simulation study shows that our method achieves good performance for the variable selection and prediction. Different criteria for evaluating the importance of the explanatory variables and the prediction performance are reported. Our procedure is illustrated on a genomic dataset with gene expression measurements from early breast cancer patients.

Conclusions

In the presence of nonsusceptible patients among the studied population, our procedure represents an efficient way to select event-related explanatory covariates with potential higher-order interaction and identify homogeneous groups of susceptible patients.
A distributional approach to obtain adjusted comparisons of proportions of a population at risk
Authors: Sauzet Odile , Breckenkamp Jürgen , Borde Theda , Brenne Silke , David Matthias , Razum Oliver , Peacock Janet L.
Published: June 2016

Background

Dichotomisation of continuous data has statistical drawbacks such as loss of power but may be useful in epidemiological research to define high risk individuals.

Methods

We extend a methodology for the presentation of comparison of proportions derived from a comparison of means for a continuous outcome to reflect the relationship between a continuous outcome and covariates in a linear (mixed) model without losing statistical power. The so called “distributional method” is described and using perinatal data for illustration, results from the distributional method are compared to those of logistic regression and to quantile regression for three different outcomes.

Results

Estimates obtained using the distributional method for the comparison of proportions are consistently more precise than those obtained using logistic regression. For one of the three outcomes the estimates obtained from the distributional method and from logistic regression disagreed highlighting that the relationships between outcome and covariate differ conceptually between the two models.

Conclusion

When an outcome follows the required condition of distribution shift between exposure groups, the results of a linear regression model can be followed by the corresponding comparison of proportions at risk. This dual approach provides more precise estimates than logistic regression thus avoiding the drawback of the usual dichotomisation of continuous outcomes.
Surface-wave methods for anomaly detection
Authors: Schwenk J. Tyler , Sloan Steven D. , Ivanov Julian , Miller Richard D.
Published: June 2016

Perimeter-defense operations, geohazard assessment, and engineering characterization require the detection and localization of subsurface anomalies. Seismic waves incident upon these discontinuities generate a scattered wavefield. We have developed various surface-wave techniques, currently being fielded, that have consistently delivered accurate and precise results across a wide range of survey parameters and geographical locations. We use the multichannel analysis of surface waves approach to study the multimode Rayleigh wave, the backscatter analysis of surface waves (BASW) method to detect anomalies, 3D visualization for efficient seismic interpretation, BASW correlation for attribute analysis, and instantaneous-amplitude integration in the complex BASW method. Discrete linear moveout functions and [Formula: see text]-[Formula: see text] filter designs are optimized for BASW considering the fundamental and higher mode dispersion trends of the Rayleigh wave. Synthetic and field data were used to demonstrate multimode BASW and mode separation, which accentuated individual scatter events, and ultimately increased confidence in points of interest. Simple correlation algorithms between fundamental and higher-mode BASW data offer attribute analysis that limits the subjective interpretation of BASW images. Domain sorting and Hilbert transforms allow for 3D visualization and rapid interpretation of an anomaly’s wavefield phenomena within an amplitude cube. Furthermore, instantaneous-amplitude analysis can be incorporated into a more robust complex BASW method that forgives velocity-estimation inaccuracies, while requiring less rigorous preprocessing. Our investigations have suggested that a multifaceted surface-wave analysis provides a valuable tool for today’s geophysicists to fulfill anomaly-detection survey requirements.
Method for calculating the fracture porosity of tight-fracture reservoirs
Authors: Xu Jingling , Zhang Baoying , Qin Yuxing , Cao Guangwei , Zhang Hui
Published: June 2016

Identifying fractures and evaluating the parameters of tight reservoirs are important problems. Developing methods to accurately interpret logging data for tight sandstone and shale reservoirs is of great significance, especially when only conventional logging data can be obtained. Identifying natural fractures with limited available data is challenging. Comparing and analyzing the log response characteristics of the natural fracture zone of a tight reservoir indicate that acoustic (AC) and density (DEN) data are highly sensitive to fractures in tight reservoirs. First, we have obtained the characteristics and differences of the log response of natural fractures. Second, we established a model that is based on these sensitive log-response characteristics (AC and DEN) to identify fractures (correlation coefficient method with window lengths), and we analyzed the cut-off of the correlation coefficient. Then, we established a model (the revised Wyllie difference method) to characterize the fracture porosity based on the difference in the sensitive log responses of the fracture (the difference in the AC and DEN curves). Finally, we applied this methodology to a case study of a tight reservoir in the Sichuan Basin, China, and the AC-DEN correlation coefficient and fracture porosity are calculated. The AC-DEN correlation coefficient adequately identifies fractures, and the calculated fracture porosity is consistent with the fracture porosity from full borehole microresistivity imaging. Thus, this method is applicable to evaluating fractures in tight-fracture reservoirs.
Chemotherapy Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia
Authors: Krull Kevin R. , Cheung Yin Ting , Liu Wei , Fellah Slim , Reddick Wilburn E. , Brinkman Tara M. , Kimberg Cara , Ogg Robert , Srivastava Deokumar , Pui Ching-Hon , Robison Leslie L. , Hudson Melissa M.
Published: June 2016

Purpose

To examine associations among methotrexate pharmacodynamics, neuroimaging, and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy-only protocol.

Patients and Methods

This longitudinal study linked pharmacokinetic assays collected during therapy to neurocognitive and brain imaging outcomes during long-term follow-up. A total of 218 (72.2%) of 302 eligible long-term survivors were recruited for outcome studies when they were more than 5 years post-diagnosis and older than 8 years of age. At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis, and 51% were male. Neurocognitive testing, functional magnetic resonance imaging (MRI) during an executive function task, and structural MRI with diffusion tensor imaging were conducted. Generalized linear models were developed to identify predictors, and models were adjusted for age at diagnosis, sex, and parent education.

Results

Intelligence was within normal limits (mean, 98; standard deviation, 14) compared with population expectations (mean, 100; standard deviation, 15), though measures of executive function, processing speed, and memory were less than population means (all P < .02 after correction for false discovery rates). Higher plasma concentration of methotrexate was associated with a poorer executive function score (P < .02). Higher plasma methotrexate was also associated with higher functional MRI activity, with thicker cortices in dorsolateral prefrontal brain regions, and with white matter microstructure in the frontostriatal tact. Neurocognitive impairment was associated with these imaging findings as well. Associations did not change after adjustment for age or dose of leucovorin rescue.

Conclusion

Survivors of childhood acute lymphoblastic leukemia treated on contemporary chemotherapy-only protocols demonstrate executive dysfunction. A higher plasma concentration of methotrexate was associated with executive dysfunction as well as with a thicker cortex and higher activity in frontal brain regions, regions often associated with executive function.
Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study
Authors: Lesokhin Alexander M. , Ansell Stephen M. , Armand Philippe , Scott Emma C. , Halwani Ahmad , Gutierrez Martin , Millenson Michael M. , Cohen Adam D. , Schuster Stephen J. , Lebovic Daniel , Dhodapkar Madhav , Avigan David , Chapuy Bjoern , Ligon Azra H. , Freeman Gordon J. , Rodig Scott J. , Cattry Deepika , Zhu Lili , Grosso Joseph F. , Bradley Garelik M. Brigid , Shipp Margaret A. , Borrello Ivan , Timmerman John
Published: June 2016

Purpose

Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies.

Methods

In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti–PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression.

Results

Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks.

Conclusion

Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.
Reduced-Intensity Transplantation for Lymphomas Using Haploidentical Related Donors Versus HLA-Matched Sibling Donors: A Center for International Blood and Marrow Transplant Research Analysis
Authors: Ghosh Nilanjan , Karmali Reem , Rocha Vanderson , Ahn Kwang Woo , DiGilio Alyssa , Hari Parameswaran N. , Bachanova Veronika , Bacher Ulrike , Dahi Parastoo , de Lima Marcos , D’Souza Anita , Fenske Timothy S. , Ganguly Siddhartha , Kharfan-Dabaja Mohamed A. , Prestidge Tim D. , Savani Bipin N. , Smith Sonali M. , Sureda Anna M. , Waller Edmund K. , Jaglowski Samantha , Herrera Alex F. , Armand Philippe , Salit Rachel B. , Wagner-Johnston Nina D. , Fuchs Ephraim , Bolaños-Meade Javier , Hamadani Mehdi
Published: June 2016

Purpose

Related donor haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplantation cyclophosphamide (PT-Cy) is increasingly used in patients lacking HLA-matched sibling donors (MSD). We compared outcomes after Haplo-HCT using PT-Cy with MSD-HCT in patients with lymphoma, using the Center for International Blood and Marrow Transplant Research registry.

Materials and Methods

We evaluated 987 adult patients undergoing either Haplo-HCT (n = 180) or MSD-HCT (n = 807) following reduced-intensity conditioning regimens. The haploidentical group received graft-versus-host disease (GVHD) prophylaxis with PT-Cy with or without a calcineurin inhibitor and mycophenolate. The MSD group received calcineurin inhibitor–based GVHD prophylaxis.

Results

Median follow-up of survivors was 3 years. The 28-day neutrophil recovery was similar in the two groups (95% v 97%; P = .31). The 28-day platelet recovery was delayed in the haploidentical group compared with the MSD group (63% v 91%; P = .001). Cumulative incidence of grade II to IV acute GVHD at day 100 was similar between the two groups (27% v 25%; P = .84). Cumulative incidence of chronic GVHD at 1 year was significantly lower after Haplo-HCT (12% v 45%; P < .001), and this benefit was confirmed on multivariate analysis (relative risk, 0.21; 95% CI, 0.14 to 0.31; P < .001). For Haplo-HCT v MSD-HCT, 3-year rates of nonrelapse mortality (15% v 13%; P = .41), relapse/progression (37% v 40%; P = .51), progression-free survival (48% v 48%; P = .96), and overall survival (61% v 62%; P = .82) were similar. Multivariate analysis showed no significant difference between Haplo-HCT and MSD-HCT in terms of nonrelapse mortality (P = .06), progression/relapse (P = .10), progression-free survival (P = .83), and overall survival (P = .34).

Conclusion

Haplo-HCT with PT-Cy provides survival outcomes comparable to MSD-HCT, with a significantly lower risk of chronic GVHD.
Efficacy of High-Intensity Local Treatment for Metastatic Urothelial Carcinoma of the Bladder: A Propensity Score–Weighted Analysis From the National Cancer Data Base
Authors: Seisen Thomas , Sun Maxine , Leow Jeffrey J. , Preston Mark A. , Cole Alexander P. , Gelpi-Hammerschmidt Francisco , Hanna Nawar , Meyer Christian P. , Kibel Adam S. , Lipsitz Stuart R. , Nguyen Paul L. , Bellmunt Joaquim , Choueiri Toni K. , Trinh Quoc-Dien
Published: June 2016

Purpose

Evidence from studies of other malignancies has indicated that aggressive local treatment (LT), even in the presence of metastatic disease, is beneficial. Against a backdrop of stagnant mortality rates for metastatic urothelial carcinoma of the bladder (mUCB) at presentation, we hypothesized that high-intensity LT of primary tumor burden, defined as the receipt of radical cystectomy or ≥ 50 Gy of radiation therapy delivered to the bladder, affects overall survival (OS).

Patients and Methods

We identified 3,753 patients within the National Cancer Data Base who received multiagent systemic chemotherapy combined with high-intensity versus conservative LT for primary mUCB. Patients who received no LT, transurethral resection of the bladder tumor alone, or < 50 Gy of radiation therapy delivered to the bladder were included in the conservative LT group. Inverse probability of treatment weighting (IPTW) –adjusted Kaplan-Meier curves and Cox regression analyses were used to compare OS of patients who received high-intensity versus conservative LT.

Results

Overall, 297 (7.91%) and 3,456 (92.09%) patients with mUCB received high-intensity and conservative LT, respectively. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer in the high-intensity LT group than in the conservative LT group (14.92 [interquartile range, 9.82 to 30.72] v 9.95 [interquartile range, 5.29 to 17.08] months, respectively; P < .001). Furthermore, in IPTW-adjusted Cox regression analysis, high-intensity LT was associated with a significant OS benefit (hazard ratio, 0.56; 95% CI, 0.48 to 0.65; P < .001).

Conclusion

We report an OS benefit for individuals with mUCB treated with high-intensity versus conservative LT. Although the findings are subject to the usual biases related to the observational study design, these preliminary data warrant further consideration in randomized controlled trials, particularly given the poor prognosis associated with mUCB.
Safety and Efficacy of Durvalumab (MEDI4736), an Anti–Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer
Authors: Massard Christophe , Gordon Michael S. , Sharma Sunil , Rafii Saeed , Wainberg Zev A. , Luke Jason , Curiel Tyler J. , Colon-Otero Gerardo , Hamid Omid , Sanborn Rachel E. , O’Donnell Peter H. , Drakaki Alexandra , Tan Winston , Kurland John F. , Rebelatto Marlon C. , Jin Xiaoping , Blake-Haskins John A. , Gupta Ashok , Segal Neil H.
Published: June 2016

Purpose

To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC).

Methods

A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1–positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1.

Results

A total of 61 patients (40 PD-L1–positive, 21 PD-L1–negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1–positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1–negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks).

Conclusion

Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1–positive patients with UBC, many of whom were heavily pretreated.
Role of mTOR Inhibitors in Growth Hormone-Producing Pituitary Adenomas Harboring Different FGFR4 Genotypes
Authors: Jalali Shahrzad , Monsalves Eric , Tateno Toru , Zadeh Gelareh
Published: June 2016

Pituitary adenomas (PAs) are common intracranial lesions. Available medical therapies are limited in PAs, and therefore, it is essential to identify treatments that control PA growth when surgery is not an option. Fibroblast growth factor 4 is implicated in PA pathogenesis; therefore, in this study, we used an isogenic mammosomatotroph cell line (GH4C1) harboring different fibroblast growth factor receptor (FGFR)-4 genotypes to establish and characterize intracranial xenograft mouse models that can be used for preclinical drug testing. We show that proliferating GH4C1 tumors have an average latency of 3 weeks to form. Histological analysis revealed that prototypic FGFR4 (G388) tumors express increased prolactin and less GH, whereas tumors possessing the polymorphic variant of FGFR4 (R388) express increased GH relative to prolactin. All tumors show abundant mammalian target of rapamycin (mTOR) signaling as confirmed using phosphorylated (p)-S6 and p-4E-binding protein 1 as downstream regulators of this pathway. We subsequently demonstrate that the mTOR inhibitor RAD001 decreases tumor growth rate and reduces p-S6 but not p-4E-binding protein 1 activation, regardless of FGFR4 status. More importantly, GH activity was significantly reduced after mTOR inhibition in the R388 polymorphic variant tumors. This reduction was also associated with a concomitant reduction in serum IGF-1 levels in the R388 group. In summary, we demonstrate that the GH4C1 FGFR polymorphic xenograft is a useful model for examining PAs. Furthermore, we show that RAD001 can efficiently reduce tumor growth rate by a reduction in mTOR signaling and more importantly results in control of GH expression and IGF-1 secretion, providing further support for using mTOR inhibitors in PA patients, in particular GH-producing adenomas.
Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy
Authors: Garcia Eric L. , Wen Ying , Praveen Kavita , Matera A. Gregory
Published: June 2016

Survival motor neuron (SMN) functions in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) that catalyze pre-mRNA splicing. Here, we used disruptions in Smn and two additional snRNP biogenesis genes, Phax and Ars2, to classify RNA processing differences as snRNP-dependent or gene-specific in Drosophila. Phax and Smn mutants exhibited comparable reductions in snRNAs, and comparison of their transcriptomes uncovered shared sets of RNA processing changes. In contrast, Ars2 mutants displayed only small decreases in snRNA levels, and RNA processing changes in these mutants were generally distinct from those identified in Phax and Smn animals. Instead, RNA processing changes in Ars2 mutants support the known interaction of Ars2 protein with the cap-binding complex, as splicing changes showed a clear bias toward the first intron. Bypassing disruptions in snRNP biogenesis, direct knockdown of spliceosomal proteins caused similar changes in the splicing of snRNP-dependent events. However, these snRNP-dependent events were largely unaltered in three Smn mutants expressing missense mutations that were originally identified in human spinal muscular atrophy (SMA) patients. Hence, findings here clarify the contributions of Phax, Smn, and Ars2 to snRNP biogenesis in Drosophila, and loss-of-function mutants for these proteins reveal differences that help disentangle cause and effect in SMA model flies.
Additive Technology in the Innovative Development of Educational Organization and Implementation of Social Projects Related to Improving the Living Conditions of People with Visual Disability
Authors: Мясникова  , Myasnikova L. , Пономарев  , Ponomarev Vladimir , Самборская  , Samborskaya L.
Published: June 2016

Tasks of the educational organization that additive technologies solve, the main problems encountered in the implementation of 3D-printing technology in the educational process, ways of additive technology’s commercialization and benefits to educational organization provided as a result of it implementation are considered in the article. The results of the analysis of 3D-modeling and 3D-printing technology using in the implementation of social projects related to improving the living conditions of people with visual disabilities are described.
Features of Distance Education in Higher Education of Modern Russia
Authors: Положенцева  , Polozhentseva I.
Published: June 2016

The article examines the features of organization of distance education at the higher school of Russia. It is emphasized that high-tech, innovative nature of the development of the education system envisages the expansion of the spectrum of fundamental and applied scientific studies, deepening the integration of science, education and production, the modernization of educational content, educational technologies and educational environment, training and coaching, causes certain changes in the organizational structure of the education system and administration of educational activities, and also requires a targeted, adequate and timely funding. The author points out that from a technological point of view this character cause: informatization of education, the emergence of new ICT-based pedagogical and learning technologies and the latest learning tools, the creation and use of pedagogical systems of modern, computer-oriented learning environment, gradual formation and development of computer-technological platform of information educational space.
Psychological and Pedagogical Problems of Formation of Managerial Personnel Reserve
Authors: Мальцева  , Maltseva T.
Published: June 2016

This article deals with the problem formation of personnel

reserve, it analyzes the elements of personnel management system,

the quality of the manager´s personality, facilitate effective and constructive

management.
Cognitive Interest As an Actual problem of Upbringing of Pupils
Authors: Бельгибаева  , Belgibaeva G. , Кенесбекова  , Kenesbekova S.
Published: June 2016

The article is devoted to problems of development of

cognitive interest of pupils. The authors examined the concept of

"cognitive interest", "interest" from the point of view of various

scientists. They had proposed definition of "interest" based on the

analysis of existing definitions. Pupils ´ interest in teaching is a

determining factor in the process of mastering their knowledge.

The interest in the acquisition of knowledge of students is formed

only by relevant organization teacher training activities. It should

be directed to the development of pupils cognitive interests.
Improving quality of care and reducing unnecessary hospital admissions: a literature review
Authors: Means Tracy
Published: June 2016

As the UK population lives to older ages, with more complex health and social care needs, there comes a time when going to live in a care home might be essential for a frail, older person. Residents and their families expect high-quality care in return for the costs of their placements, but often find this is not the case ( Help the Aged, 2006 ). In order to improve quality in care homes, the Lincolnshire Community Health Services NHS Trust are piloting a care home support team. The new service aims to provide education and training to an unpredictable workforce, with the addition of regular ward rounds in care homes to ensure more proactive care for residents, in order to reduce unnecessary hospital admissions and improve the quality of care offered. This article looks at the literature relating to education and training for staff in care homes to support this service. It also aims to use the reviewed articles to identify specific training and education needed to improve quality of care for residents and reduce avoidable hospital admissions.