bluuebunny/crossref_metadata_2025 huggingface dataset:
Using adaptive processes and adverse outcome pathways to develop meaningful, robust, and actionable environmental monitoring programs
Authors: Arciszewski Tim J , Munkittrick Kelly R , Scrimgeour Garry J , Dubé Monique G , Wrona Fred J , Hazewinkel Rod R
Published: April 2017

The primary goals of environmental monitoring are to indicate whether unexpected changes related to development are occurring in the physical, chemical, and biological attributes of ecosystems and to inform meaningful management intervention. Although achieving these objectives is conceptually simple, varying scientific and social challenges often result in their breakdown. Conceptualizing, designing, and operating programs that better delineate monitoring, management, and risk assessment processes supported by hypothesis-driven approaches, strong inference, and adverse outcome pathways can overcome many of the challenges. Generally, a robust monitoring program is characterized by hypothesis-driven questions associated with potential adverse outcomes and feedback loops informed by data. Specifically, key and basic features are predictions of future observations (triggers) and mechanisms to respond to success or failure of those predictions (tiers). The adaptive processes accelerate or decelerate the effort to highlight and overcome ignorance while preventing the potentially unnecessary escalation of unguided monitoring and management. The deployment of the mutually reinforcing components can allow for more meaningful and actionable monitoring programs that better associate activities with consequences. Integr Environ Assess Manag 2017;13:877–891. © 2017 The Authors. Integrated Environmental Assessment and Management Published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)

Key Points

Many monitoring programs struggle to achieve their stated objectives. Periodic adaptation of a monitoring program is a powerful tool to achieve the goals of stakeholders. Adaptive monitoring and adaptive management are distinct but complementary processes.
The use of human umbilical vein endothelial cells (HUVECs) as an in vitro model to assess the toxicity of nanoparticles to endothelium: a review
Authors: Cao Yi , Gong Yu , Liu Liangliang , Zhou Yiwei , Fang Xin , Zhang Cao , Li Yining , Li Juan
Published: April 2017

With the rapid development of nanotechnologies, nanoparticles (NPs) are increasingly produced and used in many commercial products, which could lead to the contact of human blood vessels with NPs. Thus, it is necessary to understand the adverse effects of NPs to relevant cells lining human blood vessels, especially endothelial cells (ECs) that cover the lumen of blood vessels. Human umbilical vein endothelial cells (HUVECs) are among one of the most popular models used for ECs in vitro. In the present review, we discussed studies that have used HUVECs as a model to investigate the EC–NP interactions, the toxic effects of NPs on ECs and the mechanisms. The results of these studies indicated that NPs could be internalized into HUVECs by the endocytosis pathway as well as transported across HUVECs by exocytosis and paracellular pathways. Exposure of HUVECs to NPs could induce cytotoxicity, genotoxicity, eNOS uncoupling and endothelial activation, which could be explained by NP‐induced oxidative stress, inflammatory response and dysfunction of organelles. In addition, some studies have also evaluated the influences of microenvironment (e.g. the presence of proteins and excessive nutrients), the physiological and/or pathological stimuli related to the diversity of ECs (e.g. shear stress, cyclic stretch and inflammatory stimuli), and the physicochemical properties of NPs on the responses of ECs to NP exposure. In conclusion, it has been suggested that HUVECs could be considered as a relatively reliable and simple in vitro model for ECs to predict and evaluate the toxicity of NPs to endothelium. Copyright © 2017 John Wiley & Sons, Ltd.
Evaluation of four hemoglobin separation analyzers for hemoglobinopathy diagnosis
Authors: Degandt Simon , Coens Rémy , Cauwelier Barbara , Devos Helena , Langlois Michel , Emmerechts Jan
Published: April 2017

Background

Four automated hemoglobin separation devices are compared in their ability to detect hemoglobinopathies, both in HbA1c and in hemoglobinopathy mode.

Methods

Quality control material and 58 samples, including one heterozygous α‐thalassemia sample, six heterozygote β‐thalassemia samples and 32 samples with a known hemoglobin variant, were used to assess imprecision of HbF and HbA2 measurements, correlation with the gold standard and sensitivity for detecting β‐thalassemia and Hb variants on D‐100 (Bio‐Rad Laboratories), HA 8180T (Menarini), HLC‐723G8 (Tosoh Bioscience) and Capillarys 2 Flex Piercing (Sebia).

Results

Imprecision was <10% for both HbF and HbA2 in all modes of all analyzers. Correlation studies for HbF and HbA2 demonstrated statistically significant but small biases when compared to the gold standard. All six β‐thalassemia samples but one were detected on all analyzers using a HbA2 cut‐off value of 3.5%. D‐100, HA8180T and the Hb‐pathy mode of the HLC‐723G8 and the Capillarys are able to detect the most common important Hb variants (Hb C, D, E and S), but more seldom variants can be missed as they co‐elute with HbA0. The HbA1c mode of the Capillarys correctly detected all measured hemoglobin variants and can therefore be used as a hemoglobinopathy screening device. This was also the case for the most common important Hb variants on the HbA1c mode of the HLC‐723G8, but two rare variants were not detected.

Conclusion

This study stresses the importance for individual laboratories to know the advantages and drawbacks of their hemoglobin separation analyzer and its different modes in the diagnosis of hemoglobinopathies.
Differential expression of urinary exosomal microRNAs in IgA nephropathy
Authors: Min Qing‐Hua , Chen Xi‐Min , Zou Ye‐Qing , Zhang Jing , Li Jing , Wang Yan , Li Shu‐Qi , Gao Qiu‐Fang , Sun Fan , Liu Jing , Xu Yan‐Mei , Lin Jin , Huang Lin‐Feng , Huang Bo , Wang Xiao‐Zhong
Published: April 2017

Background

Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis in the world. Reliable biomarkers are required for the non‐invasive diagnosis and monitoring of IgAN. This study aims to investigate the difference in urinary exosomal microRNA (miRNA) expression profiles between patients with IgA nephropathy (IgAN) and healthy controls, which may provide clues to identify novel potential non‐invasive miRNA biomarkers for renal diseases.

Methods

Urine samples were collected from eighteen healthy controls and eighteen patients with IgAN. Differential centrifugation was performed to isolate exosomes from urine samples. High‐throughput sequencing and real‐time quantitative polymerase chain reaction (RT‐qPCR) were sequentially used to screen and further validate miRNA expression profiles in urinary exosomes of patients with IgAN in two independent cohorts.

Results

Urinary exosomes were successfully isolated to obtain exosomal miRNAs. MiR‐215‐5p and miR‐378i were significantly upregulated in urinary exosomes of patients with IgAN compared with healthy controls (P<.01), while miR‐29c and miR‐205‐5p were significantly downregulated (P<.05). MiR‐215‐5p, miR‐378i, miR‐365b‐3p and miR‐135b‐5p were found to have altered expression in patients with IgAN from validation cohorts, which was consistent with the high‐throughput sequencing analysis.

Conclusion

This study suggests that there is a significant difference in urinary exosomal miRNA profiles between patients with IgAN and healthy controls. These exosomal miRNAs, such as miR‐29c, miR‐146a and miR‐205 may potentially serve as novel non‐invasive biomarkers for IgAN.
Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice
Authors: Lee Yong‐Soo , Kim Ja‐Yeon , Oh Kyung‐Soo , Chung Seok Won
Published: April 2017

Background

Fatty infiltration in skeletal muscle is directly linked to loss of muscle strength and is associated with various adverse physical outcomes such as muscle atrophy, inflammation, insulin resistance, mobility impairments, and even mortality in the elderly. Aging, mechanical unloading, muscle injury, and hormonal imbalance are main causes of muscle fat accumulation, and the fat cells are derived from muscle stem cells via adipogenic differentiation. However, the pathogenesis and molecular mechanisms of fatty infiltration in muscles are still not fully defined. Fatty acid‐binding protein 4 (FABP4) is a carrier protein for fatty acids and is involved in fatty acid uptake, transport, and lipid metabolism. Rotator cuff tear (RCT) usually occurs in the elderly and is closely related with fatty infiltration in injured muscle. To investigate potential mechanisms for fatty infiltration other than adipogenic differentiation of muscle stem cells, we examined the role of FABP4 in muscle fatty infiltration in an RCT mouse model.

Methods

In the RCT model, we evaluated the expression of FABP4 by qRT‐PCR, western blotting, and immunohistochemical analyses. Histological changes such as inflammation and fat accumulation in the injured muscles were examined immunohistochemically. To evaluate whether hypoxia induces FABP4 expression, the levels of FABP4 mRNA and protein in C3H10T1/2 cells after hypoxia were examined. Using a transient transfection assay in 293T cells, we assessed the promoter activity of FABP4 by hypoxia‐inducible factors (HIFs). Additionally, we evaluated the reduction in FABP4 expression and fat accumulation using specific inhibitors for HIF1 and FABP4, respectively.

Results

FABP4 expression was significantly increased after RCT in mice, and its expression was localized in the intramuscular fatty region. Rotator cuff tear‐induced FABP4 expression was up‐regulated by hypoxia. HIF1α, which is activated by hypoxia, augmented the promoter activity of FABP4, together with HIF1β. Hypoxia‐induced FABP4 expression was significantly decreased by HIF1 inhibitor treatment. Furthermore, in RCT model mice, fat accumulation was remarkably reduced by FABP4 inhibitor treatment.

Conclusions

This study shows that RCT induces FABP4 expression, leading to fat accumulation in injured muscle. FABP4 transcription is regulated by the direct binding of HIF1 to the FABP4 promoter in the hypoxic condition induced by RCT. Fat accumulation in injured muscle was reduced by the inhibition of FABP4. Ultimately, in the RCT model, we identified a novel mechanism for fatty infiltration by FABP4, which differs from adipogenic differentiation of muscle stem cells, and we found that fatty infiltration might be regulated by inhibition of HIF1 or FABP4.
Recovery of an yttrium europium oxide phosphor from waste fluorescent tubes using a Brønsted acidic ionic liquid, 1‐methylimidazolium hydrogen sulfate
Authors: Schaeffer Nicolas , Feng Xiaofan , Grimes Sue , Cheeseman Christopher
Published: April 2017

BACKGROUND

Spent fluorescent lamps, classified as hazardous waste in the EU, are segregated at source. Processes for the recovery of critical rare‐earth (RE) elements from the phosphor powder waste, however, often involve use of aggressive acid or alkali digestion, multi‐stage separation procedures, and production of large aqueous waste streams which require further treatment.

RESULTS

To overcome these difficulties phosphor powder pre‐treated with dilute HCl was leached with a 1:1 wt. [Hmim][HSO4]:H2O solution at a solid:liquid ratio of 5%, at 80 °C for 4 h with stirring at 300 rpm to recover 91.6 wt% of the Y and 97.7 wt% of the Eu present. The yttrium‐europium oxide (YOX), (Y0.95Eu0.05)2O3, recovered by precipitating the dissolved RE elements from the leach solution with oxalic acid and converting the oxalate to an oxide phase by heating, was characterised by FTIR, XRD and luminescence analysis. The analyses suggest the recovered oxide has the potential to be directly reused as YOX phosphor. Regeneration and reuse of the ionic liquid is achieved with only minor leaching efficiency losses found over four leaching/recovery cycles.

CONCLUSION

The recovery of yttrium europium oxide from waste fluorescent tube phosphor by a simple efficient low cost ionic liquid process has been developed. © 2017 Society of Chemical Industry
Lag of Immunity Across Seasonal Acclimation States in Gopher Tortoises (Gopherus Polyphemus)
Authors: Goessling Jeffrey M. , Koler Shane A. , Overman Brian D. , Hiltbold Elizabeth M. , Guyer Craig , Mendonça Mary T.
Published: April 2017

Disease outbreaks are of increasing importance to ectothermic vertebrates as one of numerous results of global change. Anthropogenic climate change is predicted to increase climatic instability, thereby altering natural thermal environments. In this study, we evaluated the direct effects of rapid temperature change on immunity in Gopher Tortoises (Gopherus polyphemus). Specifically, we tested the lag hypothesis, which predicts significant misalignment of optimal and realized immunity when temperature rapidly changes. We assayed constitutive innate immunity, B‐cell humoral responses, and heterophil: lymphocyte ratios in response to rapid temperature changes corresponding to realistic changes in body temperature between winter and summer. We found that during summer, rapid temperature reduction caused a series of changes in immunity, including reduced bactericidal ability (P = 0.002), reduced humoral response (P < 0.0001), and increased heterophil:lymphocyte ratios (P < 0.0001). During winter, we found that a temperature increase provided no benefit to immunity. Specifically, there was no increase in bactericidal ability as was predicted by the lag hypothesis. In winter, humoral responses were significantly reduced as a result of rapid warming (P = 0.011) and the rapid warming caused a significant reduction in heterophil:lymphocyte ratios (P < 0.0001). Independent of temperature, we found a significant acclimation effect of winter relative to summer conditions in humoral response (P < 0.001), which showed an overall increase in this parameter during winter. Our findings demonstrate that rapid temperature change, regardless of its direction, is a constraint on immunity in ectothermic vertebrates.
Spatial and temporal variability of dryness characteristics in Turkey
Authors: Kutiel H. , Türkeş M.
Published: April 2017

Drought may occur in almost every climatic region on Earth at any time. Understanding the nature and magnitude of the dryness and drought events are crucial mainly in semi‐arid regions characterized by water shortage and warm/hot and dry Mediterranean type climate. The present article analyses the major patterns of the spatial and temporal characteristics of the climatological dryness in Turkey.

This study adopts a relatively new approach for characterizing the dryness over a certain region; dry days since last rain (DDSLR). The DDSLR in a certain place can be evaluated using three different metrics; its severity, consistency and temporal uncertainty enabling to present intra‐ and inter‐annual variations of the dryness. The DDSLR is also coupled with the Mediterranean Climate Index (MCI) approach, measuring the seasonality of rainfall. Analyses were based on daily precipitation data recorded at 69 principal climatological and synoptic meteorological stations of the Turkish Meteorological Service network during the period 1970–2011.

The spatial distributions of the MCI and the various DDSLR metrics are presented and analysed. Overall, the three metrics of the DDSLR show their highest values in southern parts of Turkey along the Mediterranean and the borders with Syria and Iraq. These dryness indices are even larger than in central Turkey which receives less annual rainfall. On the other hand, dryness is at its minimum along the Black Sea in northern Turkey.

Logarithmic equations of the type f(DDSLR) = a × ln(MCI) + b were fitted to describe the dependence of these metrics on the MCI. All regressions are highly significant and enable to evaluate these metrics even in regions without daily data. Finally, linear trends of the longest DDSLR in each year were calculated and reveal trends toward more severe dry conditions in north‐western Turkey and less severe dry conditions in east Turkey.
The relationship between extent of hemoglobin purification and the performance characteristics of a blood‐based flocculant
Authors: Garcia Rafael A , Bumanlag Lorelie P , Piazza George J
Published: April 2017

BACKGROUND

Whole blood is a highly complex substance. Hemoglobin, the most abundant blood protein, can function as a flocculant; most of the other blood components exhibit poor flocculant activity. For the purpose of processing raw whole blood into a flocculant product, the practical value of hemoglobin purification is uncertain.

RESULTS

This study compares the flocculant performance of whole blood to that of three different semi‐purified hemoglobin preparations. The whole blood is processed to remove the plasma proteins, the solid cell components, or both. The flocculant performance of whole blood and each hemoglobin preparation is compared over wide ranges of flocculant dose and suspension pH. The clarified liquids are examined for increases in chemical oxygen demand and Kjeldahl nitrogen. Hemoglobin preparations that excluded plasma gave peak flocculation performance at approximately 30 mg solids per gram of suspended kaolin, and gave greatly reduced performance at higher doses; preparations that included plasma gave very similar peak performance, but also maintained relatively high performance at doses up to at least 200 mg g−1.

CONCLUSION

It is shown that removal of the plasma and the cell solids does not improve the flocculant performance or lessen the residual pollutants in the treated water. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
Functional outcome after surgery in patients with bone sarcoma around the knee; results from a long‐term prospective study
Authors: van Egmond‐van Dam Janneke C. , Bekkering W. Peter , Bramer Jos A.M. , Beishuizen Auke , Fiocco Marta , Dijkstra P.D. Sander
Published: April 2017

Background and Objectives

In a previous conducted study functional outcome of young patients with bone sarcoma located around the knee was longitudinally evaluated during the first 2 years postoperatively. Functional outcome improved significantly over the first 2 years. The purpose of this descriptive study was to evaluate the functional outcome of these patients at long‐term follow‐up of 7 years.

Methods

Functional outcome was assessed with the TESS, MSTS, Baecke questionnaire, and three functional performance tests: time up and down stairs (TUDS), various walking activities (VWA), and the 6‐min walking test (6MWT). Linear Mixed Model has been employed for the repeated measurements.

Results

Twenty patients of the original study (n = 44) participated in the current study. Fifteen limb‐salvage and five ablative surgery patients, median follow‐up 7.4 years (6.8‐8.0) (CI 95%), mean age 22.3 years (18.2‐31.6). Between 2 and 7 years after surgery, 8 limb‐salvage patients (53%) encountered surgery related complications. Questionnaires and functional performance tests showed no significant difference in functional outcome between 2 years and 7 years after surgery (P < 0.05).

Conclusions

Between 2 years and follow‐up at average 7 years after surgery no further improvements were noticed at young patients with a bone sarcoma located around the knee.
Structural uncertainty limits generality of fall harvest strategies for wild turkeys
Authors: Stevens Bryan S. , Bence James R. , Porter William F. , Parent Chad J.
Published: April 2017

Wild turkey (Meleagris gallopavo) populations are broadly distributed, occupy a variety of habitats, and have demographic rates that are heterogeneous through space and time. Dynamics of turkey populations are sensitive to the magnitude of fall either‐sex harvest, yet there have been few attempts to study performance of fall harvests systematically across a range of plausible demographic scenarios. Thus robustness of existing recommendations to structural uncertainty in population dynamics is marginally understood. We used a stochastic, sex‐specific theta‐logistic model to simulate performance of fall harvests (0–15%) across scenarios representing uncertainty about current rates of population productivity (3 levels), female losses during spring hunting (2 levels), and spring male harvest (3 levels), with uncertainty in the strength of density dependence as a common attribute. We demonstrated that performance of previously recommended fall harvests was not robust to changes in demographic parameters that occur within and among populations, and thus previous management recommendations may not be appropriate for all regions. Fall harvest rates capable of maintaining large populations with high probability varied from 0–6% with changes to population productivity, when median male and female spring harvests were 30% and 5%, respectively. In general, risks and management tradeoffs accompanying fall harvests were tightly linked to assumed values of population parameters, where changes to productivity and female loss had particularly strong effects on management outcomes. Specifically, reduced productivity or increased female loss decreased the ability to maintain large populations for a given fall harvest rate. Thus, fall harvest recommendations deduced from models that considered only a small portion of the demographic parameter space may not meet modern management objectives over a broader range of conditions. Moreover, our results suggest that future management could be improved by reducing structural uncertainty about turkey demography to allow for region‐specific harvest strategies, or by using decision‐theoretic approaches to identify harvest strategies that are robust to uncertainty about population parameters. © 2017 The Wildlife Society.
Living Anionic Polymerization of 1‐Adamantyl 4‐vinylphenyl ketone
Authors: Matsuoka Daigo , Goseki Raita , Uchida Satoshi , Ishizone Takashi
Published: April 2017

The anionic polymerization of 1‐adamantyl 4‐vinylphenyl ketone (1), a styrene derivative carrying an electrophilic carbonyl group, is carried out in tetrahydrofuran (THF). Although no polymerization of 1 occurs with sec‐BuLi at −78 °C for 48 h, a polymeric product of 1 is obtained with diphenylmethyllithium in 10% yield under similar conditions. The resulting poly(1) has a very broad molar‐mass dispersity (Đ
M = M
w/M
n = 1.72) and a molecular weight higher than the calculated value based on the molar ratio of the monomer and initiator and the conversion. On the other hand, the polymerization of 1 with diphenylmethylpotassium or diphenylmethylcesium quantitatively proceeds in THF at −78 °C within 48 h to form the polymers with predicted molecular weights and narrow molecular weight distributions (M
w/M
n < 1.1). The stability of the propagating carbanion derived from 1 is demonstrated by the quantitative efficiency of the postpolymerization (sequential monomer addition). The reaction of the adamantyl ketone moieties of poly(1) with methylmagnesium iodide quantitatively proceeds in THF/diethyl ether at room temperature, indicating the high electrophilicity of ketone groups. The resulting poly(1) has a high glass transition temperature at 193 °C, indicating the effect of the bulky adamantyl substituent.

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Effect of the Degree of Quaternization and Molar Mass on the Cloud Point of Poly[2‐(dimethylamino)ethyl methacrylate] Aqueous Solutions: A Systematic Investigation
Authors: Yañez‐Macias Roberto , Alvarez‐Moises Isaac , Perevyazko Igor , Lezov Alexey , Guerrero‐Santos Ramiro , Schubert Ulrich S. , Guerrero‐Sanchez Carlos
Published: April 2017

A systematic investigation to fine‐tune the cloud point of thermoresponsive poly[2‐(dimethylamino)ethyl methacrylate) (p(DMAEMA)) aqueous solutions in a broad temperature interval is reported. For this research, p(DMAEMA)s of different molar mass are quaternized at distinct degrees with methyl iodide to obtain an expanded library of poly[DMAEMA‐co‐poly[2‐(methacryloyloxy) ethyl] trimethylammonium iodide]s. Turbidity measurements show that depending on the molar mass of p(DMAEMA) and its degree of quaternization, the cloud point of the corresponding aqueous solutions can be adjusted within a rather broad temperature range from 23 to 70 °C. The cloud point and dynamics of the aggregation behavior of these polymers in the aqueous medium are also investigated by dynamic the light scattering. Furthermore, it is also found that the relationship between the molar mass and the cloud point of the respective aqueous solutions obeys an Arrhenius‐type model.

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Upregulated miR‐132 in Lgr5+ gastric cancer stem cell‐like cells contributes to cisplatin‐resistance via SIRT1/CREB/ABCG2 signaling pathway
Authors: Zhang Lanfang , Guo Xiaohe , Zhang Dezhong , Fan Yingying , Qin Lei , Dong Shuping , Zhang Lanfang
Published: April 2017

Cisplatin resistance has long been a major problem that restricts its use. A novel paradigm in tumor biology suggests that gastric tumor chemo‐resistance is driven by gastric cancer stem cell‐like (GCSCs). Growing evidence has indicated that microRNAs (miRNAs) contributes to chemo‐resistance in gastric cancer (GC). Here, Lgr5+ cells derived from gastric cancer cell lines displayed stem cell‐like features. Flow cytometry demonstrated the presence of a variable fraction of Lgr5 in 19 out of 20 GC specimens. By comparing the miRNA expression profiles of Lgr5+ GCSCs and Lrg5− cells, we established the upregulation of miR‐132 in Lgr5+ GCSCs. The enhanced miR‐132 expression correlated chemo‐resistance in GC patients. Kaplan‐Meier survival curve showed that patients with low miR‐132 expression survived obviously longer. Functional assays results indicated that miR‐132 promoted cisplatin resistance in Lgr5+ GCSCs in vitro and in vivo. Further dual‐luciferase reporter gene assays revealed that SIRT1 was the direct target of miR‐132. The expression of miR‐132 was inversely correlated with SIRT1 in gastric cancer specimens. Furthermore, through PCR array we discovered ABCG2 was one of the downstream targets of SIRT1. Overexpression of SIRT1 down‐regulated ABCG2 expression by promoting the de‐acetylation of the transcription factor CREB. CREB was further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription. Thus, we concluded that miR‐132 regulated SIRT1/CREB/ABCG2 signaling pathway contributing to the cisplatin resistance and might serve as a novel therapeutic target against gastric cancer.
Uniparental disomy determined by whole‐exome sequencing in a spectrum of rare motoneuron diseases and ataxias
Authors: Bis Dana M. , Schüle Rebecca , Reichbauer Jennifer , Synofzik Matthis , Rattay Tim W. , Soehn Anne , de Jonghe Peter , Schöls Ludger , Züchner Stephan
Published: April 2017

Background

The genetic causes of many rare inherited motoneuron diseases and ataxias (MND and ATX) remain largely unresolved, especially for sporadic patients, despite tremendous advances in gene discovery. Whole exome data is often available for patients, but it is rarely evaluated for unusual inheritance patterns, such as uniparental disomy (UPD). UPD is the inheritance of two copies of a chromosomal region from one parent, which may generate homozygosity for a deleterious recessive variant from only one carrier‐parent. Detection of UPD‐caused homozygous disease‐causing variants is detrimental to accurate genetic counseling. Whole‐exome sequencing can allow for the detection of such events.

Methods

We systematically studied the exomes of a phenotypically heterogeneous cohort of unresolved cases (n = 96 families) to reveal UPD events hindering a diagnosis and to evaluate the prevalence of UPD in recessive MND and ATX.

Results

One hereditary spastic paraplegia case harbored homozygous regions spanning 80% of chromosome 16. A homozygous disease‐causing mutation in the SPG35 disease gene was then identified within this region.

Conclusion

This study demonstrates the ability to detect UPD in exome data of index patients. Our results suggest that UPD is a rare mechanism for recessive MND and ATX.
Regional assessment of in vivo myocardial stiffness using 3D magnetic resonance elastography in a porcine model of myocardial infarction
Authors: Arunachalam Shivaram P. , Arani Arvin , Baffour Francis , Rysavy Joseph A. , Rossman Phillip J. , Glaser Kevin J. , Lake David S. , Trzasko Joshua D. , Manduca Armando , McGee Kiaran P. , Ehman Richard L. , Araoz Philip A.
Published: April 2017

Purpose

The stiffness of a myocardial infarct affects the left ventricular pump function and remodeling. Magnetic resonance elastography (MRE) is a noninvasive imaging technique for measuring soft‐tissue stiffness in vivo. The purpose of this study was to investigate the feasibility of assessing in vivo regional myocardial stiffness with high‐frequency 3D cardiac MRE in a porcine model of myocardial infarction, and compare the results with ex vivo uniaxial tensile testing.

Methods

Myocardial infarct was induced in a porcine model by embolizing the left circumflex artery. Fourteen days postinfarction, MRE imaging was performed in diastole using an echocardiogram‐gated spin‐echo echo‐planar‐imaging sequence with 140‐Hz vibrations and 3D MRE processing. The MRE stiffness and tensile modulus from uniaxial testing were compared between the remote and infarcted myocardium.

Results

Myocardial infarcts showed increased in vivo MRE stiffness compared with remote myocardium (4.6 ± 0.7 kPa versus 3.0 ± 0.6 kPa, P = 0.02) within the same pig. Ex vivo uniaxial mechanical testing confirmed the in vivo MRE results, showing that myocardial infarcts were stiffer than remote myocardium (650 ± 80 kPa versus 110 ± 20 kPa, P = 0.01).

Conclusions

These results demonstrate the feasibility of assessing in vivo regional myocardial stiffness with high‐frequency 3D cardiac MRE. Magn Reson Med 79:361–369, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
Constrained binary classification using ensemble learning: an application to cost‐efficient targeted PrEP strategies
Authors: Zheng Wenjing , Balzer Laura , van der Laan Mark , Petersen Maya ,   the SEARCH Collaboration
Published: April 2017

Binary classification problems are ubiquitous in health and social sciences. In many cases, one wishes to balance two competing optimality considerations for a binary classifier. For instance, in resource‐limited settings, an human immunodeficiency virus prevention program based on offering pre‐exposure prophylaxis (PrEP) to select high‐risk individuals must balance the sensitivity of the binary classifier in detecting future seroconverters (and hence offering them PrEP regimens) with the total number of PrEP regimens that is financially and logistically feasible for the program. In this article, we consider a general class of constrained binary classification problems wherein the objective function and the constraint are both monotonic with respect to a threshold. These include the minimization of the rate of positive predictions subject to a minimum sensitivity, the maximization of sensitivity subject to a maximum rate of positive predictions, and the Neyman–Pearson paradigm, which minimizes the type II error subject to an upper bound on the type I error. We propose an ensemble approach to these binary classification problems based on the Super Learner methodology. This approach linearly combines a user‐supplied library of scoring algorithms, with combination weights and a discriminating threshold chosen to minimize the constrained optimality criterion. We then illustrate the application of the proposed classifier to develop an individualized PrEP targeting strategy in a resource‐limited setting, with the goal of minimizing the number of PrEP offerings while achieving a minimum required sensitivity. This proof of concept data analysis uses baseline data from the ongoing Sustainable East Africa Research in Community Health study. Copyright © 2017 John Wiley & Sons, Ltd.
Causal inference in survival analysis using pseudo‐observations
Authors: Andersen Per K. , Syriopoulou Elisavet , Parner Erik T.
Published: April 2017

Causal inference for non‐censored response variables, such as binary or quantitative outcomes, is often based on either (1) direct standardization (‘G‐formula’) or (2) inverse probability of treatment assignment weights (‘propensity score’). To do causal inference in survival analysis, one needs to address right‐censoring, and often, special techniques are required for that purpose.

We will show how censoring can be dealt with ‘once and for all’ by means of so‐called pseudo‐observations when doing causal inference in survival analysis. The pseudo‐observations can be used as a replacement of the outcomes without censoring when applying ‘standard’ causal inference methods, such as (1) or (2) earlier. We study this idea for estimating the average causal effect of a binary treatment on the survival probability, the restricted mean lifetime, and the cumulative incidence in a competing risks situation.

The methods will be illustrated in a small simulation study and via a study of patients with acute myeloid leukemia who received either myeloablative or non‐myeloablative conditioning before allogeneic hematopoetic cell transplantation. We will estimate the average causal effect of the conditioning regime on outcomes such as the 3‐year overall survival probability and the 3‐year risk of chronic graft‐versus‐host disease. Copyright © 2017 John Wiley & Sons, Ltd.
Color‐Convertible, Unimolecular, Micelle‐Based, Activatable Fluorescent Probe for Tumor‐Specific Detection and Imaging In Vitro and In Vivo
Authors: Huang Yu , Qiu Feng , Chen Dong , Shen Lingyue , Xu Shuting , Guo Dongbo , Su Yue , Yan Deyue , Zhu Xinyuan
Published: April 2017

Recent years have witnessed significant progress in molecular probes for cancer diagnosis. However, the conventional molecular probes are designed to be “always‐on” by attachment of tumor‐targeting ligands, which limits their abilities to diagnose tumors universally due to the variations of targeting efficiency and complex environment in different cancers. Here, it is proposed that a color‐convertible, activatable probe is responding to a universal tumor microenvironment for tumor‐specific diagnosis without targeting ligands. Based on the significant hallmark of up‐regulated hydrogen peroxide (H2O2) in various tumors, a novel unimolecular micelle constructed by boronate coupling of a hydrophobic hyperbranched poly(fluorene‐co‐2,1,3‐benzothiadiazole) core and many hydrophilic poly(ethylene glycol) arms is built as an H2O2‐activatable fluorescent nanoprobe to delineate tumors from normal tissues through an aggregation‐enhanced fluorescence resonance energy transfer strategy. This color‐convertible, activatable nanoprobe is obviously blue‐fluorescent in various normal cells, but becomes highly green‐emissive in various cancer cells. After intravenous injection to tumor‐bearing mice, green fluorescent signals are only detected in tumor tissue. These observations are further confirmed by direct in vivo and ex vivo tumor imaging and immunofluorescence analysis. Such a facile and simple methodology without targeting ligands for tumor‐specific detection and imaging is worthwhile to further development.
Haboobs, dust spouts and Lawrence of Arabia
Authors: Rooney G. G.
Published: April 2017

In 1917, T. E. Lawrence recorded his experience of the passage of a dust storm, or haboob, while travelling in Hejaz in Arabia. The account was published that year in The Arab Bulletin, an intelligence journal. The description of this encounter is vivid, and it is sufficiently detailed that it allows comparison with more recent scientific investigations of the phenomena described. These storms are still subjects of research, which is aimed at improving representation of their weather‐ and climate‐related effects.
Ultra‐small superparamagnetic iron oxides for metastatic lymph node detection: back on the block
Authors: Fortuin Ansje S. , Brüggemann Roger , van der Linden Janine , Panfilov Ilia , Israël Bas , Scheenen Tom W.J. , Barentsz Jelle O.
Published: April 2017

In the past 15 years, encouraging clinical results for the detection of small lymph node metastases was obtained by the use of Combidex‐enhanced MRI (CEM, also known as magnetic resonance lymphography). Withdrawal of the European Medicines Agency approval application by the manufacturer made it impossible for patients to benefit from this agent; a loss, especially for men with prostate cancer. Current conventional imaging techniques are not as accurate as CEM is, thus a surgical diagnostic exploration (extended lymph node dissection) is still the preferred technique to evaluate the lymph nodes, resulting in peri‐ and postoperative complications. In 2013, the Radboud University Medical Center (Radboudumc) obtained all licenses and documentation for the production process of Combidex (ferumoxtran‐10), and manufactured the contrast agent under supervision of the Department of Pharmacy. Since 2014, 310 men with prostate cancer have been examined with CEM in the Radboudumc. Within this cohort, seven minor possibly contrast‐related adverse effects were observed after administration of Combidex. As the contrast agent is now back again in the Netherlands, this review highlights the working mechanism, previous results, observed side effects since the reintroduction, and the future perspectives for Combidex. WIREs Nanomed Nanobiotechnol 2018, 10:e1471. doi: 10.1002/wnan.1471

This article is categorized under:

Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Well Behaved Asymptotical Convex Functions
Authors: Crouzeix J.P. , Auslender A.A.
Published: April 2017

In this paper, we introduce the class

\mathcal F

of proper closed convex functions for which satisfy the following property.

“For all sequences

\{x_n\}

,

\{c_n\}

such that

c_n \in ∂f(x_n)

and

\lim\limits_{n\rightarrow ∞}\: c_n = 0

we have

\lim\limits_{n\rightarrow ∞}\: f(x_n) = \inf(f(x)\mid x\in \mathbb R^N)

”

Characterizations and applications are then given.
A PDE Approach to Certain Large Deviation Problems for Systems of Parabolic Equations
Authors: Evans L.C. , Souganidis P.E.
Published: April 2017

We prove an exponential decay estimate for solutions of certain scaled systems of parabolic PDE. Our techniques employ purely PDE methods, mainly the theory of viscosity solutions of Hamilton-Jacobi equations, and provide therefore an alternate approach to the probabilistic large deviation methods of Freidlin-Wentzell, Donsker-Varadhan, etc.
Directional Lipschitzian Optimal Solutions and Directional Derivative for the Optimal Value Function in Nonlinear Mathematical Programming
Authors: Gauvin J. , Janin R.
Published: April 2017

This paper gives very accurate conditions to have Lipschitz behaviour for the optimal solutions of a mathematical programming problem with natural perturbations in some fixed direction. This result is then used to obtain the directional derivative for the optimal value function.
An Intrinsic Characterization of Foldings of Euclidean Space
Authors: Lawrence J. , Spingarn J.E.
Published: April 2017

A
folding

q : R^d → R^d

is a nonexpansive mapping that is piecewise isometric. Every such function determines a polyhedral complex whose

d

-dimensional elements are the maximal sets on which

q

is an isometry. We characterize the complexes which arise from a folding in this manner.
A Variational Convergence that Yields Chattering Systems
Authors: Artstein Z.
Published: April 2017

Chattering variational problems are introduced and employed as limits of a variational convergence mode which is compact and preserves the optimal values. The phenomenon arises in systems with highly oscillatory coefficients. Robustness of, and approximations to, optimal controls in such cases are examined.
Frequent users of the pediatric emergency department
Authors: Seguin Jade , Osmanlliu Esli , Zhang Xun , Clavel Virginie , Eisman Harley , Rodrigues Robert , Oskoui Maryam
Published: April 2017

Objectives

Emergency department (ED) crowding is associated with increased morbidity and mortality. Its etiology is multifactorial, and frequent ED use (defined as more or equal to five visits per year) is a major contributor to high patient volumes. Our primary objective is to characterize the frequent user population. Our secondary objective is to examine risk factors for frequent emergency use.

Methods

We conducted a retrospective cohort study of pediatric emergency department (PED) visits at the Montreal Children’s Hospital using the Système Informatique Urgence (SIURGE), electronic medical record database. We analysed the relation between patient’s characteristics and the number of PED visits over a 1-year period following the index visit.

Results

Patients totalling 52,088 accounted for 94,155 visits. Of those, 2,474 (4.7%) patients had five and more recurrent visits and accounted for 16.6% (15,612 visits) of the total PED visits. Lower level of acuity at index visit (odds ratio [OR] 0.85) was associated with a lower number of recurrent visits. Lower socioeconomic status (social deprivation index OR 1.09, material deprivation index OR 1.08) was associated with a higher number of recurrent visits. Asthma (OR 1.57); infectious ear, nose, and sinus disorders (OR 1.33); and other respiratory disorders (OR 1.56) were independently associated with a higher incidence of a recurrent visit within the year following the first visit.

Conclusion

Our study is the first Canadian study to assess risk factors of frequent pediatric emergency use. The identified risk factors and diagnoses highlight the need for future evidence-based, targeted innovative research evaluating strategies to minimize ED crowding, to improve health outcomes and to improve patient satisfaction.
When state capacity dissolves: Explaining variation in violent conflict and conflict moderation
Authors: Gledhill John
Published: April 2017

When state capacity dissolves, we ordinarily assume that violent conflict will break out, and then spiral towards a high degree of intensity. However, this is not always the case. Rather, on occasion, states suffer a sharp and severe loss of capacity, but little or no collective violence follows. And, on other occasions, violent conflict erupts, but that conflict does not escalate into civil war; rather, it plateaus, and then recedes. This article offers an analytic framework for explaining such variation in the presence, absence, and intensity of violent conflict following a dissolution of state capacity. I argue that the strength of state and societal organspriorto a loss of state capacity shapes the broad trajectory of violenceaftersuch a loss. In making that claim, I associate three state-society dynamics before state dissolution with three levels of violent conflict, post-dissolution. Drawing on multi-country fieldwork, I illustrate the proposed framework by presenting three diverse cases of dissolving state capacity and conflict: Georgia (1991–3); Albania (1991–2); and Yemen (2011–13).
Deriving Second Position
Authors: Roberts Taylor
Published: April 2017

An examination of Pashto’s second-position pronominal clitics reveals that they are best regarded as agreement morphemes rather than as arguments of the verb. By base-generating these clitics as heads of agreement projections, their appearance in second position may be derived without recourse to phonological reordering rules, which have been necessary in earlier analyses.
TIMING OF SEXUAL DEBUT AMONG UNMARRIED YOUTHS AGED 15–24 YEARS IN SUB-SAHARAN AFRICA
Authors: Amo-Adjei Joshua , Tuoyire Derek Anamaale
Published: April 2017

This study aimed to contribute to the evidence on the timing of sexual debut in young people in sub-Saharan African countries. Data were extracted from 34 nationally representative surveys conducted in the region between 2006 and 2014. The study sample comprised unmarried women (n=167,932) and men (n=76,900) aged 15–24 years. Descriptive techniques and Cox proportional regression models were used to estimate the timing of sexual debut, and Kaplan–Meier hazard curves were used to describe the patterns of sexual debut in each country by sex. For the countries studied, sexual debut for both women and men occurred between the ages of 15 and 18 years, with median ages of 16 for women and 17 for men. Overall, education and household wealth provided significant protection against early sexual debut among women, but the reverse was found among men for wealth. Women in rural areas, in female-headed households and in Central, South and West Africa reported higher hazards of early commencement of sexual activity than their counterparts in urban, male-headed households and East Africa. However, the impact of these variables on male sexual debut did not follow a consistent pattern. Varied timing, as well as country-specific risk factors associated with sexual debut for young women and men across sub-Saharan Africa, were identified. Sexual health programmes and interventions for young people may require different approaches for young women and men.
Long-term changes in muddy fine sand community of the Rance Basin: role of recruitment
Authors: Desroy Nicolas , Retière Christian
Published: April 2017

Dynamics of the Abra alba muddy fine sand community of the Rance Basin (western English Channel), initially sampled in one station by Retière at the beginning of the 1970s after the tidal power station built at the mouth of the estuary went into service, was reassessed from 1995 to 1997. Results showed a more ‘mature’ community in 1995–1997 with an increase in the number of species. After a short period, in spring 1995, during which the structure of the community was comparable to those described in 1972–1973, the assemblage was characterized by a great interannual structural stability. Densities of dominant species seem to fluctuate around a mean value comparable to the carrying capacity of the biota for these species. The recruitment of the dominant species with a long life span appears low compared to the densities of adults but seems sufficient to assure the replacement of individuals. Our results suggest that the pattern of massive recruitment followed by high mortality rates could not be the general rule and that a pattern of moderate recruitment followed by low post-settlement mortality of recruits should be more frequent.
Associations between two species of snapping shrimp, Alpheus inca and Alpheopsis chilensis (Decapoda: Caridea: Alpheidae)
Authors: Boltaña S. , Thiel M.
Published: April 2017

This study examined the association pattern of two snapping shrimp species that inhabit burrows at exposed rocky shores of the Chilean Pacific coast. The two species Alpheus inca and Alpheopsis chilensis were frequently found to share the same burrows. In most burrows an heterosexual pair of each species was found. A strong positive correlation between the body length of female and male conspecifics cohabiting in a burrow was found both for Alpheus inca and for Alpheopsis chilensis. Similarly, a positive correlation existed between the mean body length of Alpheus inca and that of Alpheopsis chilensis occurring together in one burrow. Thus, a size-relationship between burrow cohabitants exists both in the intra-specific as well as in the inter-specific association of these shrimps. Most females, regardless of their reproductive stage, were accompanied by males. Within a particular burrow, females of the two species often were in the same reproductive stage, i.e. both were with embryos in a similar developmental stage, or both were without embryos. These data suggest that male and female conspecifics, as well as the pairs of the two species, remain together in the same burrow for relatively long time periods. It is proposed that the intra-specific communication system of snapping shrimp facilitates the development of inter-specific associations, such as the one reported herein.