bluuebunny/crossref_metadata_2025_split huggingface dataset:
COMPREHENSIVE ASSESSMENT OF COMPLEX TECHNOLOGIES: INTEGRATING VARIOUS ASPECTS IN HEALTH TECHNOLOGY ASSESSMENT
Authors: Lysdahl Kristin Bakke , Mozygemba Kati , Burns Jacob , Brönneke Jan Benedikt , Chilcott James B. , Ward Sue , Hofmann Bjørn 
Published: August 2017

Objectives: Despite recent development of health technology assessment (HTA) methods, there are still methodological gaps for the assessment of complex health technologies. The INTEGRATE-HTA guidance for effectiveness, economic, ethical, socio-cultural, and legal aspects, deals with challenges when assessing complex technologies, such as heterogeneous study designs, multiple stakeholder perspectives, and unpredictable outcomes. The objective of this article is to outline this guidance and describe the added value of integrating these assessment aspects.Methods: Different methods were used to develop the various parts of the guidance, but all draw on existing, published knowledge and were supported by stakeholder involvement. The guidance was modified after application in a case study and in response to feedback from internal and external reviewers.Results: The guidance consists of five parts, addressing five core aspects of HTA, all presenting stepwise approaches based on the assessment of complexity, context, and stakeholder involvement. The guidance on effectiveness, health economics and ethics aspects focus on helping users choose appropriate, or further develop, existing methods. The recommendations are based on existing methods’ applicability for dealing with problems arising with complex interventions. The guidance offers new frameworks to identify socio-cultural and legal issues, along with overviews of relevant methods and sources.Conclusions: The INTEGRATE-HTA guidance outlines a wide range of methods and facilitates appropriate choices among them. The guidance enables understanding of how complexity matters for HTA and brings together assessments from disciplines, such as epidemiology, economics, ethics, law, and social theory. This indicates relevance for a broad range of technologies.
Successional status, seed dispersal mode and overstorey species influence tree regeneration in tropical rain-forest fragments in Western Ghats, India
Authors: Osuri Anand M. , Chakravarthy Dayani , Mudappa Divya , Raman T. R. Shankar , Ayyappan N. , Muthuramkumar S. , Parthasarathy N. 
Published: August 2017

Abstract:The effects of fragmentation and overstorey tree diversity on tree regeneration were assessed in tropical rain forests of the Western Ghats, India. Ninety plots were sampled for saplings (1–5 cm diameter at breast height (dbh); 5×5-m plots) and overstorey trees (>9.55 cm dbh; 20×20-m plots) within two fragments (32 ha and 18 ha) and two continuous forests. We tested the hypotheses that fragmentation and expected seed-dispersal declines (1) reduce sapling densities and species richness of all species and old-growth species, and increase recruitment of early-successional species, (2) reduce the prevalence of dispersed recruits and (3) increase influence of local overstorey on sapling densities and richness. Continuous forests and fragments had similar sapling densities and species richness overall, but density and richness of old-growth species declined by 62% and 48%, respectively, in fragments. Fragments had 39% lower densities and 24% lower richness of immigrant saplings (presumed dispersed into sites as conspecific adults were absent nearby), and immigrant densities of old-growth bird-dispersed species declined by 79%. Sapling species richness (overall and old-growth) increased with overstorey species richness in fragments, but was unrelated to overstorey richness in continuous forests. Our results show that while forest fragments retain significant sapling diversity, losses of immigrant recruits and increased overstorey influence strengthen barriers to natural regeneration of old-growth tropical rain forests.
Anthracycline-induced cardiotoxicity in patients with paediatric bone sarcoma and soft tissue sarcoma
Authors: Bini Ilaria , Asaftei Sebastian D. , Riggi Chiara , Tirtei Elisa , Manicone Rosaria , Biasin Eleonora , Basso Maria Eleonora , Agnoletti Gabriella , Fagioli Franca 
Published: August 2017

AbstractObjectivesAnthracycline cardiotoxicity is an important side-effect in long-term childhood cancer survivors. We evaluated the incidence of and factors associated with anthracycline cardiotoxicity in a population of patients diagnosed with bone or soft tissue sarcoma.Materials and methodsWe retrospectively enrolled patients diagnosed with bone or soft tissue sarcoma, from 1995 to 2011, treated with anthracycline chemotherapy at our Centre and with a follow-up echocardiography carried out ⩾3 years from cardiotoxic therapy completion. Cardiac toxicity was graded using Common Terminology Criteria for Adverse Events version 4.0.ResultsA total of 82 patients were eligible. The median age at treatment was 11.9 years (1.44–18). We evaluated the median cumulative anthracycline dose, age at treatment, sex, thoracic radiotherapy, hematopoietic stem cell transplantation, and high-dose cyclophosphamide treatment as possible risk factors for cardiotoxicity. The median cumulative anthracycline dose was 390.75 mg/m2(80–580). Of the 82 patients, 12 (14.6%) developed cardiotoxicity with grade ⩾2 ejection fraction decline: four patients were asymptomatic and did not receive any treatment; six patients were treated with pharmacological heart failure therapy; one patient with severe cardiomyopathy underwent heart transplantation and did not need any further treatment; and one patient died while waiting for heart transplantation. The median time at cardiac toxicity, from the end of anthracycline frontline chemotherapy, was 4.2 years (0.05–9.6). Cumulative anthracycline dose ⩾300 mg/m2(p 0.04) was the only risk factor for cardiotoxicity on statistical analyses.ConclusionsIn our population, the cumulative incidence of cardiotoxicity is comparable to rates in the literature. This underlines the need for primary prevention and lifelong cardiac toxicity surveillance programmes in long-term childhood cancer survivors.
The origin of a primordial genome through spontaneous symmetry breaking
Authors: Takeuchi Nobuto , Hogeweg Paulien , Kaneko Kunihiko 
Published: August 2017

AbstractThe heredity of a cell is provided by a small number of non-catalytic templates—the genome. How did genomes originate? Here, we demonstrate the possibility that genome-like molecules arise from symmetry breaking between complementary strands of self-replicating molecules. Our model assumes a population of protocells, each containing a population of self-replicating catalytic molecules. The protocells evolve towards maximising the catalytic activities of the molecules to increase their growth rates. Conversely, the molecules evolve towards minimising their catalytic activities to increase their intracellular relative fitness. These conflicting tendencies induce the symmetry breaking, whereby one strand of the molecules remains catalytic and increases its copy number (enzyme-like molecules), whereas the other becomes non-catalytic and decreases its copy number (genome-like molecules). This asymmetry increases the equilibrium cellular fitness by decreasing mutation pressure and increasing intracellular genetic drift. These results implicate conflicting multilevel evolution as a key cause of the origin of genetic complexity.
Vertical ocean heat redistribution sustaining sea-ice concentration trends in the Ross Sea
Authors: Lecomte Olivier , Goosse Hugues , Fichefet Thierry , de Lavergne Casimir , Barthélemy Antoine , Zunz Violette 
Published: August 2017

AbstractSeveral processes have been hypothesized to explain the slight overall expansion of Antarctic sea ice over the satellite observation era, including externally forced changes in local winds or in the Southern Ocean’s hydrological cycle, as well as internal climate variability. Here, we show the critical influence of an ocean–sea-ice feedback. Once initiated by an external perturbation, it may be sufficient to sustain the observed sea-ice expansion in the Ross Sea, the region with the largest and most significant expansion. We quantify the heat trapped at the base of the ocean mixed layer and demonstrate that it is of the same order of magnitude as the latent heat storage due to the long-term changes in sea-ice volume. The evidence thus suggests that the recent ice coverage increase in the Ross Sea could have been achieved through a reorganization of energy within the near-surface ice-ocean system.
Perceptions of asthma control in the United Kingdom: a cross-sectional study comparing patient and healthcare professionals’ perceptions of asthma control with validated ACT scores
Authors: Menzies-Gow Andrew , Chiu Gavin 
Published: August 2017

AbstractPerceptions of asthma control often vary between patients and physicians. This cross-sectional survey provided UK-specific data on actual and perceived asthma control in patients (18–75 years) attending routine asthma reviews in primary, secondary and tertiary settings. Differences between healthcare professionals’ (HCP) and patients’ perceptions of asthma control were evaluated via an online questionnaire and compared to a control—the validated asthma control test (ACT)—which patients completed. Treated patients (at least a short acting ß-agonist) with a documented diagnosis of asthma were enroled and consented within a month of their last appointment. Patients were grouped according to the British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN) 2014 treatment guidelines (BTS/SIGN steps 1–5). A total of 260 patients were screened: 234 were eligible for enrolment: 33, 52, 50, 49 and 50 patients in steps 1–5, respectively. Seventy per cent (164) were women. The percentage of patients aged 45–64 years was 47.4%. HCPs classed 70% (164) as non-smokers. 84.2% of patients and 73.9% of HCPs perceived that asthma was controlled but ACT results suggest that asthma was only controlled in 54.7% of patients (ACT score ≥20). Patients in steps 4 and 5 had the highest levels of uncontrolled asthma. Correct agreement between ACT score with perceptions of controlled or uncontrolled asthma occurred in 67.9% of patients and 68.8% of HCPs; the poorest levels of agreement occurred in patients in steps 4 and 5. Uncontrolled asthma is common in UK patients. High proportions of patients and HCPs have incorrect perceptions of asthma control, especially in relation to patients with asthma in steps 4 and 5.
The global burden of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A systematic review and meta-analysis
Authors: Lee Shaun Wen Huey , Chan Esther Mei Ching , Lai Yin Key 
Published: August 2017

AbstractBenign prostatic hyperplasia is a common non-malignant condition among older men, but the epidemiology is poorly characterised. We summarised and determined the global prevalence of benign prostatic hyperplasia. A systematic search on PubMed, EMBASE and CENTRAL was performed up until 31st July 2016. Studies that described the epidemiology of benign prostatic hyperplasia were included and cumulative plots of prevalence estimates were calculated. A total of 31 prevalence rate estimates from 25 countries were identified. The combined prevalence estimates showed that the lifetime prevalence of BPH was 26.2% (95% CI: 22.8–29.6%). We found that there was an increasing prevalence of BPH with age. However, we found no significant difference between (a) rural, urban or mixed sites, (b) different countries, (c) respondent representativeness. (d) sample size or (e) study quality. We also found no significant change in the prevalence over the past 20 years. While there is substantial variation between sites estimates, results suggest that nearly 1 in 4 men will suffer from BPH over their lifetime. The study revealed there are significant gaps in knowledge, which provides opportunities for future research to further enrich the epidemiological landscape with data.
Plasma GDF15 level is elevated in psychosis and inversely correlated with severity
Authors: Kumar Parvin , Millischer Vincent , Villaescusa J. Carlos , Nilsson Ida A. K. , Östenson Claes-Göran , Schalling Martin , Ösby Urban , Lavebratt Catharina 
Published: August 2017

AbstractAccumulating evidence suggests that GDF15 is a biomarker for ageing and morbidity of many somatic disorders such as cancer and inflammatory disorders. Recently, elevated serum GDF15 level was proposed as a marker for mood disorder. However, psychosis severity was not investigated in relation to plasma GDF15 levels. In the present study we measured GDF15 levels in plasma of 120 psychosis patients compared to 120 age and gender matched healthy controls. Within the patient cohort GDF15 levels were evaluated for association with age, gender, lifestyle factors, C-reactive protein levels, psychosis severity and metabolic disorder. Psychosis patients had elevated GDF15 levels compared to controls (medianPsychosis = 744 ng/mL, mediancontrols = 516 ng/mL, p < 0.001). Within the psychosis cohort, GDF15 levels, when corrected for age, metabolic health and lifestyle factors, were negatively correlated with psychosis severity (β = −0.218, p = 0.012). While GDF15 levels were elevated in patients versus healthy controls, the negative correlation between psychosis severity and GDF15 suggests a loss of anti-inflammatory GDF15 mediated functionality in severe psychosis. Study replication in larger cohorts will be necessary to assess the potential of GDF15 as a prognostic biomarker in psychosis.
Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH
Authors: Rao Jyotsna U. , Coman Daniel , Walsh John J. , Ali Meser M. , Huang Yuegao , Hyder Fahmeed 
Published: August 2017

AbstractGliomas maintain an acidic extracellular pH (pHe), which promotes tumor growth and builds resistance to therapy. Given evidence that acidic pHe beyond the tumor core indicates infiltration, we hypothesized that imaging the intratumoral pHe in relation to the peritumoral pHe can provide a novel readout of therapeutic influence on the tumor microenvironment. We used Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which utilizes chemical shifts of non-exchangeable protons from macrocyclic chelates (e.g., DOTP8−) complexed with paramagnetic thulium (Tm3+), to generate pHe maps in rat brains bearing U251 tumors. Following TmDOTP5− infusion, T2-weighted MRI provided delineation of the tumor boundary and BIRDS was used to image the pHe gradient between intratumoral and peritumoral regions (ΔpHe) in both untreated and temozolomide treated (40 mg/kg) rats bearing U251 tumors. Treated rats had reduced tumor volume (p < 0.01), reduced proliferation (Ki-67 staining; p < 0.03) and apoptosis induction (cleaved Caspase-3 staining; p < 0.001) when compared to untreated rats. The ΔpHe was significantly higher in untreated compared to treated rats (p < 0.002), suggesting that temozolomide, which induces apoptosis and hinders proliferation, also normalizes intratumoral pHe. Thus, BIRDS can be used to map the ΔpHe in gliomas and provide a physiological readout of the therapeutic response on the tumor microenvironment.
Dead-end complex, lipid interactions and catalytic mechanism of microsomal glutathione transferase 1, an electron crystallography and mutagenesis investigation
Authors: Kuang Qie , Purhonen Pasi , Ålander Johan , Svensson Richard , Hoogland Veronika , Winerdal Jens , Spahiu Linda , Ottosson-Wadlund Astrid , Jegerschöld Caroline , Morgenstern Ralf , Hebert Hans 
Published: August 2017

AbstractMicrosomal glutathione transferase 1 (MGST1) is a detoxification enzyme belonging to the Membrane Associated Proteins in Eicosanoid and Glutathione Metabolism (MAPEG) superfamily. Here we have used electron crystallography of two-dimensional crystals in order to determine an atomic model of rat MGST1 in a lipid environment. The model comprises 123 of the 155 amino acid residues, two structured phospholipid molecules, two aliphatic chains and one glutathione (GSH) molecule. The functional unit is a homotrimer centered on the crystallographic three-fold axes of the unit cell. The GSH substrate binds in an extended conformation at the interface between two subunits of the trimer supported by new in vitro mutagenesis data. Mutation of Arginine 130 to alanine resulted in complete loss of activity consistent with a role for Arginine 130 in stabilizing the strongly nucleophilic GSH thiolate required for catalysis. Based on the new model and an electron diffraction data set from crystals soaked with trinitrobenzene, that forms a dead-end Meisenheimer complex with GSH, a difference map was calculated. The map reveals side chain movements opening a cavity that defines the second substrate site.
Incoherent scattering can favorably influence energy filtering in nanostructured thermoelectrics
Authors: Singha Aniket , Muralidharan Bhaskaran 
Published: August 2017

AbstractInvestigating in detail the physics of energy filtering through a single planar energy barrier in nanostructured thermoelectric generators, we reinforce the non-trivial result that the anticipated enhancement in generated power at a given efficiency via energy filtering is a characteristic of systems dominated by incoherent scattering and is absent in ballistic devices. In such cases, assuming an energy dependent relaxation time τ(E) = kE
r
, we show that there exists a minimum value r
min
beyond which generation can be enhanced by embedding nanobarriers. For bulk generators with embedded nanobarriers, we delve into the details of inter sub-band scattering and show that it has finite contribution to the enhancement in generation. We subsequently discuss the realistic aspects, such as the effect of smooth transmission cut-off and show that for r > r
min
, the optimized energy barrier is just sufficiently wide enough to scatter off low energy electrons, a very wide barrier being detrimental to the performance. Analysis of the obtained results should provide general design guidelines for enhancement in thermoelectric generation via energy filtering. Our non-equilibrium approach is typically valid in the absence of local quasi-equilibrium and hence sets the stage for future advancements in thermoelectric device analysis, for example, Peltier cooling near a barrier interface.
Mapping physiological inputs from multiple photoreceptor systems to dopaminergic amacrine cells in the mouse retina
Authors: Zhao Xiwu , Wong Kwoon Y. , Zhang Dao-Qi 
Published: August 2017

AbstractIn the vertebrate retina, dopamine is synthesized and released by a specialized type of amacrine cell, the dopaminergic amacrine cell (DAC). DAC activity is stimulated by rods, cones, and melanopsin-expressing intrinsically photosensitive retinal ganglion cells upon illumination. However, the relative contributions of these three photoreceptor systems to the DAC light-induced response are unknown. Here we found that rods excite dark-adapted DACs across a wide range of stimulation intensities, primarily through connexin-36-dependent rod pathways. Similar rod-driven responses were observed in both ventral and dorsal DACs. We further found that in the dorsal retina, M-cones and melanopsin contribute to dark-adapted DAC responses with a similar threshold intensity. In the ventral retina, however, the threshold intensity for M-cone-driven responses was two log units greater than that observed in dorsal DACs, and melanopsin-driven responses were almost undetectable. We also examined the DAC response to prolonged adapting light and found such responses to be mediated by rods under dim lighting conditions, rods/M-cones/melanopsin under intermediate lighting conditions, and cones and melanopsin under bright lighting conditions. Our results elucidate the relative contributions of the three photoreceptor systems to DACs under different lighting conditions, furthering our understanding of the role these cells play in the visual system.
CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current
Authors: Toyoda Futoshi , Mesirca Pietro , Dubel Stefan , Ding Wei-Guang , Striessnig Joerg , Mangoni Matteo E. , Matsuura Hiroshi 
Published: August 2017

AbstractThe spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca2+ dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na+ current (Ist), a key player in SAN automaticity, is still unknown. Here we show that Ist and the L-type Ca2+ current (ICa,L) share CaV1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that Ist is activated in the diastolic depolarization range, and displays Na+ permeability and minimal inactivation and sensitivity to ICa,L activators and blockers. Both CaV1.3-mediated ICa,L and Ist were abolished in CaV1.3-deficient (CaV1.3−/−) SAN cells but the CaV1.2-mediated ICa,L current component was preserved. In SAN cells isolated from mice expressing DHP-insensitive CaV1.2 channels (CaV1.2DHP−/−), Ist and CaV1.3-mediated ICa,L displayed overlapping sensitivity and concentration–response relationships to the DHP blocker nifedipine. Consistent with the hypothesis that CaV1.3 rather than CaV1.2 underlies Ist, a considerable fraction of ICa,L was resistant to nifedipine inhibition in CaV1.2DHP−/− SAN cells. These findings identify CaV1.3 channels as essential molecular components of the voltage-dependent, DHP-sensitive Ist Na+ current in the SAN.
Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains
Authors: Caillet-Saguy Célia , Toto Angelo , Guerois Raphael , Maisonneuve Pierre , di Silvio Eva , Sawyer Kristi , Gianni Stefano , Wolff Nicolas 
Published: August 2017

AbstractHuman protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death. The active form of human PTPN4 consists of two globular domains, a PDZ (PSD-95/Dlg/ZO-1) domain and a phosphatase domain, tethered by a flexible linker. Targeting its PDZ domain abrogates this protection and triggers apoptosis. We previously demonstrated that the PDZ domain inhibits the phosphatase activity of PTPN4 and that the mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. We demonstrate here that the linker connecting the PDZ domain and the phosphatase domain is involved in the regulation of the phosphatase activity in both PDZ-related inhibition and PDZ ligand-related activation events. We combined bioinformatics and kinetic studies to decipher the role of the linker in the PTPN4 activity. By comparing orthologous sequences, we identified a conserved patch of hydrophobic residues in the linker. We showed that mutations in this patch affect the regulation of the PTPN4 bidomain indicating that the PDZ-PDZ ligand regulation of PTPN4 is a linker-mediated mechanism. However, the mutations do not alter the binding of the PDZ ligand. This study strengthens the notion that inter-domain linker can be of functional importance in enzyme regulation of large multi-domain proteins.