bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018
Authors: Wouters Olivier J. , McKee Martin , Luyten Jeroen
Published: March 2020

Importance

The mean cost of developing a new drug has been the subject of debate, with recent estimates ranging from $314 million to $2.8 billion.

Objective

To estimate the research and development investment required to bring a new therapeutic agent to market, using publicly available data.

Design and Setting

Data were analyzed on new therapeutic agents approved by the US Food and Drug Administration (FDA) between 2009 and 2018 to estimate the research and development expenditure required to bring a new medicine to market. Data were accessed from the US Securities and Exchange Commission, Drugs@FDA database, and ClinicalTrials.gov, alongside published data on clinical trial success rates.

Exposures

Conduct of preclinical and clinical studies of new therapeutic agents.

Main Outcomes and Measures

Median and mean research and development spending on new therapeutic agents approved by the FDA, capitalized at a real cost of capital rate (the required rate of return for an investor) of 10.5% per year, with bootstrapped CIs. All amounts were reported in 2018 US dollars.

Results

The FDA approved 355 new drugs and biologics over the study period. Research and development expenditures were available for 63 (18%) products, developed by 47 different companies. After accounting for the costs of failed trials, the median capitalized research and development investment to bring a new drug to market was estimated at $1141.7 million (95% CI, $888.1 million-$1480.8 million), and the mean investment was estimated at $1559.1 million (95% CI, $1271.0 million-$1893.8 million) in the base case analysis. Median estimates by therapeutic area (for areas with ≥5 drugs) ranged from $765.9 million (95% CI, $323.0 million-$1473.5 million) for nervous system agents to $2771.6 million (95% CI, $2051.8 million-$5366.2 million) for antineoplastic and immunomodulating agents. Data were mainly accessible for smaller firms, orphan drugs, products in certain therapeutic areas, first-in-class drugs, therapeutic agents that received accelerated approval, and products approved between 2014 and 2018. Results varied in sensitivity analyses using different estimates of clinical trial success rates, preclinical expenditures, and cost of capital.

Conclusions and Relevance

This study provides an estimate of research and development costs for new therapeutic agents based on publicly available data. Differences from previous studies may reflect the spectrum of products analyzed, the restricted availability of data in the public domain, and differences in underlying assumptions in the cost calculations.
Older Women and Cinema: Audiences, Stories, and Stars
Authors: Dolan Josephine
Published: March 2020

Despite some positive changes when compared with earlier decades, contemporary Hollywood's engagement with older women is deeply troubling across the spectrum of audiences, stories, and stars. The tastes of older women audiences are routinely ignored while aging female characters speak less dialogue than male counterparts, shore up stereotypes of passive, feminine victimhood, and are effaced from sequel storylines that feature aging action heroes. Some genres do offer positive representations of older women mobilized through discourses of ongoing desirability or genteel intelligence, though these are undermined through the objectification of the aging female body, by a preponderance of female characters bearing the representational burden of abjection in feminized dementia storylines that reiterate superior male intelligence, and by fantasy dramas that rearticulate postfeminist backlash through the figure of the cronish witch‐queen. As narrative closure serves to contain abjection's queer liminal potential it also distances older female stars from the abjection they perform, securing them as acclaimed actors and as embodiments of successfully aging femininity, either as exemplars of a problematic rejuvenatory regime epitomized by the fantasy genre's witch‐queen, or as embodiments of the regulatory and exclusionary regimes of graceful aging and chronological decorum circulating between screens, older female stars, and audiences. Given that both on‐ and off‐screen appearances by aging stars is concealed labor, such appearances contribute to the ideological normalization of deferred retirement as a solution to crisis of aging discourses. Overall, the new visibility of older female stars is both a cause for celebration and deeply troubling.
Muslim Women, Sport, and Social Media
Authors: Ahmad Nida
Published: March 2020

This entry addresses the use of social media by Muslim sportswomen. Social media augment another layer where everyday lives are mediated both online and off‐line. The depiction of how individuals are represented in the media can have repercussions, both positive and negative. To date, the literature on Muslim sportswomen has focused on the Olympic Games or on their participation in physical activity, but with the rise of new media, Muslim women are using social media in various ways.
Photosynthetic Biohybrid Nanoswimmers System to Alleviate Tumor Hypoxia for FL/PA/MR Imaging‐Guided Enhanced Radio‐Photodynamic Synergetic Therapy
Authors: Zhong Danni , Li Wanlin , Qi Yuchen , He Jian , Zhou Min
Published: March 2020

Biohybrid microswimmers have recently shown to be able to actively perform in targeted delivery and in vitro biomedical applications. However, more envisioned functionalities of the microswimmers aimed at in vivo treatments are still challenging. A photosynthetic biohybrid nanoswimmers system (PBNs), magnetic engineered bacteria‐Spirulina platensis, is utilized for tumor‐targeted imaging and therapy. The engineered PBNs is fabricated by superparamagnetic magnetite (Fe3O4 NPs) via a dip‐coating process, enabling its tumor targeting ability and magnetic resonance imaging property after intravenous injection. It is found that the PBNs can be used as oxygenerator for in situ O2 generations in hypoxic solid tumors through photosynthesis, modulating the tumor microenvironment (TME), thus improving the effectiveness of radiotherapy (RT). Furthermore, the innate chlorophyll released from the RT‐treated PBNs, as a photosensitizer, can produce cytotoxic reactive oxygen species under laser irradiation to achieve photodynamic therapy. Excellent tumor inhibition can be realized by the combined multimodal therapies. The PBNs also possesses capacities of chlorophyll‐based fluorescence and photoacoustic imaging, which can monitor the tumor therapy and tumor TME environment. These intriguing properties of the PBNs provide a promising microrobotic platform for TME hypoxic modulation and cancer theranostic applications.
Characterization of Enzymatically Synthesized Titania Thin Films Using Positron Annihilation Spectroscopy Reveals Low‐Cost Approach for Organic/Inorganic Photovoltaic Cells
Authors: van Amelrooij Edward F. , Schut Henk , Egger Werner , Dickmann Marcel , Hugenschmidt Christoph , Mallée Lloyd , Hanefeld Ulf , McMillan Duncan G. G. , Eijt Stephan W. H.
Published: March 2020

A new method is developed to produce mesoporous titania thin films at room temperature using the enzyme papain in a dip‐coating procedure, providing low‐cost titania films in a sustainable manner. Quartz crystal microbalance, positron annihilation Doppler broadening and lifetime spectroscopy, scanning electron microscopy, and X‐ray diffraction are used to determine the deposition and structural properties of the films. As‐deposited films have low densities ρ ≈ 0.6 g cm−3, contain small micropores and proteins, and exhibit corrugated surfaces. Annealing at temperatures of 300 °C or higher leads to the destruction and evaporation of most of the organic material, resulting in a thickness decrease of 50–60%, more pure titania films with increased density, an increase in micropore size and a decrease in the concentration and size of atomic‐scale vacancies. Up to 50 layers could be stacked, allowing easy control over the total layer thickness. Based on these titania films, first test devices consisting of natural dye‐sensitized solar cells are produced, that show photovoltaic activity and indicate possibilities for low‐cost, accessible, organic production of solar cells. Given the wide range of other applications for titania, this new method is a promising candidate for improving the fabrication of those products with respect to cost, sustainability, and production speed.
Foldable Semitransparent Organic Solar Cells for Photovoltaic and Photosynthesis
Authors: Song Wei , Fanady Billy , Peng Ruixiang , Hong Ling , Wu Lirong , Zhang Wenxia , Yan Tingting , Wu Tao , Chen Sanhui , Ge Ziyi
Published: March 2020

Semitransparent organic solar cells (ST‐OSCs) have attracted extensive attention for their potential greenhouse applications. Conventional ST‐OSCs are typically based on indium tin oxide (ITO) electrodes which suffer from mechanical brittleness. Therefore, alternatives for ITO are required for realization of foldable‐flexible ST‐OSCs (FST‐OSCs). Herein, flexible poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) electrodes are prepared as ITO alternatives via polyhydroxy compound (xylitol) microdoping and acid treatment. As a result, flexible opaque OSCs based on PBDB‐T‐2F:Y6 photoactive system yield a high efficiency of 14.20%. The desirable optical properties of modified PEDOT:PSS electrodes in the visible light region and PBDB‐T‐2F:Y6 photoactive layer in the near‐infrared region facilitate the fabrication of FST‐OSCs with over 10% efficiency and 21% average visible light transmittance. Those FST‐OSCs also display excellent mechanical stability against bending and folding due to the xylitol doping, where over 80% of the initial efficiency can still be maintained even after 1000 folding cycles. Meanwhile, parallel comparisons between plants grown under direct sunlight with a FST‐OSCs roof and those under direct sunlight yield very similar results in terms of branch sturdiness and hypertrophic leaves. The results pave the way for realizing high‐performing FST‐OSCs based on PEDOT:PSS electrodes that could utilize visible light for plant growth and infrared light for power generation.
Nickel or Palladium‐Catalyzed Decarbonylative Transformations of Carboxylic Acid Derivatives
Authors: Wang Zhenhua , Wang Xiu , Nishihara Yasushi
Published: March 2020

Carboxylic acid derivatives containing acyl halides, anhydrides, esters, amides and acyl nitriles are highly appealing electrophiles in transition‐metal‐catalyzed carbon‐carbon bond‐forming reactions due to their ready availability and low cost, which can provide divergent transformations of carboxylic acids into other value‐added products. In this Minireview, we focus on the recent advances of decarbonylative transformations of carboxylic acid derivatives in carbon‐carbon bond formations using Ni or Pd catalysts. A series of reaction types, product classifications and reaction pathways are presented herein, which show the advantageous features of carboxylic acid derivatives as alternative to aryl or alkyl halides in terms of reactivity and compatibility. The well‐accepted mechanism of nickel‐ or palladium‐catalyzed decarbonylative transformations involves initial oxidative addition of carboxylic acid derivatives, followed by decarbonylation or transmetalation (or insertion), and reductive elimination to generate the products, thereby regenerating the catalysts.
Two‐dimensional materials of group‐IVA boosting the development of energy storage and conversion
Authors: Guo Qiang , Chen Nan , Qu Liangti
Published: March 2020

Graphene, an emerging fabric of carbon atoms, has manifested its versatility in all kinds of fields encompassing electronics, optoelectronics, thermoelectrics, taking advantage of its excellent mechanical strength, exceptional electronic and thermal conductivities, high surface specific area, and so forth. The prosperity of graphene never seen before has led the attention to silicene, siloxene, germanene, stanene, and plumbene due to their promising applications in the quantum spin Hall effect, topological insulator, batteries, capacitors, catalysis, and topological superconductivity. Herein, we review the existing production methods, numerous applications of two‐dimensional group‐IVA materials, and critically discuss the challenges of these materials, providing potential implications to the exploration of uncharted material systems.
Phosphorrecycling durch Mitverwertung von Klärschlammaschen bei der Phosphorsäureherstellung
Authors: Herr Patrick , Mocker Mario , Zollfrank Cordt , Gaderer Matthias , Mayer Wolfgang
Published: March 2020

Es wurde der Ansatz der Phosphorrückgewinnung aus Klärschlammasche durch Mitverwertung bei der konventionellen nasschemischen Phosphorsäureherstellung untersucht. Laborversuche mit realen Klärschlammaschen unter simulierten Industriebedingungen ergaben, dass eine direkte Beimischung der Asche zum Primärrohstoff Rohphosphat verschiedene verfahrenstechnische Nachteile mit sich bringt. Als Alternative zur direkten Beimischung wird das verfahrenstechnische Konzept der Rückstromextraktion vorgeschlagen, dessen Umsetzung einige der identifizierten Nachteile umgeht.
Cytomorphologic findings of cervical Pap smears from female‐to‐male transgender patients on testosterone therapy
Authors: Williams Michael P.A. , Kukkar Vinita , Stemmer Melissa N. , Khurana Kamal K.
Published: March 2020

Background

The cervical cancer screening recommendation for transgender female‐to‐male (FTM) patients is the same as that for cisgender females. A lack of literature on testosterone‐induced changes in cervical cytology in these patients may result in interpretation errors, especially without a proper clinical history. The aim of this study was to delineate the Papanicolaou (Pap) test findings in this patient population.

Methods

A pathology laboratory information system was used to obtain a cohort of FTM transgender patients on testosterone therapy (2009‐2019). A cohort of age‐matched, atrophic, control cisgender female patients (postpartum or menopausal) was selected. A retrospective review of the cytomorphologic findings on cervical Pap smears, pertinent follow‐up, and human papillomavirus (HPV) test results was performed.

Results

Fourteen transgender patients (age range, 21‐64 years; mean age, 42.5 years) receiving testosterone therapy with 17 Pap smears were identified. One of the 5 available HPV tests was positive for HPV, and 4 were negative. A Pap smear review revealed the following: negative for intraepithelial lesion (NILM; 82.4%), unsatisfactory (5.9%), atypical squamous cells of undetermined significance (ASCUS; 5.9%), and low‐grade squamous intraepithelial lesion (5.9%). The Pap smears of the atrophic cisgender cohort (102 patients) revealed the following: NILM (92.5%), unsatisfactory (0.9%), ASCUS (5.6%), and high‐grade squamous intraepithelial lesion (0.9%). The difference between the rates of epithelial cell abnormality in the 2 cohorts was not statistically significant. Although atrophy was noted in both groups, cytomorphologic findings of transitional cell metaplasia (TCM; 88.2%) and “small cells” (82.4%) were characteristic of the testosterone‐treated transgender cohort. Histologic correlates of TCM and small cells were noted in hysterectomy specimens from 6 patients.

Conclusions

Small cells and TCM are common cytomorphologic findings in Pap smears of testosterone‐treated transgender (FTM) patients. On the basis of histologic follow‐up, small cells most likely represent atrophic parabasal cells of cervical‐vaginal epithelium.
An evolutionary bargaining‐based approach for incentivized cooperation in opportunistic networks
Authors: Nazih Ossama , Benamar Nabil , Younis Mohamed
Published: March 2020

Opportunistic networking enables users to communicate in an environment where connectivity is intermittent or unstable. However, such networking scheme assumes that mobile nodes voluntary cooperate, which cannot be guaranteed. Some nodes can simply exhibit selfish behavior and thus diminish the effectiveness of the approach. In this paper, a game scenario is formulated in which the nodes try to convince each other to participate in packets forwarding. Each node is considered as a player in this game. When a node comes in the communication range of another, a bargaining game starts between them as part of the message forwarding process. Both players try to have a mutual agreement on a price for message forwarding. We present a new incentive mechanism called evolutionary bargaining‐based incentive scheme (EBIS) to motivate selfish nodes to cooperate in data forwarding. In EBIS, a node negotiates with other nodes to obtain an agreeable amount of credit for its forwarding service. Nodes apply a sequential bargaining game and then adapt their strategies using an evolutionary model to maximize the probability of reaching an agreement. Unlike classical bargaining games, nodes in our model are boundedly rational. In addition, we use the evolutionary stable strategy (ESS) concept to determine the adaptive strategies for the nodes. The comparison of EBIS with a benchmarked model demonstrates that EBIS performs better in terms of packet delivery ratio and average latency.
The relevance of a multidomain geriatric assessment in older patients with heart failure
Authors: Kleipool Emma E.F. , Wiersinga Julia H.I. , Trappenburg Marijke C. , van Rossum Albert C. , van Dam Carmen S. , Liem Su‐San , Peters Mike J.L. , Handoko M. Louis , Muller Majon
Published: March 2020

Aims

Physical frailty screening is more commonly performed at outpatient heart failure (HF) clinics. However, this does not incorporate other common geriatric domains. This study assesses whether a multidomain geriatric assessment, in comparison with HF severity or physical frailty, is associated with short‐term adverse outcomes.

Methods and results

This is a prospective cohort study of 197 patients with HF (mean age 78, 44% female) attending outpatient HF clinics. HF severity was assessed with New York Heart Association class (I‐II versus III‐IV) and N‐terminal pro b‐type natriuretic peptide levels. Physical frailty was assessed with the Fried frailty criteria (not frail, pre‐frail, and frail). The following geriatric domains were assessed: physical function, nutrition, polypharmacy, cognition, and dependency in activities of daily living. Logistic regression analyses adjusted for age, sex, diabetes and kidney function assessed 3 month risk of adverse health outcomes (emergency department visits, hospital admissions, and/or death) according to HF severity, physical frailty, and number of affected domains. Number (%) of patients with HF with no, 1, 2, and ≥3 domains affected were 36 (18%), 61 (31%), 58 (29%), and 42 (21%). Seventy‐four adverse outcomes were experienced in 50 patients at follow‐up. Severity of HF and physical frailty were not significantly associated with an increased risk of adverse health outcomes. However, increasing number of affected domains were significantly associated with an increased risk of adverse outcomes. Compared with no domains affected, odds ratios (95% confidence interval) for 1, 2, and ≥3 domains were 1.8 (0.5–6.5), 4.5 (1.3–15.4), and 7.2 (2.0–26.3) (P‐trend <0.01). Further adjustment for HF severity and frailty status slightly attenuated the effect estimates (P‐trend 0.02).

Conclusions

Having limitations in multiple domains appears more strongly associated with short‐term adverse outcomes than HF severity and physical frailty. This may illustrate the potential added value of a multidomain geriatric assessment in the evaluation and treatment of patients with HF with respect to relevant short‐term health outcomes.
Turbulence statistics and flow structure in fluid flow using particle image velocimetry technique: A review
Authors: Ayegba Paul Onubi , Edomwonyi‐Otu Lawrence C.
Published: March 2020

Particle image velocimetry (PIV) measurement technique provides an excellent opportunity for investigating instantaneous spatial structures which are not always possible with point measurements techniques like laser Doppler velocimetry. In this review, it was shown that PIV technique provides an effective means of visualizing important structures of Newtonian and drag‐reducing fluid flows. Such structures include large‐scale‐events that constitute an important portion of the Reynolds stress tensor; shear layers of drag‐reducing flows, which have been suggested to constitute the mechanism of drag reduction (DR); and near wall vortices/low speed streaks which constitute the mechanism of turbulence production. PIV investigations of turbulence statistics in Newtonian and drag‐reducing fluid flows were reviewed with the view of providing explanation to DR by additives. Results of turbulence statistics, for Newtonian fluid flow, showed that streamwise velocity fluctuations and turbulence intensity had peak values close to the wall, in a region of high mean velocity gradient, while radial fluctuating velocity and Reynolds stress tensor had peaks further from the wall and at approximately the same detachment from the wall. In single‐ and two‐phase flows in horizontal channels, the velocity profile of polymer solution, in the turbulent regime, show asymmetric behavior. This review highlighted important interfacial characteristics in gas‐liquid flows such as S‐shaped velocity profile as well as the turbulences statistics in each phase and across the interface region. Drag‐reducing agents (DRAs)‐imposed changes on turbulence statistics and flow structures were also examined. PIV studies of drag‐reducing flows showed that DRAs act to dampen wall‐normal‐, streamwise fluctuating velocity, and Reynolds stress tensor. The reduction in Reynolds stress tensor is higher than the reduction of both wall‐normal and streamwise velocity fluctuations and this discrepancy has been associated with the decorrelation of the component of fluctuating velocity. Furthermore, the addition of DRA produces a shift of the peak of wall‐normal velocity fluctuations further from the wall due to increased buffer layer thickness. DRAs do not only act to reduce drag but also to modify the flow structure. The major influence of DRAs on flow structures is seen in the reduced strength and population of vortices close to the wall, increased spacing between low‐speed streaks, reduced frequency of large‐scale events and reduced concentration of small eddies. Effect of DRAs on flow structures depends not only on the level of DR but also on the concentration and molecular weight. The effect of concentration is linked to the elastic properties of the DRA. The influence of DRA on oil‐water flows in similar to its effect on single phase water flow with regards to changes in near wall structures and turbulence statistics. A few research gaps and limitations of the PIV techniques were also highlighted.
Evidences of neotectonic activity along Goriganga River, Higher Central Kumaun Himalaya, India
Authors: Kothyari Girish C. , Kotlia Bahadur S. , Talukdar Riyanka , Pant Charu C. , Joshi Moulishree
Published: March 2020

This paper focuses on the analysis of geomorphic landform development, particularly between the Trans Himadri Fault and the Main Central Thrust including Berinag Thrust and other major NNE–SSW and NW–SE striking faults/thrusts in the Higher Central Kumaun Himalaya. Digital analysis of remote sensing data, field investigations including drainage analysis, and development of landforms have been carried out to understand the morphotectonic evolution and, thereby, the neotectonics in this region. A number of morphometric indices [(stream length‐gradient index (SL), steepness index (ks), Chi (χ)] were computed together with knick point analysis. Offsetting of the major river and tributaries was observed along a NNW–SSE direction. Other tectonic landforms, including truncated saddles and disturbed terrace patterns, show that the area is presently undergoing active deformation. The valley floor morphology in the vicinity of the major thrusts provides evidence for aggradation of recent fluvial activity. Developments of various neotectonic features, such as starth terraces, off‐streams, truncated saddles, disrupted terraces, and palaeolake deposits, are evidences for recent tectonic activities associated with the major thrusts/faults. Cut‐and‐fill terraces with thick alluvial cover, debris‐flow terraces, and alluvial fan terraces are significant aggradational landforms observed within the valley that provide signatures of past climatic records. Our study reveals that the fluvially modified debris‐flow terraces were formed between 5 and 20 ka. We infer that the major phase of valley‐fill happened between 5 and 12 ka, whereas the youngest phase of aggradation may have responded to the Holocene tectonic activity that took place around 5–6 ka. The study is significant to understand the recent geomorphic development and tectonic deformation in the study area and may be helpful for future infrastructural development in the region.
Isotopic (H─O─S─Pb) geochemistry and zircon U─Pb geochronology of the Kaladaban Pb─Zn deposit, in Xinjiang, NW China
Authors: Jia Wenbin , Li Yongsheng , Yu Xiaofei , Sun Fengyue , Du Ze‐Zhong , Wang Da
Published: March 2020

The Kaladaban Pb─Zn─Cu volcanogenic massive sulphide deposit (VMS), located within the Altyn region of Xinjiang in NW China, is an economically significant deposit with known reserves of 414,400 t Zn with a grade of 4.14%, 265,200 t Pb with a grade of 2.52%, and 149,200 t Cu with a grade of 1.10%. The mineralization is hosted in basalt, rhyolite, and rhyolite porphyry, with the latter two rock types yielding zircon U─Pb ages of 516 and 505 Ma, respectively, representing the timing of crystallization. Samples of the host volcanic rocks show fractionated rare‐earth element (REE) patterns and enrichment in both large‐ion lithophile elements (e.g., Ba, Rb, U, and light REEs) and high‐field‐strength elements (e.g., Th, Hf, and Zr). These features are similar to those of oceanic island basalt. δ18O values of ore fluids from quartz in orebodies range from +8.1‰ to +13.4‰, and fluid δ18Dwater values vary from −68.5‰ to −99.1‰, indicating a mixture of magmatic hydrothermal and seawater. δ34S values range from +8.5‰ to +14.9‰, suggesting that S that in the Kaladaban ore minerals had a mixed origin of magmatic hydrothermal fluids and sulphate‐reduced seawater. Ratios of 206Pb/204Pb, 207Pb/204Pb, and 208Pb/204Pb from metal minerals in Kaladaban deposit are 18.513–18.740, 15.633–15.727, and 38.236–38.398, respectively, indicating extremely radiogenic characteristics, similar to the host volcanic rocks. We infer that the Kaladaban Pb─Zn deposit formed in an active continental margin setting related to southward subduction of the North Altyn oceanic crust during the early Palaeozoic.
Middle Miocene depositional evolution of the central Roer Valley Rift System
Authors: Deckers Jef , Munsterman Dirk
Published: March 2020

Correlations between bio‐ and/or lithostratigraphically analysed boreholes provide new insights on the late‐early to early‐late Miocene depositional evolution of the central Roer Valley Rift System (RVRS) as part of the southern North Sea Basin. This evolution started with a major regression that occurred in two steps, one during the late Burdigalian and another during the earliest Langhian. Each step coincides with a coarsening of the grain size, reduction in the content of glauconite and increase in the lignite content. The amount of open marine dinocysts also showed a strong decrease. Regression continued up to the middle Langhian as a large delta system builded out in the central RVRS. The main phase of regression ended in the late Langhian. Around the Langhian/Serravallian boundary, a major marine ingression drowned the former delta system. Transgression was evidenced by an increase in the content of glauconite and open marine dinocysts and a decrease in the lignite content. Maximum flooding occurred in the middle/late Serravallian and was followed by another regression. This regression ended in a regional latest Serravallian‐earliest Tortonian hiatus with locally deep erosion. During the early Tortonian, the whole region was transgressed again which was expressed by an increase in the content of glauconite and open marine dinocysts and decrease in the lignite content in the central RVRS. The late‐early to early‐late Miocene depositional evolution of the southern North Sea Basin corresponds very well with that previously described for the eastern and central (Danish) part of the North Sea Basin, but not with the global sea‐level curves, which show mainly the opposite trends. These mismatches could be explained by tectonics and/or changes in sedimentation rates.
Targeting alveolar macrophages shows better treatment response than deletion of interstitial macrophages in EGFR mutant lung adenocarcinoma
Authors: Alikhanyan Kristina , Chen Yuanyuan , Kraut Simone , Sotillo Rocio
Published: March 2020

Introduction

Alveolar macrophages (AMs) are critical in the development of lung adenocarcinoma driven by epidermal growth factor receptor (EGFR) mutations. Whether interstitial macrophages (IMs) are also involved in lung tumorigenesis is still unclear. Thus, the aim of this study is to evaluate the role of both AM and IM in the development of EGFR mutant driven lung adenocarcinoma.

Methods

We used the EGFR mutant doxycycline‐inducible mouse model of lung adenocarcinoma to deplete interstitial or AMs by clodronate‐encapsulated liposomes administered intravenously (IV) and intratracheally (IT), respectively. Tumor burden, AMs, and the tumor microenvironment were examined by immunohistochemistry, bronchoalveolar lavage fluid or flow cytometry.

Results

Clodronate treatment resulted in a significant reduction of tumor burden compared with vehicle liposomes alone. Elimination of AMs resulted in a significant reduction of proliferation compared with IV treatment. However, both treatments resulted in a significantly higher number of Ki67 positive cells compared with control mice, suggesting that tumor cells still proliferate despite the treatment. The number of natural killer cells decreased during tumor development, and it remained low even after the elimination of AMs. We also observed that IT instillation of clodronate significantly increased the number of CD8+ T cells, which was higher compared with vehicle‐treated mice and mice where only IMs were depleted. The similar trend was observed in immunohistological analyses of CD8+ T cells.

Conclusions

These results suggest that the reduction of AMs has a stronger impact on restricting tumor progression compared with targeting IMs. The depletion of AMs leads to an elevated infiltration of CD8+ T cells into the lung that might be responsible for tumor growth impairment. Altogether, elimination of AMs is a better strategy to reduce EGFR mutant tumor growth and is less toxic, suggesting the selectively targeting of AMs to complement established therapies.
Assessing the Recyclability of Supramolecularly Assembled Organocatalytic Species: A Theoretical Insight
Authors: Llorens Lluis , Llanes Patricia , Fianchini Mauro , Pericàs Miquel A.
Published: March 2020

Asymmetric organocatalytic synthesis is a powerful tool in organic chemistry to achieve desired stereoisomers in high purity via mild catalytic routes. The immobilization of homogeneous catalytic species onto heterogeneous phases embodies the evolution of asymmetric catalysis, since it allows the recycling of the catalyst for several runs until degradation. Previously reported non‐covalent immobilization of proline‐based catalysts for aldol reaction onto magnetic nanoparticles functionalized with β‐cyclodextrin (MNP‐β‐CB) demonstrated the viability of the methodology. This paper proposes two new catalyst recycling strategies based on Cucurbit[7]uril (CB[7]) for the aldol reaction and the Robinson annulation. These recycling methodologies are conceptually different. The former relies on the homogeneous encapsulation of the catalyst in cucurbituril, CB[7] ⋅ Cat, and its recycling in the aqueous phase by extraction of the aldol product with organic solvents. The latter relies on the heterogeneous encapsulation of the catalyst as MNP‐CB[7] ⋅ Cat2 system and its recycling by magnetic harvesting. Density functional theory (DFT) calculations have been employed to rationalize the thermodynamics of experimental results, and to suggest caveats and plausible improvements in view of a future catalytic design.
Downregulation of serum exosomal miR‐320d predicts poor prognosis in hepatocellular carcinoma
Authors: Li Wenxiao , Ding Xuemei , Wang Shaohong , Xu Li , Yin Tao , Han Shuangxi , Geng Jianli , Sun Wenbing
Published: March 2020

Background

MicroRNAs (miRNAs) is a class of functional regulator of tumorigenesis of human cancer including hepatocellular carcinoma (HCC). However, the potential clinical significance of serum exosomal miR‐320d in HCC has not been elucidated.

Methods

Real‐time reverse transcription PCR was used to detect the expression pattern of serum exosomal miR‐320d in patients with HCC, and the correlation between the deregulation of serum exosomal miR‐320d and the clinical outcome of HCC was explored. The biological function of exosomal miR‐320d in HCC was also investigated.

Results

Our results showed that the expression levels of exosomal miR‐320d were remarkably reduced in the serum samples of HCC patients and the culture medium of HCC cell lines compared with their respective controls. Serum exosomal miR‐320d could differentiate the HCC patients from healthy controls with high accuracy. In addition, its level was remarkably increased in the HCC patients who had received surgical treatment. Moreover, reduced serum exosomal miR‐320d was associated with advanced tumor stage, positive lymph node metastasis, and poorly differentiated tumors. HCC patients with lower serum exosomal miR‐320d had shorter overall and disease‐free survival. Low serum exosomal miR‐320d was identified to be an independent unfavorable prognostic factor for HCC. Finally, overexpression of miR‐320d inhibited the proliferation and invasion of HCC cells, and BMI1 was demonstrated to be a direct target of miR‐320d.

Conclusion

Taken together, serum exosomal miR‐320d could be a potential non‐invasive biomarker for the diagnosis and prognosis of HCC.
Multivariate network meta‐analysis of survival function parameters
Authors: Cope Shannon , Chan Keith , Jansen Jeroen P.
Published: March 2020

Background

Network meta‐analysis (NMA) of survival data with a multidimensional treatment effect has been introduced as an alternative to NMA based on the proportional hazards assumption. However, these flexible models have some limitations, such as the use of an approximate likelihood based on discrete hazards, rather than a likelihood for individual event times. The aim of this article is to overcome the limitations and present an alternative implementation of these flexible NMA models for time‐to‐event outcomes with a two‐step approach.

Methods

First, for each arm of every randomised controlled trial (RCT) connected in the network of evidence, reconstructed patient data are fit to alternative survival distributions, including the exponential, Weibull, Gompertz, log‐normal, and log‐logistic. Next, for each distribution, its scale and shape parameters are included in a multivariate NMA to obtain time‐varying estimates of relative treatment effects between competing interventions.

Results

An illustrative analysis is presented for a network of RCTs evaluating multiple interventions for advanced melanoma regarding overall survival. Alternative survival distributions were compared based on model fit criteria. Based on the log‐logistic distribution, the difference in shape and scale parameters for each treatment versus dacarbazine (DTIC) was identified and the corresponding log hazard and survival curves were presented.

Conclusions

The presented two‐step NMA approach provides an evidence synthesis framework for time‐to‐event outcomes grounded in standard practice of parametric survival analysis. The method allows for a more transparent and efficient model selection process.
Wall Shear Stress Measurements Based on Ultrasound Vector Flow Imaging
Authors: Du Yigang , Goddi Alfredo , Bortolotto Chandra , Shen Yingying , Dell'Era Alex , Calliada Fabrizio , Zhu Lei
Published: March 2020

Wall shear stress (WSS) is considered as a key factor for atherosclerosis development. Previous WSS research based on pulsed wave Doppler (PWD) showed limitations in complex flows. To improve accuracy for nonlaminar flow, a commercial ultrasound vector flow imaging (UVFI)‐based WSS calculation is proposed. Errors for PWD are presented theoretically when flow is not laminar. Based on this, simulations of WSS calculations between PWD and UVFI were set up for different turbulent flows. Our simulations show that UVFI has obviously better performance than PWD in WSS calculations. Wall shear stress results in different flow conditions at carotid bifurcations are described.
Changes in the Interventricular Septal Curvature in Healthy Full‐term Neonates During the First 14 Days of Life
Authors: Zhan Ying , Ren Weidong , Xiao Yangjie , Qiao Wei , Song Guang , Sun Lu
Published: March 2020

Objectives

Interventricular septal geometry and motion reflect the interaction between the ventricles, and an abnormal shape and abnormal motion are always regarded as signs of increased right ventricular or pulmonary artery pressure. During the neonatal period, there are profound changes in the cardiac circulation. The aims of this study were to quantitatively analyze neonatal septal deformations under normal physiologic conditions and evaluate the changes in association with the hemodynamic changes occurring during the transitional period.

Methods

This was a retrospective study of 114 healthy full‐term neonates from birth to 14 days of age. Normalized septal curvatures were measured on left ventricular parasternal short‐axis views during end diastole and end systole. The interventricular pressure gradient, ratio of ventricular volumes, septal strain, thickness, and some clinical characteristics were assessed, along with the association of these parameters with septal curvature.

Results

All 4 normalized septal curvatures were found to have a significant correlation with the trans‐septal pressure gradient (TSPG) and the end‐diastolic volume ratio of the left and right ventricles (P < .0001). The TSPG had the highest impact on septal curvature, and among the 4 curvatures, the middle end‐systolic normalized septal curvature had the highest correlation with the TSPG (r2 = 0.948; P < .0001).

Conclusions

There were significant correlations between septal curvature and the interventricular pressure gradient and ventricular volume ratio in healthy full‐term neonates. The normalized septal curvatures gradually increased with increasing age and could be good indicators of the hemodynamic changes occurring during the transitional period.
On the value of QSM from MPRAGE for segmenting and quantifying iron‐rich deep gray matter
Authors: Naji Nashwan , Sun Hongfu , Wilman Alan H.
Published: March 2020

Purpose

Quantitative susceptibility mapping (QSM) has been employed for both iron evaluation and segmentation of deep gray matter (DGM), but QSM sequences are not typically used in standard brain volumetric studies, which use T1‐weighted magnetization‐prepared rapid acquisition with gradient echo (MPRAGE) with short TE. Here, QSM produced directly from standard MPRAGE phase (

) is evaluated for segmentation and quantification of highly iron‐rich DGM regions.

Methods

Simulations were used to explore quality and possible limitations. In addition, QSM from a standard multi‐echo gradient‐echo (

) was compared to

in 40 healthy adults at 3T. DGM structures with weak contrast on MPRAGE magnitude were evaluated for improving segmentation with

, with focus on the iron‐rich globus pallidus (GP). Furthermore, susceptibility quantification was assessed on six DGM nuclei and compared to standard

.

Results

Limited by TE and signal‐to‐noise ratio, only iron‐rich regions like GP and dentate nucleus produced adequate contrast on

, confining applications to such regions.

improved GP segmentation with mean Dice scores raised by 9.0%, and mean volumetric differences reduced by 9.7%. Simulations suggested that phase contrast‐to‐noise ratio (CNR) should be above 3.0 to attain segmentation improvement. For quantification purposes, higher CNR is required, and typical

provided comparable estimates to

in large iron‐rich DGM nuclei.

Conclusion

Despite the short TE of standard MPRAGE,

can improve GP segmentation over the use of MPRAGE magnitude alone and roughly quantify high‐iron regions in DGM. Thus, reconstructing

can be a useful addition to volumetric studies that rarely include standard

.
Natural Recolonization by Pacific Lampreys in a Southern California Coastal Drainage: Implications for Their Biology and Conservation
Authors: Reid Stewart B. , Goodman Damon H.
Published: March 2020

The historical range of anadromous Pacific Lamprey Entosphenus tridentatus includes coastal drainages from Alaska south to northern Baja California. However, there has been a widespread loss of distribution inland due to the construction of dams that form impassable barriers as well as a loss of Pacific Lampreys from some historically occupied drainages in the south. These losses have prompted the consideration of suitable approaches to reestablishing Pacific Lamprey populations through either active intervention or natural processes. While Pacific Lampreys apparently do not home to natal streams, they are thought to use cues that are related to such factors as flow patterns or the presence of ammocoete (larval lamprey) pheromones in offshore river plumes to identify suitable rivers for spawning and rearing. In this report, we present documentation of natural recolonization of the San Luis Obispo drainage by Pacific Lampreys on the central California coast, located 130 km south of the nearest freshwater population of Pacific Lampreys and with no existing ammocoete population. We also review recent observations of adult Pacific Lampreys in other southern rivers, recolonization of the Carmel River following dam removal, and indications that Pacific Lampreys are still using oceanic habitat off southern California. The results of our investigation demonstrate that Pacific Lampreys are fully capable of returning to an isolated drainage from which they have been extirpated and then rapidly reestablishing a viable population of ammocoetes, contradicting the hypothesis that they are dependent on existing ammocoete pheromones or adult sex pheromones to attract adults. These results indicate the importance of proactive management for Pacific Lampreys in drainages within their historical range, even if they are not currently present. The results also demonstrate that recolonization does not necessarily require active reintroduction efforts. Rather, conservation efforts should focus on identifying factors that may have led to the loss of Pacific Lamprey and removing potential impediments in order to facilitate natural recolonization.
Application of low‐rank approximation using truncated singular value decomposition for noise reduction in hyperpolarized 13C NMR spectroscopy
Authors: Francischello R. , Geppi M. , Flori A. , Vasini E.M. , Sykora S. , Menichetti L.
Published: March 2020

Dissolution dynamic nuclear polarization allows in vivo studies of metabolic flux using 13C‐hyperpolarized tracers by enhancing signal intensity by up to four orders of magnitude. The T1 for in vivo applications is typically in the range of 10–50 s for the different 13C‐enriched metabolic substrates; the exponential loss of polarization due to various relaxation mechanisms leads to a strong reduction of the signal‐to‐noise ratio (SNR). A common solution to the problem of low SNR is the accumulation/averaging of consecutive spectra. However, some limitations related to long delays between consecutive scans occur: in particular, following biochemical kinetics and estimate apparent enzymatic constants becomes time critical when measurement scans are repeated with the typical delay of about 3 T1. Here we propose a method to dramatically reduce the noise, and therefore also the acquisition times, by computing, via truncated singular value decomposition, a low‐rank approximation to the individual complex time‐domain signals. Moreover, this approach has the additional advantage that the phase correction can be applied to the spectra already denoised, thus greatly reducing phase correction errors. We have tested the method on (1) simulated data; (2) performing dissolution of hyperpolarized 1‐13C‐pyruvate in standard conditions and (3) in vivo data sets, using a porcine model injected with hyperpolarized Na‐1‐13C‐acetate. It was shown that the presented method reduces the noise level in all the experimental data sets, allowing the retrieval of signals from highly noisy data without any prior phase correction pre‐processing. The effects of the proposed approach on the quantification of metabolic kinetics parameters have to be shown by full quantification studies.
Rare Metal‐Free High‐Performance Zinc–Tin Oxide Thin Film Transistors Using Efficient Energy Conversion of Microwave Annealing
Authors: Min Shin-yi , Cho Won-Ju
Published: March 2020

Herein, a rare metal‐free oxide‐based semiconductor channel layer is constructed with excellent electrical properties and stabilities by fabricating zinc–tin oxide (ZTO) thin film transistors (TFTs) using tin (Sn) as the dopant element in ZnO. Furthermore, to improve the performance and stability of ZTO TFTs, microwave annealing (MWA) powered by energy conversion from electromagnetic energy to heat energy rather than heat transfer is conducted as the post‐deposition annealing (PDA) process of the ZTO channel layer. As a result, the electrical performance of ZTO TFTs is improved by MWA despite the much shorter PDA time because of the efficient energy transfer compared with that of furnace‐used thermal annealing (FTA) in conventional furnaces. The ZTO TFTs subjected to MWA exhibit a high on/off current ratio of 1.7 × 107, a high field‐effect mobility of 20.6 cm2 V−1 s−1, a small hysteresis voltage of 0.9 V, and a low interface trap density of 1.8 × 1012 cm−2 eV−1. In addition, the instabilities due to the positive and negative gate bias stresses at various operating temperatures are evaluated, and the results show that the instability of the ZTO TFT is significantly reduced by MWA.
On active disturbance rejection control for nonlinear systems with multiple uncertainties and nonlinear measurement
Authors: Chen Sen , Xue Wenchao , Huang Yi
Published: March 2020

The paper proposes a novel control design for nonlinear systems with multiple uncertainties and nonlinear measurement. The output linearization is utilized to handle the nonlinearities in system dynamics and measurement. Firstly, the integrator chain for nonlinear systems with multiple uncertainties is analyzed. Based on the fundamental integrator chain form, the equivalent total effect of multiple uncertainties is summarized as total disturbance. By timely estimating and compensating for the total disturbance, an active disturbance rejection control design to handle both multiple uncertainties and nonlinear measurement is proposed. Moreover, the transient performance of the corresponding closed‐loop system is rigorously studied, which theoretically reveals the high consistence of the tracking performance despite various multiple uncertainties.