bluuebunny/crossref_metadata_2025_split huggingface dataset:
FDA Approval Summary: Atezolizumab and Durvalumab in Combination with Platinum-Based Chemotherapy in Extensive Stage Small Cell Lung Cancer
Authors: Mathieu Luckson , Shah Sujay , Pai-Scherf Lee , Larkins Erin , Vallejo Jonathon , Li Xiaoxue , Rodriguez Lisa , Mishra-Kalyani Pallavi , Goldberg Kirsten B. , Kluetz Paul G. , Theoret Marc R. , Beaver Julia A. , Pazdur Richard , Singh Harpreet 
Published: March 2021

Abstract

The U.S. Food and Drug Administration (FDA) granted approval to atezolizumab and durvalumab in March of 2019 and 2020, respectively, for use in combination with chemotherapy for first-line treatment of patients with extensive stage small cell lung cancer. These approvals were based on data from two randomized controlled trials, IMpower133 (atezolizumab) and CASPIAN (durvalumab). Both trials demonstrated an improvement in overall survival (OS) with anti–programmed death ligand 1 antibodies when added to platinum-based chemotherapy as compared with chemotherapy alone. In IMpower133, patients receiving atezolizumab with etoposide and carboplatin demonstrated improved OS (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.54–0.91; p = .0069), with median OS of 12.3 months compared with 10.3 months in patients receiving etoposide and carboplatin. In CASPIAN, patients receiving durvalumab with etoposide and either cisplatin or carboplatin also demonstrated improved OS (HR, 0.73; 95% CI, 0.59–0.91; p = .0047) with median OS of 13.0 months compared with 10.3 months in patients receiving etoposide and either cisplatin or carboplatin. The safety profiles of both drugs were generally consistent with known toxicities of immune-checkpoint inhibitor therapies. This review summarizes the FDA perspective and data supporting the approval of these two agents.

Implications for Practice
Effective therapeutic options for small cell lung cancer (SCLC) are limited, and there has been modest improvement in the overall survival (OS) of patients with SCLC over the past 3 decades. The approvals of atezolizumab and of durvalumab in combination with chemotherapy for first-line treatment of patients with extensive stage SCLC represent the first approved therapies with OS benefit for this patient population since the approval of etoposide in combination with other approved chemotherapeutic agents. Additionally, the efficacy results from IMpower133 and CASPIAN lay the groundwork for possible further evaluation in other treatment settings in this disease.
Should treatment of ALK‐positive anaplastic large cell lymphoma be stratified according to minimal residual disease?
Authors: Rigaud Charlotte , Abbas Rachid , Grand David , Minard‐Colin Véronique , Aladjidi Nathalie , Buchbinder Nimrod , Garnier Nathalie , Plat Geneviève , Couec Marie‐Laure , Duplan Mylène , Lambilliotte Anne , Schmitt Claudine , Leblanc Thierry , Lamant Laurence , Brugières Laurence 
Published: March 2021

AbstractIn anaplastic lymphoma kinase (ALK)‐positive anaplastic large cell lymphoma (ALK+ ALCL), positive minimal residual disease (MRD+) after the first chemotherapy course was proven of strong prognostic significance. We aimed to validate these results in 138 French patients. Eighty‐seven patients had a detectable minimal disseminated disease at diagnosis (MDD+). Early MRD assessment was performed in 33 of 87 patients and was positive in 18 and negative in 15 (MRD−). Three‐year progression‐free survival was significantly correlated with the MDD/MRD status: 81.1% in MDD−, 69.6% in MDD+/MRD−, and 15.2% in MDD+/MRD+ patients. In conclusion, we confirmed on an independent cohort that the MDD/MRD status has strong prognosis significance in ALK+ ALCL.
One‐step creation of hierarchical fractal structures
Authors: Neerincx Peter E. , Hofmann Martin , Gorodetskyi Oleksandr , Feldman Kirill , Vermant Jan , Meijer Han E. H. 
Published: March 2021

AbstractRelatively recently, we advanced a route to create, in a controlled fashion, combined horizontal and vertical stratified structures by simple and energy‐efficient processing operations employing static mixing elements. While in state‐of‐the‐art static mixing the focus is on layer multiplication, here the aim is to create hierarchical fractal structures. Therefore, the main question addressed in this article is how structures, rather than layers, can be multiplied. The key aspect is the addition of layers on the sides or in the midplane of the flow during the process; every addition step increases the hierarchy by one level. This article derives the general formalism for forming fractal structures with controlled hierarchy, and we develop the language required to design and construct the dies. The main part of the article addresses this main topic and is based on the splitting serpentine static mixer geometry that can be easily made on the parting surfaces of a mold on both the micro‐ and the macroscale. The second part of the article addresses the strategy to minimize the number of mirroring steps, eventually avoiding mirroring completely, and is based on the rotation‐free multiflux static mixer geometry. With the design language derived, complex hierarchical fractal structures can be generated simply by changing the number and sequence of operators within extrusion dies or molds, providing a one‐step solution to produce material structures for potential use in diverse applications ranging from advanced mechanical systems to photovoltaic devices, where controlled assembly of dissimilar materials, and the realization of huge interfaces and genuine cocontinuity throughout the cross section, is critical.
Preparation and Characterization of Nitrocellulose Nanofiber
Authors: Okada Ken , Saito Yasuko , Akiyoshi Miyako , Endo Takashi , Matsunaga Takehiro 
Published: March 2021

AbstractA novel procedure for the preparation of nanosized nitrocellulose (NC) was developed. Cellulose nanofiber (CNF) water suspension was obtained by disk‐milling of cotton powder. CNF was first pretreated using sulfonic acid to enhance the esterification process using HNO3 and H2SO4. The esterification process generated nitrocellulose nanofiber (NCNF) with a nitrogen content of 9.0 %–13.7 %. The Brunauer‐Emmett‐Teller (BET) specific surface area of NCNF was ten times larger than that of NC, and the burning rate of NCNF was 3.5 times faster than that of NC. Differential scanning calorimetry (DSC) was conducted to assess the difference between the thermal stability of NCNF and NC. NCNF and NC exhibited the same onset exothermic temperature (200 °C), the height of the exothermic peak of NCNF was 20 % higher than that of NC. Thus, NCNF has great potential to be used in explosives due to its high combustion performance.
Estimands in hematologic oncology trials
Authors: Sun Steven , Weber Hans‐Jochen , Butler Emily , Rufibach Kaspar , Roychoudhury Satrajit 
Published: March 2021

AbstractThe estimand framework included in the addendum to the ICH E9 guideline facilitates discussions to ensure alignment between the key question of interest, the analysis, and interpretation. Therapeutic knowledge and drug mechanism play a crucial role in determining the strategy and defining the estimand for clinical trial designs. Clinical trials in patients with hematological malignancies often present unique challenges for trial design due to complexity of treatment options and existence of potential curative but highly risky procedures, for example, stem cell transplant or treatment sequence across different phases (induction, consolidation, maintenance). Here, we illustrate how to apply the estimand framework in hematological clinical trials and how the estimand framework can address potential difficulties in trial result interpretation. This paper is a result of a cross‐industry collaboration to connect the International Conference on Harmonisation (ICH) E9 addendum concepts to applications. Three randomized phase 3 trials will be used to consider common challenges including intercurrent events in hematologic oncology trials to illustrate different scientific questions and the consequences of the estimand choice for trial design, data collection, analysis, and interpretation. Template language for describing estimand in both study protocols and statistical analysis plans is suggested for statisticians' reference.
Key parameters for droplet evaporation and mixing at the cloud edge
Authors: Fries J. , Sardina G. , Svensson G. , Mehlig B. 
Published: March 2021

AbstractThe distribution of liquid water in ice‐free clouds determines their radiative properties, a significant source of uncertainty in weather and climate models. Evaporation and turbulent mixing cause a cloud to display large variations in droplet number density, but quite small variations in droplet size (Beals et al., Science, 2015, vol. 350, pp. 87–90). However, direct numerical simulations of the joint effect of evaporation and mixing near the cloud edge predict quite different behaviours, and how to reconcile these results with the experimental findings remains an open question. To infer the history of mixing and evaporation from observational snapshots of droplets in clouds is challenging, because clouds are transient systems. We formulated a statistical model that provides a reliable description of the evaporation–mixing process as seen in direct numerical simulations and allows us to infer important aspects of the history of observed droplet populations, highlighting the key mechanisms at work and explaining the differences between observations and simulations.
A sum of squares triple exponentially weighted moving average control chart
Authors: Chatterjee Kashinath , Koukouvinos Christos , Lappa Angeliki 
Published: March 2021

AbstractControl charts are widely known quality tools used to detect and control industrial process deviations in statistical process control. In the current paper, we propose a new single memory‐type control chart, called the sum of squares triple exponentially weighted moving average control chart (referred as SS‐TEWMA chart), that simultaneously detects shifts in the process mean and/or process dispersion. The run length performance of the proposed SS‐TEWMA control chart is compared with that of the sum of squares EWMA, sum of squares double EWMA, sum of squares generally weighted moving average, and sum of squares double generally weighted moving average, control charts, through Monte Carlo simulations. The comparisons indicate that the proposed chart is more efficient, than the competing ones, in detecting small shifts in the process mean and/or variability for most of the considered scenarios, while it has comparable performance for some others in identifying large shifts in the process mean and small to large shifts in the process variability. Finally, two illustrative examples are provided to explain the application of the SS‐TEWMA control chart.
Control charts for the shape parameter of reflected power function distribution under classical estimators
Authors: Zaka Azam , Akhter Ahmad Saeed , Jabeen Riffat , Sanaullah Aamir 
Published: March 2021

AbstractThe reflected power function distribution (RPFD) has applications in the fields of reliability engineering and survival analysis. To identify and remove the variation in different reliability processes and also to monitor the reliability of machines where the number of errors follows RPFD, we develop control charts to keep the process in control. A memory less control chart like a Shewhart control chart, and two memory‐based control charts like an exponentially weighted moving average (EWMA) control chart and a hybrid exponentially weighted moving average (HEWMA) control chart are discussed and compared with each other. Proposal of these control charts is based on two different estimators, the percentile estimator (PE) and the modified maximum likelihood estimator (MMLE). This study shows that an HEWMA control chart based on PE performs better than PE‐based Shewhart and EWMA control charts, as well as MMLE‐based Shewhart, EWMA, and HEWMA control charts.
Midlife family financial strain, sense of control and pain in later years: An investigation of rural husbands and wives
Authors: Wickrama Kandauda A. S. , Klopack Eric T. , O'Neal Catherine Walker 
Published: March 2021

AbstractResearch focussing on individual biopsychosocial processes leading to physical pain as a health condition is rare. The present study investigated sense of control as a mechanism linking early midlife stress to later‐life physical pain for husbands and wives in long‐term marriages. Using data from 508 rural husbands and wives over 27 years (1991–2017) with respondents in their early middle years (<42 years on average) in 1991 and in their later years (>67 years on average) in 2017, this study utilized a comprehensive analytical model in an structural equation modelling framework. Family financial stress (FFS) trajectories in early middle years were associated with depleted sense of control, which was related to increased physical pain in later years after controlling for concurrent physical illness, family income and age. In cross‐lagged analyses FFS influenced physical pain over mid‐later years. Physical pain also influenced FFS, suggesting a bi‐directional association between FFS and physical pain. Findings elucidate how early midlife FFS influences the progression of physical pain over mid‐later years through sense of control. Findings suggest effective intervention and prevention programs should focus on FFS in early years of adulthood as well as the maintenance and development of adults' sense of control.
Frequency‐dependent layer‐specific differences in short‐term synaptic plasticity in the dorsal and ventral CA1 hippocampal field
Authors: Koutsoumpa Andriana , Papatheodoropoulos Costas 
Published: March 2021

AbstractInformation from the entorhinal cortex arrives to the hippocampal CA1 microcircuit directly through the temporoammonic path (TA) that terminates in the stratum lacunosum‐moleculare (SLM), and indirectly through Schaffer collateral pathway (SC) that terminates in the stratum radiatum (SR). By virtue of this input convergence, CA1 circuitry may act to compare and integrate incoming cortical information. Although a remarkable dorsal‐ventral difference in short‐term plasticity (STP) has been recently described at SC‐CA1 synapses, the corresponding properties at TA‐CA1 synapses have not been examined. Here, we report that stimulation of TA in the dorsal hippocampus produces significant facilitation of all conditioned responses evoked by 1–30 Hz, peaking at 20–30 Hz, and significant depression of steady‐state responses to 50–100 Hz. Dorsal SC‐CA1 synapses display a similar pattern of responses, yet, facilitation peaked at 10 Hz and depression (at 75–100 Hz) is weaker. Strikingly, stimulation of TA in the ventral hippocampus produces facilitation of steady‐state responses to 1–30 Hz and highly contrasts with the depression of SC‐CA1 synapses. Steady‐state responses to 40–100 Hz in the ventral hippocampus depress in both layers similarly. High‐frequency TA input (40–100 Hz) to the dorsal hippocampus depresses more in proximal than in distal SLM, while low‐frequency (1–3 Hz) TA input to the ventral hippocampus facilitates more in distal than in proximal SLM. The present evidence suggests that direct and indirect entorhinal cortical inputs across the septotemporal extent of hippocampal CA1 field display frequency selectivity both in the radial and transverse axes, and that a rapid information processing may take place through direct ventral hippocampal CA1‐EC circuit interactions independently of trisynaptic circuit.
Fluorescent nanotechnology for in vivo imaging
Authors: Guo Zhengyuan , Cui Zongqiang 
Published: March 2021

AbstractFluorescent imaging in living animals gives an intuitive picture of the dynamic processes in the complex environment within a living being. However, animal tissues present a substantial barrier and are opaque to most wavelengths of visible light. Fluorescent nanoparticles (NPs) with new photophysical characteristics have shown excellent performance for in vivo imaging. Hence, fluorescent NPs have been widely studied and applied for the detection of molecular and biological processes in living animals. In addition, developments in the area of nanotechnology have allowed materials to be used in intact animals for disease detection, diagnosis, drug delivery, and treatment. This review provides information on the different types of fluorescent particles based on nanotechnology, describing their unique individual properties and applications for detecting vital processes in vivo. The development and application of new fluorescent NPs will provide opportunities for in vivo imaging with better penetration, sensitivity, and resolution.This article is categorized under:
Diagnostic Tools > in vivo Nanodiagnostics and Imaging
Intermediates en Route Towards Tetranitrosyl‐bis(diorganophosphanido)diiron Complexes
Authors: Heinemann Jan , Mayer Tobias , Böttcher Hans‐Christian 
Published: March 2021

AbstractThe reaction of the coordinatively unsaturated complexes [Fe2(CO)5(μ‐PR2)(μ‐PR′2)] (1 a: R=R′=tBu; 1 b: R=tBu, R′=Cy) with nitric oxide was investigated in more detail. Thus, the novel complex [Fe2(CO)3(NO)2(μ‐PtBu2)2] (2) was obtained which can be seen as an intermediate on the way to the already described tetranitrosyl complex [Fe2(NO)4(μ‐PtBu2)2] (3 a). Compound 2 was characterized by spectroscopic means and its molecular structure was confirmed by single‐crystal X‐ray diffraction. An additional in situ IR measurement gave insight in the reaction pathway. In addition, the molecular structure of the known mixed phosphanido‐bridged species [Fe2(NO)4(μ‐PCy2)(μ‐PtBu2)] (3 b) was determined.
Restoring Perivascular Adipose Tissue Function in Obesity Using Exercise
Authors: Saxton Sophie N , Toms Lauren K , Aldous Robert G , Withers Sarah B , Ohanian Jacqueline , Heagerty Anthony M 
Published: March 2021

Abstract
Purpose
Perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and β3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function.

Methods
Vascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of β3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT.

Results
High fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via β3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing β3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored.

Conclusion
Loss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity.
Two conceptions of fraction equivalence
Authors: Pedersen Pernille Ladegaard , Bjerre Mette 
Published: March 2021

AbstractIn this study, we present a mathematical analysis distinguishing two conceptions of equivalence: proportional equivalence and unit equivalence. These two conceptions have distinct meanings in relation to equivalent fractions: one is grounded in proportionality, while the other is grounded in equal wholes. We argue that (a) the distinction of equivalence gives a unified framework of equal fractions that has not previously been described in the literature; (b) a conceptual understanding of both fraction equivalences is integral to understanding rational numbers; and (c) knowledge of both conceptions of equivalence is important for developing a conceptual understanding of fraction arithmetic. Past research has largely overlooked the distinction between the two types of equivalence. However, this may provide an important foundation for central topics that build on equivalence, and a better understanding of these two types of equivalence may support a more flexible understanding of fractions. Last, we propose future directions for teaching equivalence in mathematics.
Detecting the gravito-magnetic field of the dark halo of the Milky Way - the LaDaHaD mission concept
Authors: Tartaglia Angelo , Bassan Massimo , Casalino Lorenzo , Crosta Mariateresa , Lattanzi Mario , Lorenzini Enrico , Lucchesi David , Peron Roberto , Pucacco Giuseppe , Ruggiero Matteo Luca , Santoli Francesco , Valko Pavol , Vecchiato Alberto , Vespe Francesco , Visco Massimo 
Published: March 2021

AbstractWe propose to locate transponders and atomic clocks in at least three of the Lagrange points of the Sun-Earth pair, with the aim of exploiting the time of flight asymmetry between electromagnetic signals travelling in opposite directions along polygonal loops having the Lagrange points at their vertices. The asymmetry is due to the presence of a gravito-magnetic field partly caused by the angular momentum of the Sun, partly originating from the angular momentum of the galactic dark halo in which the Milky Way is embedded. We list also various opportunities which could be associated with the main objective of this Lagrange Dark Halo Detector (LaDaHaD).
Nitrogen-use efficiency of organic and conventional arable and dairy farming systems in Germany
Authors: Chmelíková Lucie , Schmid Harald , Anke Sandra , Hülsbergen Kurt-Jürgen 
Published: March 2021

AbstractOptimising nitrogen (N) management improves soil fertility and reduces negative environmental impacts. Mineral N fertilizers are of key importance in intensive conventional farming (CF). In contrast, organic farming (OF) is highly dependent on closed nutrient cycles, biological N fixation and crop rotations. However, both systems need to minimise N balances and maximise nitrogen-use efficiency (NUE). NUE of organic and conventional crop production systems was evaluated in three regions in Germany by analysing N input, N output and N balance of 30 pairs of one OF and one CF farm each from the network of pilot farms for the period 2009–2011; indicators were calculated using the farm management system REPRO. CF had higher N input in all farm pairs. In 90% of the comparisons, N output of CF was higher than OF, in 7% it was the same and in 3% lower. NUE was higher in 60% of the OF, the same in 37% and lower in only 3%. The NUE of crop production in OF was 91% (arable farms: 83%; mixed/dairy farms: 95%) and the NUE in CF was 79% (arable farms: 77%; dairy farms: 80%). N balance was lower in 90% of the OF. The yearly average N balance was four times higher in CF (59 kg N ha−1 a−1) than in OF (15 kg N ha−1 a−1). The results show a huge individual variability within OF and CF. Organic mixed/dairy farms had the lowest N balances and the highest NUE. A further expansion of OF area can help to reduce high N balances and increase the NUE of crop production.