bluuebunny/crossref_metadata_2025 huggingface dataset:
Numerical, Mechanical, and Metallurgical Investigation of an Innovative Near Net Shape Titanium Selective Laser Melting Engine Component and Comparison with the Conventional Forged One
Authors: Cecchel Silvia , Ferrario Davide , Mega Francesco , Cornacchia Giovanna
Published: March 2021

Selective laser melting (SLM) can be used to manufacture near net shape (NNS); the main benefits are a remarkable weight reduction, a lower environmental impact, the opportunity to integrate some functions, and an improvement of the performances. The current article covers the development of a Ti6Al4V NNS engine component produced by SLM. Finite element analyses of the main relevant operating conditions are performed to reach a topological optimization of the part. The main target is weight reduction keeping the same safety performances. The weight reduction achieved is 45% and 15% with respect to steel and titanium forging by replacing the original “H” section with an SLM multibranch structure. Other benefits are the manufacturing of the connecting rod (conrod) into two separate parts, avoiding the difficult machining to separate the cap from the main body and the integration of conformed cooling channels into the conrod. Then, the SLM components are produced and mechanical and metallurgical properties are investigated and compared with the titanium hot forging ones. Both the macrostructures present equiassic and isotropic behavior due to the heat treatment transformation. No defects are observed for both the technologies. The mechanical properties are verified to be aligned with the design targets.
Enhanced Liquid Propagation and Wicking Along Nanostructured Porous Surfaces
Authors: Alhosani Mohamed H. , Li Hongxia , Alketbi Afra S. , Guan Qiangshun , Aili Ablimit , Zhang TieJun
Published: March 2021

The crucial role of capillary pumping has motivated recent innovations in porous wicking materials for many energy and environment applications. Herein, the wick‐based liquid propagation along with a porous surface, including both macroscopic water transport behavior and microscopic wicking dynamics, with a group of nanostructured porous surfaces, is investigated. These hybrid wicking surfaces are fabricated in a scalable way by bonding copper micromeshes on flat surfaces and chemical etching. These nanostructured porous surfaces exhibit outstanding wickability by simultaneously improving surface hydrophilicity and minimizing viscous dissipation of water flow. Notably, the as‐fabricated surfaces also have good thermal conductivity and high solar absorptance, which are desired properties for various solar thermal applications. To directly observe water propagation processes, infrared thermal imaging in locating the propagation front and evaluating water film thickness along the propagation direction is also demonstrated. The dynamic water vapor meniscus in a representative pore unit is captured and characterized through environmental scanning electron microscopy. A capillary pressure model and permeability model to predict the liquid propagation and wicking characteristics is then developed, resulting in good agreement with experimental results for a large variety of nanostructured porous surfaces.
Thermally Stable Single‐Atom Heterogeneous Catalysts
Authors: Xiong Haifeng , Datye Abhaya K. , Wang Yong
Published: March 2021

Single‐atom catalysts (SACs) have attracted extensive attention in fields related to energy, environment, and material sciences because of the high atom efficiency and the unique properties of these materials. Many approaches have hitherto been successfully established to prepare SACs, including impregnation, pyrolysis‐involved processes, atom trapping, and coprecipitation. However, under typical reaction conditions, single atoms on catalysts tend to migrate or agglomerate, forming nanoclusters or nanoparticles, which lowers their surface free energy. Efforts are required to develop strategies for improving the thermal stability of SACs while achieving excellent catalytic performance. In this Progress Report, recent advances in the development of thermally durable single‐atom heterogeneous catalysts are discussed. Several important preparation approaches for thermally stable SACs are described in this article. Fundamental understanding of the coordination structures of thermally stable single atom prepared by these methods is discussed. Furthermore, the catalytic performances of these thermally stable SACs are reviewed, including their activity and stability. Finally, a perspective of this important and rapidly evolving research field is provided.
Degradable and Removable Tough Adhesive Hydrogels
Authors: Freedman Benjamin R. , Uzun Oktay , Luna Nadja M. Maldonado , Rock Anna , Clifford Charles , Stoler Emily , Östlund‐Sholars Gabrielle , Johnson Christopher , Mooney David J.
Published: March 2021

The development of tough adhesive hydrogels has enabled unprecedented adhesion to wet and moving tissue surfaces throughout the body, but they are typically composed of nondegradable components. Here, a family of degradable tough adhesive hydrogels containing ≈90% water by incorporating covalently networked degradable crosslinkers and hydrolyzable ionically crosslinked main‐chain polymers is developed. Mechanical toughness, adhesion, and degradation of these new formulations are tested in both accelerated in vitro conditions and up to 16 weeks in vivo. These degradable tough adhesives are engineered with equivalent mechanical and adhesive properties to nondegradable tough adhesives, capable of achieving stretches >20 times their initial length, fracture energies >6 kJ m−2, and adhesion energies >1000 J m−2. All degradable systems show complete degradation within 2 weeks under accelerated aging conditions in vitro and weeks to months in vivo depending on the degradable crosslinker selected. Excellent biocompatibility is observed for all groups after 1, 2, 4, 8, and 16 weeks of implantation, with minimal fibrous encapsulation and no signs of organ toxicity. On‐demand removal of the adhesive is achieved with treatment of chemical agents which do not cause damage to underlying skin tissue in mice. The broad versatility of this family of adhesives provides the foundation for numerous in vivo indications.
Oxime‐Derived Iminyl Radicals in Selective Processes of Hydrogen Atom Transfer and Addition to Carbon‐Carbon π‐Bonds
Authors: Krylov Igor B. , Segida Oleg O. , Budnikov Alexander S. , Terent'ev Alexander O.
Published: March 2021

Oximes represent one of the fundamental organic compound classes with a wide range of synthetic applications. In the last decade O‐substituted oximes were recognized as the synthetically available and versatile precursors of iminyl radicals via one‐electron oxidation or one‐electron reduction employing visible light photoredox catalysts, salts of abundant metals (such as Cu or Fe), or other convenient reagents. Iminyl radicals are powerful synthons for various processes of cyclization, ring‐opening, CH‐functionalization, and coupling. The present review is focused on the synthetic methods based on oxime‐derived iminyl radicals developed in the last few years excluding ring opening reactions of cyclic iminyl radicals that were summarized in recent publications. The review consists of two main parts: (1) reactions of iminyl radicals involving 1,n‐hydrogen atom transfer (n=5 in most cases) and (2) reactions involving the addition of iminyl radical to the carbon‐carbon π‐bond.

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Understanding the Effect of Solid Electrocatalysts on Achieving Highly Energy‐Efficient Lithium–Oxygen Batteries
Authors: Li Jiantao , Bi Xuanxuan , Amine Khalil , Lu Jun
Published: March 2021

Nonaqueous lithium–oxygen (Li–O2) batteries are regarded as a promising electrochemical energy storage technology because of largely defeating commercial Li‐ion batteries on theoretical energy density. However, due to the electrically insulating property of Li2O2, a typical discharge product in Li–O2 batteries, high overpotential is inevitable upon charge. Nonetheless, catalysts could regulate the electrochemical formation pathways of Li2O2, and its morphology is closely bound with the energy required to dissociate. Meanwhile, in addition to Li2O2, alternative discharge products with inherently low dissociation energy can be produced by specific catalysts. Here, fundamental oxygen reduction routes in Li–O2 batteries are focused on, catalyst‐dependent geometry formation of Li2O2 is presented, and geometry‐related charge kinetics are disscussed. Products formed under specific catalysts are further explored with an emphasis on LiO2. Future directions to in situ study the electrocatalytic mechanism are subsequently proposed, and an energy system design based on oxygen redox reactions is conceived to provide new perspectives for future electrochemical energy technologies.
MASP1‐related 3MC syndrome in a patient from Turkey
Authors: Durmaz Ceren Damla , Altıner Şule
Published: March 2021

3MC syndrome is a rare condition manifesting with typical facial appearance, postnatal growth deficiency, skeletal manifestations, and genitourinary tract anomalies. 3MC is caused by biallelic pathogenic variants in MASP1, COLEC11, or COLEC10. Here, we report an affected subject of Kurdish origin from Turkey presenting with facial dysmorphisms, such as, hypertelorism, blepharophimosis, blepharoptosis, highly arched eyebrows, umbilical hernia, and caudal appendage. These features were compatible with 3MC syndrome. Molecular analysis revealed a novel homozygous pathogenic variant, c.310C > T; p.Gln104Ter in the MASP1 gene, resulting in a premature stop codon. Few subjects with 3MC syndrome have been reported in the literature so far. Thus, detailed study of this subject contributes to the evolving clinical and genetic characterization of 3MC syndrome.
Merging Reagent Modulation and Remote Anchimeric Assistance for Glycosylation: Highly Stereoselective Synthesis of α‐Glycans up to a 30‐mer
Authors: Zhang Yunqin , He Haiqing , Chen Zixi , Huang Yingying , Xiang Guisheng , Li Penghua , Yang Xingkuan , Lu Gang , Xiao Guozhi
Published: March 2021

The efficient synthesis of long, branched, and complex carbohydrates containing multiple 1,2‐cis glycosidic linkages is a long‐standing challenge. Here, we report a merging reagent modulation and 6‐O‐levulinoyl remote anchimeric assistance glycosylation strategy, which is successfully applied to the first highly stereoselective synthesis of the branched Dendrobium Huoshanense glycans and the linear Longan glycans containing up to 30 contiguous 1,2‐cis glucosidic bonds. DFT calculations shed light on the origin of the much higher stereoselectivities of 1,2‐cis glucosylation with 6‐O‐levulinoyl group than 6‐O‐acetyl or 6‐O‐benzoyl groups. Orthogonal one‐pot glycosylation strategy based on glycosyl ortho‐alkynylbenzoates and ortho‐(1‐phenylvinyl)benzoates has been demonstrated in the efficient synthesis of complex glycans, precluding such issues as aglycon transfer inherent to orthogonal one‐pot synthesis based on thioglycosides.
Characteristics of spring consecutive dry days with different durations across China based on the objective zoning approach
Authors: Zeng Zixuan , Sun Jianqi
Published: March 2021

The duration of dry periods is closely related to drought conditions and is used to evaluate the degree of drought. In this article, using the rotated empirical orthogonal function (REOF) and K‐medoids clustering methods and considering the spatial continuity, 500 stations in China are divided into 10 clusters to analyze the variation characteristics of consecutive dry days (CDDs) with different durations in spring. In Clusters 1–5 over the middle and lower reaches of the Yangtze River, South China, North China, and eastern and western Southwest China, the contribution percentage of short‐duration CDDs to total dry days decreases, while that of medium‐ and/or long‐duration CDDs increases, which leads to an increase in the total dry days and the duration of CDDs. In Clusters 6–8, the total dry days decrease, which are mainly contributed by the decreases in medium‐duration CDDs (for Cluster 6 over southern Northeast China) or long‐duration CDDs (for Clusters 7–8 over northern Northeast China and southern Xinjiang). The total dry days change little in Clusters 9–10 over eastern Northwest China and northern Xinjiang, which is attributed to the offset among the changes in the three‐type duration CDDs. In Clusters 6–10, the duration of CDDs shortens overall. The decadal changes of spring dry days in China exhibit remarkable regional differences. The total day days and three‐type duration CDDs in some clusters (1, 4, and 8) all have significant decadal changes, but they have not in Cluster 7. And the decadal change times also exhibit regional differences. The investigation of different‐duration CDDs in this study provides more information on droughts at different time scales in China.
European trends in mortality in children with congenital anomalies: 2000–2015
Authors: Pitt Matilda J , Morris Joan K
Published: March 2021

Objective

To investigate if the survival of children with congenital anomalies has improved from 2000 to 2015 and whether there is heterogeneity in the improvements across Europe.

Design

Population‐based study of routine collected data from the WHO database on mortality and causes.

Setting

Data on 31 European countries from 2000 to 2015.

Main outcome measures

All‐cause and congenital anomaly mortality rates for infants and children up to age 9 in countries and regions of Europe.

Results

The relative odds of all‐cause mortality in 2015 compared with 2000 was 0.54 (95% CI: 0.50–0.59) for under 1, 0.48 (95% CI: 0.44–0.53) for ages 1–4, and 0.53 (95% CI: 0.49–0.56) for ages 5–9 with the relative odds of mortality from congenital anomalies being 0.49 (95% CI: 0.44–0.55), 0.51 (95% CI: 0.44–0.60), and 0.65 (95% CI: 0.53–0.80), respectively. The proportion of deaths from congenital anomalies remained relatively constant over time (26, 16, and 9% for under 1, ages 1–4, and ages 5–9, respectively) and was similar in all regions of Europe. For mortality from all causes and from congenital anomalies heterogeneity between countries and regions of Europe was high, with the countries in Eastern Europe having higher rates, but also experiencing greater relative reductions in mortality from 2000 to 2015.

Conclusion

There was a large geo‐spatial disparity in all cause and congenital anomaly mortality for infants and children up to 9. However, all regions saw a significant decrease in all cause and congenital anomaly mortality rates, with the proportions of deaths from congenital anomalies remaining constant over this time.
Anchor‐IMPACT: A standardized microfluidic platform for high‐throughput antiangiogenic drug screening
Authors: Kim Suryong , Ko Jihoon , Lee Seung‐Ryeol , Park Dohyun , Park Seunghyuk , Jeon Noo Li
Published: March 2021

In vitro models are becoming more advanced to truly present physiological systems while enabling high‐throughput screening and analysis. Organ‐on‐a‐chip devices provide remarkable results through the reconstruction of a three‐dimensional (3D) cellular microenvironment although they need to be further developed in terms of multiple liquid patterning principle, material properties, and scalability. Here we present a 3D anchor‐based microfluidic injection‐molded plastic array culture platform (Anchor‐IMPACT) that enables selective, space‐intensive patterning of hydrogels using anchor‐island for high‐throughput angiogenesis evaluation model. Anchor‐IMPACT consists of a central channel and an anchor‐island, integrating the array into an abbreviated 96‐well plate format with a standard microscope slide size. The anchor‐island enables selective 3D cell patterning without channel‐to‐channel contact or any hydrogel injection port using an anchor structure unlike conventional culture compartment. The hydrogel was patterned into defined regions by spontaneous capillary flow under hydrophilic conditions. We configured multiple cell patterning structures to investigate the angiogenic potency of colorectal cancer cells in Anchor‐IMPACT and the morphological properties of the angiogenesis induced by the paracrine effect were evaluated. In addition, the efficacy of anticancer drugs against angiogenic sprouts was verified by following dose‐dependent responses. Our results indicate that Anchor‐IMPACT offers not only a model of high‐throughput experimentation but also an advanced 3D cell culture platform and can significantly improve current in vitro models while providing the basis for developing predictive preclinical models for biopharmaceutical applications.
Integrating high cell density cultures with adapted laboratory evolution for improved Gag‐HA virus‐like particles production in stable insect cell lines
Authors: Fernandes Bárbara , Correia Ricardo , Sousa Marcos , Carrondo Manuel J. T. , Alves Paula M. , Roldão António
Published: March 2021

Stable insect cell lines are emerging as an alternative to the insect cell‐baculovirus expression vector system (IC‐BEVS) for protein expression, benefiting from being a virus‐free, nonlytic system. Still, the titers achieved are considerably lower. In this study, stable insect (Sf‐9 and High Five) cells producing Gag virus‐like particles (VLPs) were first adapted to grow under hypothermic culture conditions (22°C instead of standard 27°C), and then pseudotyped with a model membrane protein (influenza hemagglutinin [HA]) for expression of Gag‐HA VLPs. Adaptation to lower temperature led to an increase in protein titers of up to 12‐fold for p24 (as proxy for Gag‐VLP) and sixfold for HA, with adapted Sf‐9 cells outperforming High Five cells. Resulting Gag‐HA VLPs producer Sf‐9 cells were cultured to high cell densities, that is, 100 × 106 cell/ml, using perfusion (ATF® 2) in 1 L stirred‐tank bioreactors. Specific p24 and HA production rates were similar to those of batch culture, enabling to increase volumetric titers by 7–8‐fold without compromising the assembly of Gag‐HA VLPs. Importantly, the antigen (HA) quantity in VLPs generated using stable adapted cells in perfusion was ≈5‐fold higher than that from IC‐BEVS, with the added benefit of being a baculovirus‐free system. This study demonstrates the potential of combining stable expression in insect cells adapted to hypothermic culture conditions with perfusion for improving Gag‐HA VLPs production.
Assessing people‐driven factors for circular economy practices in small and medium‐sized enterprise supply chains: Business strategies and environmental perspectives
Authors: Sawe Fredrick Betuel , Kumar Anil , Garza‐Reyes Jose Arturo , Agrawal Rohit
Published: March 2021

Globalisation and technological advancements have increased the pressure on small businesses to increase their productivity and to gain competitive advantages. That pressure has been placed on the resources available, resulting in increased environmental degradation as a result of the traditional linear model of make‐use‐dispose. Circular economy (CE) practices offer the opportunity for sustainable production based on the reuse‐remanufacture and recycling of resources for small and medium‐sized enterprises (SMEs) to increase their sustainability, resulting in enhanced performance levels in terms of business strategies and environmental perspectives. But in academic literature, the role of people‐driven factors (PDFs) in the adoption of CE practices in the supply chains (SCs) of SMEs is limited. Therefore, to fill this literature gap, this research looks at analysing PDFs for the implementation of CE in the SMEs in developing countries in two phases. PDFs are identified from an extensive literature review; a DEMATEL technique is then employed to understand the significant influence of each factor in the adoption of CE practices in SCs by dividing them into cause–effect groups. The findings show that PDFs such as training and knowledge sharing, employee participation, leadership and management plus strategic alignment are considered to be the most important significant factors in the adoption. The findings of this study will help industrial managers to understand the significance of the role of PDFs for enhancing business strategies; these findings can reduce the negative environmental impact in the adoption of CE practices in the SCs of SMEs.
Administration of pilocarpine by microneedle patch as a novel method for cystic fibrosis sweat testing
Authors: Li Song , Hart Kelsey , Norton Natalie , Ryan Clare A. , Guglani Lokesh , Prausnitz Mark R.
Published: March 2021

The sweat test is the gold standard for the diagnosis of cystic fibrosis (CF). The test utilizes iontophoresis to administer pilocarpine to the skin to induce sweating for measurement of chloride concentration in sweat. However, the sweat test procedure needs to be conducted in an accredited lab with dedicated instrumentation, and it can lead to inadequate sweat samples being collected in newborn babies and young children due to variable sweat production with pilocarpine iontophoresis. We tested the feasibility of using microneedle (MN) patches as an alternative to iontophoresis to administer pilocarpine to induce sweating. Pilocarpine‐loaded MN patches were developed. Both MN patches and iontophoresis were applied on horses to induce sweating. The sweat was collected to compare the sweat volume and chloride concentration. The patches contained an array of 100 MNs measuring 600 μm long that were made of water‐soluble materials encapsulating pilocarpine nitrate. When manually pressed to the skin, the MN patches delivered >0.5 mg/cm2 pilocarpine, which was double that administered by iontophoresis. When administered to horses, MN patches generated the same volume of sweat when normalized to drug dose and more sweat when normalized to skin area compared to iontophoresis using a commercial device. Moreover, both MN patches and iontophoresis generated sweat with comparable chloride concentration. These results suggest that administration of pilocarpine by MN patches may provide a simpler and more‐accessible alternative to iontophoresis for performing a sweat test for the diagnosis of CF.
Association of Genetic Structure and Diversity in Iranian Wild Germplasms ofMentha longifoliaL. Based on Phenotypical, Biochemical, and Molecular Markers
Authors: Moshrefi‐Araghi Alireza , Nemati Hossein , Azizi Majid , Moshtaghi Nasrin , Shoor Mahmood
Published: March 2021

Mentha longifoliaL. is well‐known to be one of the most pervasive wild‐growing species of the Lamiaceae family, which has extensive beneficial properties in the fields of pharmacology and biological products. In the present study, the correlation between Inter‐simple sequence repeat (ISSR) markers and morpho‐chemical parameters of twenty differentM. longifoliaaccessions (MLACs) were assessed. The geographic information system (GIS) has been employed to interpret the original habitat of the accessions in Iran. ISSR analysis indicated a remarkable difference in the studied accessions, segregated them into three main groups, constructed by an unweighted pair‐group method with arithmetic (UPGMA) and principal coordinate analysis (PCoA). A total of 89 bands were generated by 12 ISSR primers, among which 82 (91.97 %) of them were polymorphic. The cluster analysis based on agro‐morphological data scattered MLACs into two main groups. The essential oils (EOs) were analyzed through GC/FID/MS, and four chemotypes were characterized according to the major constituents. Pulegone ranged from 0.17 to 69.50 % was the main oil constituent with the highest content. Also, HPLC‐PDA was employed to identify and to quantify the phenolic compounds in the MeOH extracts of MLACs. Heatmap cluster based on phenolic compounds produced three main categories of accessions. The components identified in the extracts were rosmarinic acid, rutin, vanillic acid, ferulic acid, chlorogenic acid, caffeic acid, 3,4‐dihydroxybenzoic acid, 2,5‐dihydroxybenzoic acid, andp‐coumaric acid, which among them rosmarinic acid (RA) varied from 39.16 to 261.55 mg/100 g (DW) as a predominant constituent. Subsequently, multiple regression analyses between ISSR fragments and morpho‐chemical data illustrated considerable relationships in the plant materials. The high variation and correlation observed in metabolic and phenotypic traits of MLACs establish an adequate source to conduct reserves conservation programs.
Characterization of mitochondrial respiratory complexes involved in the regulation of myoblast differentiation
Authors: Chabi Béatrice , Hennani Hanane , Cortade Fabienne , Wrutniak‐Cabello Chantal
Published: March 2021

During myoblast differentiation, mitochondria undergo numerous changes that are necessary for the progression of the myogenic program. Notably, we previously showed that alteration in mitochondrial activity was able to control the expression of keys regulator of cell cycle withdrawal and terminal differentiation. Here, we assessed whether inhibition of one of the respiratory complexes was a key factor in the regulation of myogenic differentiation in C2C12 cells, and was associated with alteration in reactive oxygen species (ROS) production. C2C12 cells were treated from proliferation to differentiation with specific inhibitors of mitochondrial complexes at a concentration that were inhibiting respiration but not altering cell morphology. Proliferation was significantly repressed with inhibition of complexes I, II, and III, or mitochondrial protein synthesis (using Chloramphenicol treatment), while complex IV inhibition did not alter myoblast proliferation compared to control cells. Moreover, inhibition of complexes I and II altered cell cycle regulators, with p21 protein expression upregulated since proliferation and p27 protein expression reduced at differentiation. Myotubes formation and myogenin expression were blunted with complexes I and II inhibitors while MyoD protein expression was maintained, suggesting an alteration in its transcriptional activity. Finally, a decrease in overall ROS production was observed with continuous inhibition of mitochondrial complexes I–IV. In summary, our data provide evidence that complexes I and II may be the primary regulators of C2C12 myogenic differentiation. This occurs through specific regulation of myogenic rather than cell cycle regulators expression and ROS production at mitochondrial rather than cell level.
Neurosarcoidosis with hydrocephalus as a first presenting sign: a unique case report
Authors: Schuermans Valérie N. E. , Yeung Esther , Henneman Wouter J. P. , Ackermans Linda , Heijboer Roel , Mostard Rémy L. M. , Vos Winand , Pasmans Raphaël , Schijns Olaf E. M. G.
Published: March 2021

There is a possible relationship with cerebral ischemic events and neurosarcoidosis. It should be considered in the differential diagnosis in a case of unexplained hydrocephalus, vascular white matter lesions and vasculitis related findings.
Development of an optimized risk score to predict short‐term death among acute myocardial infarction patients in rural China
Authors: Wang Sheng‐ji , Cheng Zhen‐Xiu , Fan Xiao‐ting , Lian Yong‐gang
Published: March 2021

Background

Risk stratification of patients with acute myocardial infarction (AMI) is of great clinical significance.

Hypothesis

The present study aimed to establish an optimized risk score to predict short‐term (6‐month) death among rural AMI patients from China.

Methods

We enrolled 6581 AMI patients and extracted relevant data. Patients were divided chronologically into a derivation cohort (n = 5539), to establish the multivariable risk prediction model, and a validation cohort (n = 1042), to validate the risk score.

Results

Six variables were identified as independent predictors of short‐term death and were used to establish the risk score: age, Killip class, blood glucose, creatinine, pulmonary artery systolic pressure, and percutaneous coronary intervention treatment. The area under the ROC curve (AUC) of the optimized risk score was 0.82 within the derivation cohort and 0.81 within the validation cohort. The diagnostic performance of the optimized risk score was superior to that of the GRACE risk score (AUC 0.76 and 0.75 in the derivation and validation cohorts, respectively; p < .05).

Conclusion

These results indicate that the optimized scoring method developed here is a simple and valuable instrument to accurately predict the risk of short‐term mortality in rural patients with AMI.
Access to innovation through the national early access program and clinical trials for patients with malignant melanoma
Authors: Christen Claire , Belgodère Laetitia , Guillot Bernard , Jumeau Céline , Lorence Annie , Kerouani‐Lafaye Ghania , Brunel Liora , Turcry Florence , Monard Adrien , Grudé Francoise , Guyader Gaëlle , Boudali Lotfi , Albin Nicolas
Published: March 2021

Background

The arrival of immunotherapies and targeted therapies challenged the authorities to make them available as soon as possible. France has effective tools, such as clinical trials (CTs) and a national early access program (temporary authorizations for use [ATUs] and temporary recommendations for use [RTUs]), allowing the use of innovative drugs, whether or not they have been authorized or used off‐label, for cases that have reached a therapeutic impasse.

Methods

The methodology involved real‐time data collection from ATUs, RTUs (between September 1, 2009 and September 1, 2019), and CT authorizations (from December 1, 2017 to September 1, 2019) that were filed and reviewed by the French National Agency for Medicines for metastatic melanoma (MM).

Results

In total, 45 CTs were authorized for MM (51% early phase trials and 44% phase 2 and 3 trials), mainly for the metastatic line (86%) and with an industrial sponsor (73%). Immunotherapies and targeted therapies (63% and 24%, respectively) mostly were used in combination. Three RTUs were authorized for the adjuvant treatment of MM, whereas 13 drugs were available through nominal ATUs (nATUs), of which 5 were awarded a cohort ATU (cATU). This enabled the treatment of 6538 patients (28% through nATUs and 72% through cATUs). All of these drugs were granted marketing authorization and were included in the reimbursement list.

Conclusions

Thanks to CTs and the national early access program, patients in France have been able to benefit from innovative MM treatments.

Lay Summary

Several tools allow the use of innovative drugs in France, even if they are not yet authorized or used off‐label.

From December 1, 2017 to September 1, 2019, 45 clinical trials have been authorized for metastatic melanoma, mostly using immunotherapy (63%) and targeted therapy (24%) at an early phase (51%).

Since 2010, the national early access program has treated 6538 patients, including 28% under nominative temporary authorizations for use and 72% under cohort temporary authorizations for use.

Fourteen drugs are available through nominative temporary authorizations for use, and 5 are available through cohort temporary authorizations for use, and all of these drugs were granted marketing authorization.
Posttraumatic stress disorder symptoms in patients with acute myeloid leukemia
Authors: Amonoo Hermioni L. , LeBlanc Thomas W. , Kavanaugh Alison R. , Webb Jason A. , Traeger Lara N. , Jagielo Annemarie D. , Vaughn Dagny M. , Elyze Madeleine , Longley Regina M. , Fathi Amir T. , Hobbs Gabriela S. , Brunner Andrew M. , O’Connor Nina R. , Luger Selina M. , Gustin Jillian L. , Bhatnagar Bhavana , Horick Nora K. , El‐Jawahri Areej
Published: March 2021

BACKGROUND

Patients with acute myeloid leukemia (AML) receiving intensive chemotherapy face a life‐threatening illness, isolating hospitalization, and substantial physical and psychological symptoms. However, data are limited regarding risk factors of posttraumatic stress disorder (PTSD) symptoms in this population.

METHODS

The authors conducted a secondary analysis of data from 160 patients with high‐risk AML who were enrolled in a supportive care trial. The PTSD Checklist‐Civilian Version was used to assess PTSD symptoms at 1 month after AML diagnosis. The Brief COPE and the Functional Assessment of Cancer Therapy‐Leukemia were to assess coping and quality of life (QOL), respectively. In addition, multivariate regression models were constructed to assess the relation between PTSD symptoms and baseline sociodemographic factors, coping, and QOL.

RESULTS

Twenty‐eight percent of patients reported PTSD symptoms, describing high rates of intrusion, avoidance, and hypervigiliance. Baseline sociodemographic factors significantly associated with PTSD symptoms were age (B = −0.26; P = .002), race (B = −8.78; P = .004), and postgraduate education (B = −6.30; P = .029). Higher baseline QOL (B = −0.37; P ≤ .001) and less decline in QOL during hospitalization (B = −0.05; P = .224) were associated with fewer PTSD symptoms. Approach‐oriented coping (B = −0.92; P = .001) was associated with fewer PTSD symptoms, whereas avoidant coping (B = 2.42; P ≤ .001) was associated with higher PTSD symptoms.

CONCLUSIONS

A substantial proportion of patients with AML report clinically significant PTSD symptoms 1 month after initiating intensive chemotherapy. Patients' baseline QOL, coping strategies, and extent of QOL decline during hospitalization emerge as important risk factors for PTSD, underscoring the need for supportive oncology interventions to reduce the risk of PTSD in this population.
Refined Description and Stability for Singular Solutions of the 2D Keller‐Segel System
Authors: Collot Charles , Ghoul Tej‐Eddine , Masmoudi Nader , Nguyen Van Tien
Published: March 2021

We construct solutions to the two‐dimensional parabolic‐elliptic Keller‐Segel model for chemotaxis that blow up in finite time T. The solution is decomposed as the sum of a stationary state concentrated at scale λ and of a perturbation. We rely on a detailed spectral analysis for the linearised dynamics in the parabolic neighbourhood of the singularity performed by the authors in [10], providing a refined expansion of the perturbation. Our main result is the construction of a stable dynamics in the full nonradial setting for which the stationary state collapses with the universal law

where γ is the Euler constant. This improves on the earlier result by Raphael and Schweyer and gives a new robust approach to so‐called type II singularities for critical parabolic problems. A by‐product of the spectral analysis we developed is the existence of unstable blowup dynamics with speed

© 2021 Wiley Periodicals LLC.
Malaria PK/PD and the Role Pharmacometrics Can Play in the Global Health Arena: Malaria Treatment Regimens for Vulnerable Populations
Authors: Hughes Emma , Wallender Erika , Mohamed Ali Ali , Jagannathan Prasanna , Savic Radojka M.
Published: March 2021

Malaria is an infectious disease which disproportionately effects children and pregnant women. These vulnerable populations are often excluded from clinical trials resulting in one‐size‐fits‐all treatment regimens based on those established for a nonpregnant adult population. Pharmacokinetic/pharmacodynamic (PK/PD) models can be used to optimize dose selection as they define the drug exposure‐response relationship. Additionally, these models are able to identify patient characteristics that cause alterations in the expected PK/PD profiles and through simulations can recommend changes to dosing which compensate for the differences. In this review, we examine how PK/PD models have been applied to optimize antimalarial dosing recommendations for young children, including those who are malnourished, pregnant women, and individuals receiving concomitant therapies such as those for HIV treatment. The malaria field has had great success in utilizing PK/PD models as a foundation to update treatment guidelines and propose the next generation of dosing regimens to investigate in clinical trials. We propose how the malaria field can continue to use modeling to improve therapies by further integrating PK data into clinical studies and including data on drug resistance and host immunity in PK/PD models. Finally, we suggest that other disease areas can achieve similar success in applying pharmacometrics to improve outcomes by implementing three key principals.
Crystal Morphology Prediction of Olanzapine Forms III and IV
Authors: Lu Qianqian , Ali Imran , Wei Zhiyun , Li Jinjin
Published: March 2021

It is of great significance to explore and predict crystal growth behavior that can target the optimal growth conditions and obtain ideal properties. The ability to effectively treat schizophrenia and other psychoses has led to numerous studies of olanzapine (OZPN) polymorphs. There are four reported anhydrous forms of OZPN, but two of whose crystal morphologies (forms III and IV) are still unavailable in the laboratory. Based on the advanced spiral growth model, this study predicts the crystal morphologies of OZPN forms III and IV from vapor and different solvents (i.e., water, ethyl acetate, ethanol, cyclohexane, and dichloromethane), where the potential energies between dimeric growth units (stronger than specific energy cutoff) are considered as strong bond. It is demonstrated that the growth rate of form III increases with the increase of supersaturation from 1.01 to 1.07. Form III crystallizes from solvents with the block‐like shape, whereas form IV grows with the rectangular shape, that obviously differs from the flat‐square shapes of form I and form II. This mechanistic model is able to apply on various compounds, especially for the crystals with non‐centrosymmetric molecules to obtain important guidance for their experimental preparations.
Board structure, financial performance, corporate social responsibility performance, CSR committee, and CEO duality: Disentangling the connection in healthcare
Authors: Uyar Ali , Kuzey Cemil , Kilic Merve , Karaman Abdullah S.
Published: March 2021

Despite the growing importance of responsible behavior in the healthcare sector, research on corporate social responsibility (CSR) in association with board structure is scarce. Hence, the objective of this study is twofold: (1) to test whether a board structure is associated with firm financial and CSR performance and (2) whether the CSR committee and CEO duality moderates this association in the healthcare sector. Examining the moderation of CSR committee is important to understand whether CSR committee strengthens or weakens the link between female directors and CSR performance. Moreover, CEO duality's moderation will highlight whether powerful CEOs are a barrier for female directors' monitoring role. The data for the study was derived from the Thomson Reuters Eikon database for the years between 2011–2018. Overall, the results suggest that while female directors contribute to firm performance, CEOs with dual roles and larger boards harm firm performance. Further, independent directors have a limited contribution to CSR performance whereas they have no contribution to financial performance. Moderation analysis shows that CSR committees and female directors are not the replacement of one another; they are both needed and beneficial to the corporate structure. Although CEOs with a dual role impair the performance of a firm, they do not exert considerable influence on the other directors. As one of the important functions of a board is monitoring, these findings assist healthcare firms to configure their boards to improve their monitoring functions. The results are therefore helpful in terms of alleviating agency costs and in appeasing stakeholders.
Uncovering the different scales in deer–forest interactions
Authors: Ramirez Juan Ignacio
Published: March 2021

Deer are regarded to be a keystone species as they play a crucial role in the way an ecosystem functions. Most deer–forest interaction studies apply a single scale — process of analyzing ecological interactions by only taking into account one dependent variable — to understand how deer browsing behavior shapes different forest components, but they overlook the fact that forests respond to multiple scales simultaneously. This research evaluates the effect of browsing by wild deer on temperate and boreal forests at different scales by synthesizing seminal papers, specifically (a) what are the effects of deer population density in forest regeneration? (b) What are the effects of deer when forests present diverging spatial characteristics? (c) What are the effects on vegetation at different temporal scales? and (d) What are the hierarchical effects of deer when considering other trophic levels? Additionally, a framework based on modern technology is proposed to answer the multiscale research questions previously identified. When analyzing deer–forest interactions at different scales, the strongest relationships occur at the extremes. For example: when deer assemblage occurs in low or high density and is composed of a mix of small and large species. As forests on poor soils remain restrained in size, isolated and chronically browsed. When forests harbor incomplete trophic levels, the effects spill over to lower trophic levels. To better understand the complexities in deer–forest interactions, researchers should combine technology‐based instruments like fixed sensors and drones with field‐tested methods such observational studies and experiments to tackle multiscale research questions.
Degradation modeling of water environmental DNA: Experiments on multiple DNA sources in pond and seawater
Authors: Saito Tatsuya , Doi Hideyuki
Published: March 2021

Environmental DNA (eDNA) analysis methods have been developed to detect organism distribution and abundance/biomass in various environments. eDNA degradation is critical for eDNA evaluation. However, the dynamics and mechanisms of eDNA degradation are largely unknown, especially when considering different eDNA sources, for example, cells and fragmental DNA. We experimentally evaluated the degradation rates of eDNA derived from multiple sources, including fragmental DNA (internal PCR control [IPC]), free cells (from Oncorhynchus kisutch), and resident species. We conducted the experiment with pond and seawater to evaluate the differences between freshwater and marine habitats. We quantified the eDNA copies of free cells, fragmental DNA, and resident species (Cyprinus carpio in the pond and Trachurus japonicus in the sea). We found that eDNA derived from both cells and fragmental DNA decreased exponentially in both the sea and pond samples. The degradation of eDNA from resident species showed similar behavior to the cell‐derived eDNA. We evaluated three degradation models with different assumptions and degradation steps and found that a simple exponential model was effective in most cases. Our findings on cell‐ and fragmental DNA‐derived eDNA provide fundamental information about the eDNA degradation process and can be applied to quantify eDNA behavior in natural environments.
Impact of activation energy and gyrotactic microorganisms on flow of Casson hybrid nanofluid over a rotating moving disk
Authors: Jyothi Anigere Marikempaiah , Naveen Kumar Rangaswamy , Punith Gowda Ramanahalli Jayadevamurthy , Veeranna Yarranna , Prasannakumara Ballajja Chandrappa
Published: March 2021

Many models of various non‐Newtonian fluid flows for different geometries are available for analyzing the mass and heat transfer. Nevertheless, for researchers, it is challenging to choose the most suitable model for a specific geometry. Here, we have adopted a modified Buongiorno model to explore the impact of activation energy on the Casson hybrid nanofluid flow over an upward/downward‐moving rotating disk filled with the gyrotactic microorganisms. Moreover, the external magnetic field can establish the magnetic effect, which normalizes the features of heat, mass transfer, and fluid flow. Here, we used silver and copper as nanoparticles suspended in human blood as the carrier fluid. The modeled partial differential equations are converted to ordinary differential equations by opting suitable similarity variables. The numerical solutions of these reduced equations are attained by means of Runge–Kutta–Fehlberg fourth‐fifth‐order method by adopting a shooting scheme. An investigation of the attained outcomes reveals that the flow field is affected appreciably by the activation energy, bioconvection, and magnetic effect. Peclet and concentration difference numbers diminish the microorganism's profile. A rise in values of the Brownian motion parameter leads to an increase in the rate of heat transfer.
The Kings River Experimental Watersheds: Infrastructure and data
Authors: Wagenbrenner Joseph W. , Dralle David N. , Safeeq Mohammad , Hunsaker Carolyn T.
Published: March 2021

The Kings River Experimental Watersheds (KREW) were established in 2002 to expand our knowledge of catchment physical, chemical, and biological processes in Sierra Nevada headwater forests, and to better understand the impacts of prescribed burning and forest thinning on these processes. Two elevation strata (high and low) were selected for the KREW sites, with four independent catchments and one nested catchment within each stratum. Both high and low elevation study areas were instrumented for continuous measurements of meteorology, streamflow, and turbidity. Atmospheric and stream chemistry, suspended sediment concentration, and bedload sediment delivery were measured on a regular schedule. Soil chemical and physical properties and vegetation were systematically sampled before and after the initial thinning and prescribed burning treatments, which were implemented between 2012 and 2016. Post‐treatment data collection continues today as we explore opportunities for the second round of possible treatments. The critical research infrastructure and long‐term baseline data collection has been instrumental in building partnerships with downstream managers, end users, non‐governmental organizations, academic researchers, and national research programmes. Contributions to date include fundamental understanding of magnitude and variability of nutrient deposition; carbon, nutrient, and major ion dynamics in headwater streams; aquatic algae and macroinvertebrate populations; vegetation composition and structure; and streamflow responses to precipitation in the two elevation strata. Data from the experimental watersheds also support calibration and validation of diverse hydrologic models used for water resources planning.