bluuebunny/crossref_metadata_2025 huggingface dataset:
A Quinoxaline‐Based D–A Copolymer Donor Achieving 17.62% Efficiency of Organic Solar Cells
Authors: Zhu Can , Meng Lei , Zhang Jinyuan , Qin Shucheng , Lai Wenbin , Qiu Beibei , Yuan Jun , Wan Yan , Huang Wenchao , Li Yongfang
Published: April 2021

Side‐chain engineering has been an effective strategy in tuning electronic energy levels, intermolecular interaction, and aggregation morphology of organic photovoltaic materials, which is very important for improving the power conversion efficiency (PCE) of organic solar cells (OSCs). In this work, two D–A copolymers, PBQ5 and PBQ6, are designed and synthesized based on bithienyl‐benzodithiophene (BDTT) as the donor (D) unit, difluoroquinoxaline (DFQ) with different side chains as the acceptor (A) unit, and thiophene as the π‐bridges. PBQ6 with two alkyl‐substituted fluorothiophene side chains on the DFQ units possesses redshifted absorption, stronger intermolecular interaction, and higher hole mobility than PBQ5 with two alkyl side chains on the DFQ units. The blend film of the PBQ6 donor with the Y6 acceptor shows higher and balanced hole/electron mobilities, less charge carrier recombination, and more favorable aggregation morphology. Therefore, the OSC based on PBQ6:Y6 achieves a PCE as high as 17.62% with a high fill factor of 77.91%, which is significantly higher than the PCE (15.55%) of the PBQ5:Y6‐based OSC. The PCE of 17.62% is by far one of the highest efficiencies for the binary OSCs with polymer donor and Y6 acceptor.
Sub 20 nm‐Node LiNbO3 Domain‐Wall Memory
Authors: Lian Jianwei , Chai Xiaojie , Wang Chao , Hu Xiaobing , Jiang Jun , Jiang Anquan
Published: April 2021

Conducting domain walls (DWs) induced by an in‐plane electric field applied to a mesa‐like cell fabricated at the surface of an insulating LiNbO3 single‐crystal film play a key role in the diode‐like DW memory. However, the lateral shrinking of the cell size below a 20 nm‐node technology becomes challenging due to the presence of interfacial layers with the finite thickness above 30 nm. In this work, 15 nm‐sized LiNbO3 cells are fabricated in high on/off current ratio of ≈102 on the SiO2/Si wafers immune to the interfacial‐layer effect, which can be operated below 5 V and also promising to meet the CMOS processing. It is found that the interfacial‐layer thickness reduces almost linearly with the shrinking cell size from 100 to 15 nm and the DW current increases by 25 times. The retention time of written information at +/−3 V is over 48 h, the domain switching time can approach 5 ns at 4 V in high switching endurance (≈109 cycles). These achievements imply the high storage density of a ferroelectric DW memory without the fundamental interfacial‐layer limit.
The Tunability of Oxygen Evolution Reaction in Flexible Van der Waals Manganite Membrane
Authors: Liu Huan , Qi Ji , Feng Ming , Xu Hang , Liu Ruiping , Li Nan , Wang Chen , Zhang Yuan , Zhang Yuting , Lü Weiming
Published: April 2021

Transition metal oxides (TMOs) have been intensively investigated in varied electrochemical processes owing to their features of low cost, stability, and substantial activity, etc. The strain engineering of a TMO has been proposed as a promising method for enhanced electrochemical activities due to its strongly electron correlated nature. Generally this type of investigation is carried out by separated TMO thin films on various substrates with a different lattice constant. In this study, the oxygen evolution reaction (OER) activity of Van der Waals La2/3Sr1/3MnO3 (LSMO) membrane is studied as a function of continuous strain manipulation via curvature change. It is found that a total of ≈800% OER activity tunability can be achieved by only ≈0.4% in situ strain modulation. Then the variation of in‐plane interaction strength of the eg orbital is found to correspond to the sensitive OER tunability and 3dx2−y2 orbital occupancy is favored in an OER enhancement of LSMO.
Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment
Authors: Kronstadt Stephanie M. , Pottash Alex E. , Levy Daniel , Wang Sheng , Chao Wei , Jay Steven M.
Published: April 2021

Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell‐derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell‐based therapies and have demonstrated anti‐inflammatory, anti‐apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV‐based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.
Aqueous MXene/PH1000 Hybrid Inks for Inkjet‐Printing Micro‐Supercapacitors with Unprecedented Volumetric Capacitance and Modular Self‐Powered Microelectronics
Authors: Ma Jiaxin , Zheng Shuanghao , Cao Yuexian , Zhu Yuanyuan , Das Pratteek , Wang Hui , Liu Yu , Wang Jiemin , Chi Liping , Liu Shengzhong (Frank) , Wu Zhong‐Shuai
Published: April 2021

Despite intense development of inkjet printing for scalable and customizable fabrication of power sources, one major shortcoming is the lack of eco‐friendly aqueous inks free of additives (e.g., toxic solvents, surfactants). Here, an aqueous printable MXene/poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonic acid) (MP) hybrid ink is demonstrated that has an adjustable viscosity to directly inkjet‐print micro‐supercapacitors (MP‐MSCs) with excellent performance, seamless integration, and desirable customization, which is crucial for scalable industrialization of self‐powered integrated systems. The MP‐MSCs deliver an unprecedented volumetric capacitance of 754 F cm−3 and a remarkable energy density of 9.4 mWh cm−3, superior to previously reported inkjet‐printed MSCs. Such outstanding performance is partly attributed to highly conductive PH1000 that prevents restacking of MXene nanosheets, enabling fast electron and ion diffusion throughout the microelectrodes. Moreover, MP‐MSCs present exceptional miniaturization and superior modularization featuring high voltage output up to 36 V from 60 serially connected cells and impressive areal voltage of 5.4 V cm−2 connected in tandem. Further, a printable temperature sensor integrated with the MP‐MSC and a flexible solar cell exhibits an exceptional response of 2% and mechanical flexibility without any bias voltage input. Therefore, the MXene inks are expected to create various opportunities for miniaturization and innovative construction of flexible, self‐sustaining, energy harvesting–storing–consuming microsystems for printable electronics.
Prolonged in‐hospital stay and higher mortality after Covid‐19 among patients with non‐Hodgkin lymphoma treated with B‐cell depleting immunotherapy
Authors: Duléry Rémy , Lamure Sylvain , Delord Marc , Di Blasi Roberta , Chauchet Adrien , Hueso Thomas , Rossi Cédric , Drenou Bernard , Deau Fischer Bénédicte , Soussain Carole , Feugier Pierre , Noël Nicolas , Choquet Sylvain , Bologna Serge , Joly Bertrand , Philippe Laure , Kohn Milena , Malak Sandra , Fouquet Guillemette , Daguindau Etienne , Taoufik Yassine , Lacombe Karine , Cartron Guillaume , Thiéblemont Catherine , Besson Caroline
Published: April 2021

Prolonged Covid‐19 is an emerging issue for patients with lymphoma or immune deficiency. We aimed to examine prolonged length of in‐hospital stay (LOS) due to Covid‐19 among patients with lymphoma and assess its determinants and outcomes. Adult patients with lymphoma admitted for Covid‐19 to 16 French hospitals in March and April, 2020 were included. Length of in‐hospital stay was analyzed as a competitor vs death. The study included 111 patients. The median age was 65 years (range, 19–92). Ninety‐four patients (85%) had B‐cell non‐Hodgkin lymphoma. Within the 12 months prior to hospitalization for Covid‐19, 79 patients (71%) were treated for their lymphoma. Among them, 63 (57%) received an anti‐CD20 therapy. Fourteen patients (12%) had relapsed/refractory disease. The median LOS was 14 days (range, 1–235). After a median follow‐up of 191 days (3–260), the 6‐month overall survival was 69%. In multivariable analyses, recent administration of anti‐CD20 therapy was associated with prolonged LOS (subdistribution hazard ratio 2.26, 95% confidence interval 1.42–3.6, p < 0.001) and higher risk of death (hazard ratio 2.17, 95% confidence interval 1.04–4.52, p = 0.039). An age ≥ 70 years and relapsed/refractory lymphoma were also associated with prolonged LOS and decreased overall survival. In conclusion, an age ≥ 70 years, a relapsed/refractory lymphoma and recent administration of anti‐CD20 therapy are risk factors for prolonged LOS and death for lymphoma patients hospitalized for Covid‐19. These findings may contribute to guide the management of lymphoma during the pandemic, support evaluating specific therapeutic approaches, and raise questions on the efficacy and timing of vaccination of this particular population.
Ru(II)‐Catalyzed Difluoromethylations of 7‐Azaindoles: Access to Novel Fluoro‐7‐Azaindole Derivatives
Authors: Zhu Yan‐Ying , Xu Hui‐Bei , Zhang Jing , Luo Yi , Dong Lin
Published: April 2021

Fluorinated compounds are prevalence in agrochemicals, pharmaceuticals, and biochemical sciences. Herein, we develop an efficient Ru(II)‐catalyzed site‐selective C−H functionalization/difluoromethylated reaction to separately construct 3‐difluoromethylated and remote meta‐difluoromethylated 7‐azaindole derivatives.
Research progress on compounding agent and mechanical test method of fluororubber
Authors: Xu Zehua , Zhang Yanbin , Li Anling , Wang Jiwen , Wang Guangfei , He Qiang
Published: April 2021

Fluororubber (FKM) materials have excellent mechanical properties, and are widely used in automotive and aerospace fields. As fluorine rubber is a typical representative of new special rubber, the formula and mechanical test method of fluorine rubber have become one of the important issues at present. Multi‐factor optimization of fluororubber compound plays an important role in the mechanical properties of FKM. Based on the introduction of new materials in FKM compounding agents (reinforcing agent, softening plasticizer, anti‐aging agent, accelerator, vulcanizing agent, auxiliary agent and filler), this paper focuses on the research progress of characterization methods and mechanical properties of the composite materials combined with FKM.
Pyrin Inflammasome Activation Abrogates Interleukin‐1 Receptor Antagonist, Suggesting a New Mechanism Underlying Familial Mediterranean Fever Pathogenesis
Authors: Mortensen Sussi B. , Hansen Ann‐Brit E. , Mogensen Trine H. , Jakobsen Marianne A. , Beck Hans C. , Harvald Eva B. , Lambertsen Kate L. , Johansen Isik S. , Andersen Ditte C.
Published: April 2021

Objective

Aberrant pyrin inflammasome activity triggers familial Mediterranean fever (FMF) pathogenesis, but the exact mechanism remains elusive and an obstacle to efficient treatment. We undertook this study to identify pyrin inflammasome–specific mechanisms to improve FMF treatment and diagnostics in the future.

Methods

Pyrin‐specific protein secretion was assessed by proteome analysis in U937‐derived macrophages, and specific findings were confirmed in pyrin inflammasome–activated monocytes from healthy blood donors and patients with FMF, stratified according to MEFV genotype categories corresponding to a suspected increase in FMF disease severity.

Results

Proteome data revealed a differential secretion pattern of interleukin‐1 receptor antagonist (IL‐1Ra) from pyrin‐ and NLRP3‐activated U937‐derived macrophages, which was verified by enzyme‐linked immunosorbent assay and quantitative polymerase chain reaction. Moreover, pyrin activation significantly reduced IL1RN messenger RNA expression (P < 0.001) and IL‐1Ra secretion (P < 0.01) in healthy donor and FMF monocytes, respectively. Independent of MEFV genotype, unstimulated FMF monocytes from colchicine‐treated patients secreted lower amounts of IL‐1Ra compared to healthy donors (P < 0.05) and displayed decreased ratios of IL‐1Ra:IL‐1β (P < 0.05), suggesting a reduced antiinflammatory capacity.

Conclusion

Our data show an inherent lack of IL‐1Ra expression specific to pyrin inflammasome activation, suggesting a new mechanism underlying FMF pathogenesis. The reduced IL‐1Ra levels in FMF monocytes suggest a diminished antiinflammatory capacity that potentially leaves FMF patients sensitive to proinflammatory stimuli, regardless of receiving colchicine therapy. Thus, considering the potential clinical consequence of reduced monocyte IL‐1Ra secretion in FMF patients, we suggest further investigation into IL‐1Ra dynamics and its potential implications for FMF treatment in the future.
What Does It Mean to Be a British Isles Lupus Assessment Group–Based Composite Lupus Assessment Responder? Post Hoc Analysis of Two Phase III Trials
Authors: Furie Richard , Morand Eric F. , Bruce Ian N. , Isenberg David , van Vollenhoven Ronald , Abreu Gabriel , Pineda Lilia , Tummala Raj
Published: April 2021

Objective

The British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) is a validated global measure of treatment response in systemic lupus erythematosus (SLE) clinical trials. To understand the relevance of BICLA in clinical practice, we investigated relationships between BICLA response and routine SLE assessments, patient‐reported outcomes (PROs), and medical resource utilization.

Methods

This was a post hoc analysis of pooled data from the phase III, randomized, placebo‐controlled, 52‐week TULIP‐1 (ClinicalTrials.gov identifier: NCT02446912; n = 457) and TULIP‐2 (ClinicalTrials.gov identifier: NCT02446899; n = 362) trials of intravenous anifrolumab (150/300 mg once every 4 weeks) in patients with moderate‐to‐severe SLE. Changes from baseline to week 52 in clinical assessments, PROs, and medical resource use were compared in BICLA responders versus nonresponders, regardless of treatment assignment.

Results

BICLA responders (n = 318) achieved significantly improved outcomes compared with nonresponders (n = 501), including lower flare rates, higher rates of attainment of sustained oral glucocorticoid taper to ≤7.5 mg/day, greater improvements in PROs (Functional Assessment of Chronic Illness Therapy–Fatigue, Short Form 36 Health Survey), and fewer SLE‐related hospitalizations/emergency department visits (all nominal P < 0.001). Compared with nonresponders, BICLA responders had greater improvements in global and organ‐specific disease activity (Physician’s Global Assessment, SLE Disease Activity Index 2000, Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity, and joint counts; all nominal P < 0.001). BICLA responders had fewer lupus‐related serious adverse events than nonresponders.

Conclusion

BICLA response is associated with clinical benefit in SLE assessments, PROs, and medical resource utilization, confirming its value as a clinical trial end point that is associated with measures important to patient care.
Analysis of Feasibility and Acceptability of an E‐Learning Module in Anatomy
Authors: Bhat Ghulam Mohammad , Bhat Ishfaq Hussain , Shahdad Shaheen , Rashid Saima , Khan Mudasir Ahmad , Patloo Ajaz Ahmad
Published: April 2021

Recent advance in medical education is in correlation with the advances in information technology and thus computer‐based learning is being increasingly employed. The objective of the present study was to design and evaluate an e‐learning module in anatomy and assess the perceptions of students and faculty about this e‐learning module. The participating students were randomized into three groups by block stratified randomization and Google groups were created for each of the three groups. The e‐learning module was implemented in three sessions by rotating the three groups. Validated questionnaires were sent to faculty and participating students via Google forms to obtain feedback. The results of ANOVA showed that there was a significant difference among the groups in terms of marks obtained with conventional (F = 2.403, P = 0.103), online (F = 6.050, P = 0.005), and blended (F = 5.801, P = 0.006). Post hoc comparisons using the Tukey HSD test, about the gain of knowledge, indicated that the results were insignificant when comparing the conventional group with the online group, but were significant when comparing the blended group with the conventional and online group. The qualitative data regarding the perception of students toward e‐learning were analyzed using thematic analysis. The introduction of an interactive e‐learning module in anatomy was effective and well received by the students and faculty. The study showed that blended learning has a positive impact on the students' learning by improving cognitive gain and receptive perception for e‐learning.
New Surgical Approach for Mandibular Anterior Root Coverage by Modified Tunnel Technique With Simultaneous Frenuloplasty: Technical Description and 5‐Year Recall Case Report
Authors: Rimbert Matthieu , Barré Ronan
Published: April 2021

Introduction

Root coverage of gingival recessions in the anterior mandible has limited predictability. Mandibular incisors often offers a thin phenotype, a lack of keratinized tissue and moreover a shallow vestibule with high labial frenum attachment. These conditions induce tensions on the surgical site in conventional coronally advanced flap (CAF) procedures and may compromise the complete root coverage. The purpose of this case report is to present a novel surgical technique for deep labial recessions on mandibular incisors, based on a modified tunnel technique with subepithelial connective tissue graft (CTG) in combination with simultaneous frenuloplasty.

Case Presentation

A 20‐year‐old female patient was referred to the office for treatment of an isolated RT1 in Cairo classification buccal recession on #24 with a shallow vestibule. The design of the recipient site consisted of a full‐thickness modified tunnel preparation extending 4 mm bilaterally to the recession and beyond the crestal bone. A CTG was harvested from the palate and properly adapted to the root surface. The graft and flap were secured with single‐interrupted sutures and double‐crossed sutures to achieve complete root coverage. Frenuloplasty was then performed with a single incision in the bottom of the vestibule and careful sectioning of frenum fibers to release vestibular tensions. Complete root coverage was maintained at 5 years with completely satisfactory esthetic outcomes.

Conclusion

Treatment of single deep mandibular anterior recessions with a combined tunneled CTG approach in addition to frenuloplasty appears to lead to complete long‐term root coverage in one surgery with lasting esthetics results.
Youth's experiences with inclusion, isolation, and discrimination in the LGBTQ+ community
Authors: Closson Leanna M. , Comeau Emily
Published: April 2021

It has been well established that sexual‐ and gender‐minority youth are vulnerable to judgement and maltreatment by non‐LGBTQ+ peers. However, little research has focused on the experiences and interactions among youth specifically within the LGBTQ+ community. The purpose of the present study was to examine inclusion, isolation and discrimination within the LGBTQ+ community, while considering youths' sense of identity. Participants were 122 sexual minority and gender diverse youth between the ages of 14 and 25 years old. Participants completed self‐report measures assessing self‐esteem, as well as experiences in the LGBTQ+ community and strength of LGBTQ+ identities. Results indicated that, beyond the effect of self‐esteem, youth with a strongly developed identity as LGBTQ+ reported greater inclusion and less isolation in the LGBTQ+ community. In contrast, a more strongly developed gender identity was related to greater gender identity discrimination and less inclusion in the community. Sexual orientation identity strength was unrelated to experiences in the community. The results highlight the complexity of identity development for LGBTQ+ youth. Study findings emphasize the importance of future work considering the protective role of identifying with the LGBTQ+ community as a whole in mitigating intragroup exclusionary experiences among sexual minority and gender diverse youth. Please refer to the Supplementary Material section to find this article's Community and Social Impact Statement.
Correction of sinus venosus atrial septal defects with the 10 zig covered Cheatham‐platinum stent – An international registry
Authors: Rosenthal Eric , Qureshi Shakeel A. , Jones Matthew , Butera Gianfranco , Sivakumar Kothandam , Boudjemline Younes , Hijazi Ziyad M. , Almaskary Salim , Ponder Reid D. , Salem Morris M. , Walsh Kevin , Kenny Damien , Hascoet Sebastien , Berman Darren P. , Thomson John , Vettukattil Joseph J. , Zahn Evan M.
Published: April 2021

Background

Covered stent correction of sinus venosus ASDs (SVASD) is a relatively new technique. Challenges include anchoring a sufficiently long stent in a nonstenotic superior vena cava (SVC) and expanding the stent at the wider SVC‐RA junction without obstructing the anomalous right upper pulmonary vein (RUPV). The 10‐zig covered Cheatham‐platinum (CCP) stent has the advantage of being available in lengths of 5–11 cm and dilatable to 34 mm in diameter.

Methods

An international registry reviewed the outcomes of 10‐zig CCP stents in 75 patients aged 11.4–75.9 years (median 45.4) from March 2016. Additional stents were used to anchor the stent in the SVC or close residual shunts in 33/75. An additional stent was placed in 4/5 (80%) with 5/5.5 cm CCPs, 18/29 (62%) with 6 cm CCPs, 5/18 (28%) with 7 cm CCPs, 5/22 (23%) with 7.5/8 cm CCPs and 0/1 with an 11 cm CCP. A “protective” balloon catheter was inflated in the RUPV in 17.

Results

Early stent embolization in two patients required surgical removal and defect repair and tamponade was drained in one patient. The CT at 3 months showed occlusion of the RUPV in one patient. Follow up is from 2 months to 5.1 years (median 1.8 years). QP:QS has reduced from 2.5 ± 0.5 to 1.2 ± 0.36 (p < .001) and RVEDVi from 149.1 ± 35.4 to 95.6 ± 21.43 ml/m2 (p < .001).

Conclusions

Ten‐zig CCPs of 7–8 cm appear to provide reliable SVASD closure with a low requirement for additional stents. Careful selection of patients and meticulous attention to detail is required to avoid complications.
Training oncology care providers in the assessment and treatment of tobacco use and dependence
Authors: Ostroff Jamie S. , Bolutayo Gaffney Kemi L. , O’Brien Maureen , deLeon‐Sanchez Suhana T. , Whitlock C. Will , Kotsen Chris S. , Carter‐Harris Lisa , Banerjee Smita C. , Schofield Elizabeth
Published: April 2021

BACKGROUND

Clinical practice guidelines for promoting smoking cessation in cancer care exist; however, most oncology settings have not established tobacco use assessment and treatment as standard care. Inadequate staff training and other implementation challenges have been identified as barriers for delivery of evidence‐based tobacco treatment. Providing training in tobacco treatment tailored to the unique needs of tobacco‐dependent patients with cancer is one strategy to improve adoption of best practices to promote smoking cessation in cancer care.

METHODS

A tobacco treatment training program for oncology care providers (tobacco treatment training‐oncology [TTT‐O]) consisting of a 2‐day didactic and experiential workshop followed by 6 monthly, collaboratory videoconference calls supporting participants in their efforts to implement National Comprehensive Cancer Network guidelines in their oncology settings was developed and implemented. This article presents preliminary results on program evaluation, changes in participants' self‐efficacy, and progress in implementing tobacco treatment.

RESULTS

Data have been obtained from the first 5 cohorts of TTT‐O participants (n = 110) who completed training, course evaluations, baseline and follow‐up surveys. Participants rated the training as highly favorable and reported significant gains in self‐efficacy in their ability to assess and treat tobacco dependence. Participants also demonstrated significant improvements in tobacco treatment skills and implementation of several indicators of improved adoption of best practices for tobacco treatment in their cancer care settings.

CONCLUSIONS

Implementation of tobacco treatment training for cancer care providers is feasible, acceptable, and can have a significant positive impact on participants' tobacco treatment skills, self‐efficacy, and greater adoption of tobacco treatment delivery in cancer care.
V‐Shaped Methylpyrimidinium Chromophores for Nonlinear Optics
Authors: Achelle Sylvain , Verbitskiy Egor V. , Fecková Michaela , Bureš Filip , Barsella Alberto , Robin‐le Guen Françoise
Published: April 2021

A series of four V‐shaped methylpyrimidinium salts bearing diphenylamino‐electron‐donating groups appended at various pyrimidine positions were designed. These chromophores were obtained by regioselective N(1) monomethylation by methyl methanesulfonate of the pyrimidine core. Linear optical properties were studied experimentally and electronic properties were further completed by (TD)‐DFT calculations. The second‐order nonlinear optical (NLO) properties were also studied using electric field induced second harmonic generation (EFISH) method in chloroform, and all pyrimidinium salts exhibited μβ0>1000×10−48 esu. The 2,4‐disubstituted pyrimidinium core is preferred over 4,6‐disubstitution as it enhances the NLO response and increases the dipole moment. (E,E)‐2,4‐Bis[4‐(diphenylamino)styryl]‐1‐methylpyrimidin‐1‐ium methanesulfonate appears to be the best NLO‐phore in chloroform in the series (μβ0=2500×10−48 esu) and a figure of merit μβ0/MW=3.4 10−48 esu mol g−1.
Categorisation of patients based on immune profiles: a new approach to identifying candidates for response to checkpoint inhibitors
Authors: Bornschlegl Svetlana , Gustafson Michael P , Delivanis Danae A , Ryder Mabel , Liu Minetta C , Vasmatzis George , Hallemeier Chris L , Park Sean S , Roberts Lewis R , Parney Ian F , Jelinek Diane F , Dietz Allan B
Published: April 2021

Objectives

Inhibitors to the checkpoint proteins cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) and programmed cell death protein 1 (PD‐1) are becoming widely used in cancer treatment. However, a lack of understanding of the patient response to treatment limits accurate identification of potential responders to immunotherapy.

Methods

In this study, we assessed the expression of PD‐1 and CTLA‐4 on 19 leucocyte populations in the peripheral blood of 74 cancer patients. A reference data set for PD‐1 and CTLA‐4 was established for 40 healthy volunteers to determine the normal expression patterns for these checkpoint proteins.

Results

Unsupervised hierarchical clustering found four immune profiles shared across the solid tumor types, while chronic lymphocytic leukaemia patients had an immune profile largely unique to them. Furthermore, we measured these leucocyte populations on an additional cohort of 16 cancer patients receiving the PD‐1 inhibitor pembrolizumab in order to identify differences between responders and non‐responders, as well as compared to healthy volunteers (n = 20). We observed that cancer patients had pre‐treatment PD‐1 and CTLA‐4 expression on their leucocyte populations at different levels compared to healthy volunteers and identified two leucocyte populations positive for CTLA‐4 that had not been previously described. We found higher levels of PD‐1+ CD3+ CD4− CD8− cells in patients with progressive disease and have identified it as a potential biomarker of response, as well as identifying other significant differences in phenotypes between responders and non‐responders.

Conclusion

These results are suggestive that categorisation of patients based on immune profiles may differentiate responders from non‐responders to immunotherapy for solid tumors.
Kinetics of peripheral blood neutrophils in severe coronavirus disease 2019
Authors: Metzemaekers Mieke , Cambier Seppe , Blanter Marfa , Vandooren Jennifer , de Carvalho Ana Carolina , Malengier‐Devlies Bert , Vanderbeke Lore , Jacobs Cato , Coenen Sofie , Martens Erik , Pörtner Noëmie , Vanbrabant Lotte , Van Mol Pierre , Van Herck Yannick , Van Aerde Nathalie , Hermans Greet , Gunst Jan , Borin Alexandre , Toledo N Pereira Bruna , dos SP Gomes Arilson Bernardo , Primon Muraro Stéfanie , Fabiano de Souza Gabriela , S Farias Alessandro , Proenca‐Modena José Luiz , R Vinolo Marco Aurélio ,   the CONTAGIOUS Consortium, Marques Pedro Elias , Wouters Carine , Wauters Els , Struyf Sofie , Matthys Patrick , Opdenakker Ghislain , Marques Rafael Elias , Wauters Joost , Gouwy Mieke , Proost Paul
Published: April 2021

Objectives

Emerging evidence of dysregulation of the myeloid cell compartment urges investigations on neutrophil characteristics in coronavirus disease 2019 (COVID‐19). We isolated neutrophils from the blood of COVID‐19 patients receiving general ward care and from patients hospitalised at intensive care units (ICUs) to explore the kinetics of circulating neutrophils and factors important for neutrophil migration and activation.

Methods

Multicolour flow cytometry was exploited for the analysis of neutrophil differentiation and activation markers. Multiplex and ELISA technologies were used for the quantification of protease, protease inhibitor, chemokine and cytokine concentrations in plasma. Neutrophil polarisation responses were evaluated microscopically. Gelatinolytic and metalloproteinase activity in plasma was determined using a fluorogenic substrate. Co‐culturing healthy donor neutrophils with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) allowed us to investigate viral replication in neutrophils.

Results

Upon ICU admission, patients displayed high plasma concentrations of granulocyte–colony‐stimulating factor (G‐CSF) and the chemokine CXCL8, accompanied by emergency myelopoiesis as illustrated by high levels of circulating CD10−, immature neutrophils with reduced CXCR2 and C5aR expression. Neutrophil elastase and non‐metalloproteinase‐derived gelatinolytic activity were increased in plasma from ICU patients. Significantly higher levels of circulating tissue inhibitor of metalloproteinase 1 (TIMP‐1) in patients at ICU admission yielded decreased total MMP proteolytic activity in blood. COVID‐19 neutrophils were hyper‐responsive to CXCL8 and CXCL12 in shape change assays. Finally, SARS‐CoV‐2 failed to replicate inside human neutrophils.

Conclusion

Our study provides detailed insights into the kinetics of neutrophil phenotype and function in severe COVID‐19 patients, and supports the concept of an increased neutrophil activation state in the circulation.
Detection of CAR‐T19 cells in peripheral blood and cerebrospinal fluid: An assay applicable to routine diagnostic laboratories
Authors: Johansson Ulrika , Gallagher Kathleen , Burgoyne Victoria , Maus Marcela V. , Casey Keagan S. , Brini Gabrielle G. , Frigault Matthew J. , Yam Jennifer Y. , Chavda Nikesh , Besley Caroline , Lugthart Sanne
Published: April 2021

Background

Chimeric antigen receptor‐modified T‐cells targeting CD19 (CAR‐T19) are licensed for treating relapsed/refractory diffuse large B‐cell lymphoma and B‐acute lymphoblastic leukemia. Predicting treatment responses and toxicity (e.g., cytokine release syndrome and neurotoxicity) remains a big challenge. CAR‐T19 monitoring could increase our understanding of treatment responses and be of relevance to patient management. A robust method for accurate CAR‐T19 detection is therefore extremely desirable.

Methods

An assay that uses fluorochrome‐conjugated human recombinant soluble CD19 was tested against two commercially available CAR‐T19 therapies and a CAR‐T19 cell line developed in‐house. Precision, concordance, and analyte stability were tested using peripheral blood obtained from CAR‐T19‐treated patients and controls.

Results

The assay showed good accuracy, and had a limit of blank for whole blood samples of 0.13%. Reproducibility and inter‐operator concordance were satisfactory (CVs <15%). The assay distinguished CAR‐T19 from reactive T‐cells in cerebrospinal fluid (CSF) from patients with suspected immune effector cell‐associated neurotoxicity syndrome (ICANS), and was adapted to study memory T‐cell compartments in treated patients.

Conclusion

The assay enabled routine monitoring of CAR‐T19 in blood and CSF samples. Despite profound cytopenia in many lymphoma patients, results were obtained regularly from only 4 ml of blood. The assay can be adapted easily to characterize the memory and exhaustion status of CAR‐T19 and native T‐cells. Importantly, it does not rely on CAR construct specificity; thus, it can be used to detect any CD19‐targeted CAR cell. Finally, our validation process can serve as a blueprint for other fluorochrome proteins used to detect CAR cells.
Stereo‐Defined Ferrocenyl Glycol Nucleic Acid (Fc‐GNA) Constituents: Synthesis, Electrochemistry, Mechanism of Formation, and Anticancer Activity Studies
Authors: Skiba Joanna , Kowalczyk Aleksandra , Trzybiński Damian , Woźniak Krzysztof , Vrček Valerije , Gapińska Magdalena , Kowalski Konrad
Published: April 2021

In this paper, we report the Yb(OTf)3‐mediated etherification reaction that allowed obtaining R,R and S,R isomers of ferrocenyl glycol nucleic acid (Fc‐GNA) nucleosides from their corresponding stereo‐defined (S,R) precursor. The R,R absolute configuration of the chiral carbon atoms in one of the Fc‐nucleoside isomers was assigned by single‐crystal X‐ray diffraction. Density functional theory calculations showed that the stereochemical outcome of the reaction can be explained by an exo attack of ethylene glycol on the pro‐R‐ or pro‐S‐configured α‐ferrocenyl carbenium ion intermediate. The R,R isomer was transformed into the corresponding nucleotide diethyl ester which is, to the best of our knowledge, the first Fc‐GNA nucleotide ever reported. The obtained compounds feature reversible one‐electron oxidation of the ferrocenyl portion of their molecular structures. Anticancer activity studies showed that the (S,R) nucleoside was the most active against HeLa and Ishikawa cancer cells, while it did not show any activity against nontumorigenic L929 cells. The compound induced apoptosis in HeLa cells at IC50=66.0 μM concentration upon 72 h of treatment.
Ruddlesden–Popper Oxide (La0.6Sr0.4)2(Co,Fe)O4 with Exsolved CoFe Nanoparticles for a Solid Oxide Fuel Cell Anode Catalyst
Authors: Park Seongmin , Han Hyunsu , Choi Junil , Lee Seungjun , Park Minseon , Kim Won Bae
Published: April 2021

Herein, a new ceramic‐based catalyst with exsolved CoFe nanoparticles anchored on the support of a Ruddlesden–Popper structure (La1.2Sr0.8Co0.12Fe0.88O4) is synthesized, and various physicochemical analyses are conducted to investigate its applicability as an anode of solid oxide fuel cells (SOFCs). The catalyst is fabricated by reducing La0.6Sr0.4Co0.2Fe0.8O3 in an atmosphere of a 10% H2/N2 gas mixture at 800 °C, whose condition is much milder than the typical synthesis method of Ruddlesden–Popper materials. The single cell exhibits a good electrochemical performance with a maximum power density value of 729 mW cm−2 at a temperature of 800 °C. The presence of oxygen vacancies and the low synthesis temperature should be responsible for its good catalytic activity. Moreover, exsovled CoFe nanoparticles could provide additional chemisorption and activation sites for the H2 electrooxidation reaction, leading to the improved electrochemical performance. Therefore, this Ruddlesden–Popper material with exsolved CoFe nanoparticles could be a potential anode material for SOFCs.
Seepage mechanisms and permeability differences between loess and paleosols in the critical zone of the Loess Plateau
Authors: Hou Kai , Qian Hui , Zhang Yuting , Wang Haike
Published: April 2021

The soil in the Loess Plateau has special permeability characteristics due to the alternating distribution of loess and paleosol layers. Using an analysis of the physical properties, microstructure and thermogravimetric analysis of loess and paleosol, this paper examines strata seepage mechanisms in the loess tableland area and considers the applicability of a hydraulic conductivity empirical formula. The analysis shows that hydraulic conductivity attenuation with depth can be represented by a negative exponential model, while hydraulic conductivity values are not normally distributed. The best‐fitting models of hydraulic conductivity in the horizontal (KH) and vertical (KV) directions are Gaussian models, and both have strong spatial correlations. This study of the difference in permeability between loess and paleosol found that the depositional environment was the dominant causal factor, making the average hydraulic conductivity of most loess layers greater than that of the underlying paleosol layers. Different microstructures between loess and paleosol also confirmed the microscopic explanation in permeability anisotropy and their permeability difference. Thermogravimetric analysis determined temperature ranges for different types of water lost by heat, and then calculated ratios of bound water mass to liquid limit, with an average of 0.768. A modified formula suitable for loess was obtained by integrating the consistency index method and effective porosity ratio model into the hydraulic conductivity empirical formula. Compared with the results of laboratory tests and uncorrected formulas, the modified formula provides a good estimate of strata hydraulic conductivity. Accurate understandings of seepage mechanisms and permeability differences in the loess area are important, promoting ecological restoration and providing scientific guidance for the sustainable development of the Loess Plateau.
Electrocautery‐induced molten metal particle generation from total joint replacements: Morphology and chemistry
Authors: Wiegand Michael J. , Kubacki Gregory W. , Gilbert Jeremy L.
Published: April 2021

Electrosurgical techniques are used during surgery to cauterize, and their damaging effects have primarily been documented in terms of tissue necrosis, charring, and localized heat accumulation. Metallic implants as well as the surgical blade can experience incidental electrosurgical current arcing that results in the generation and transfer of melted metallic particles. This work examines the composition, particle size distribution, and chemical state of the melted alloy surfaces and particles produced in vitro. Using scanning electron microscopy and energy dispersive spectroscopy, a flash‐melting particle generation phenomenon between source 304 SSL blades and polished cobalt‐chromium‐molybdenum (CoCrMo) and titanium‐6‐aluminum‐4‐vandaium (Ti6Al4V) surfaces was documented where 304 SSL mixed heterogeneously with the CoCrMo and Ti6Al4V ejecting “splatter” particles from the cautery site. The spherical micron‐sized particles were embedded with sub‐micron‐sized particles with 42% of the total sample population measuring between 0.25 and 0.35 μm in diameter. CoCrMo‐304 SSL particles were principally made of high concentrations of iron, oxygen, and nickel with embedded sub‐micron‐sized particles containing oxygen, chromium, and cobalt with lower concentrations of iron and molybdenum. Ti6Al4V‐304 SSL interactions resulted in similar micron‐sized particles made up of high concentrations of iron, nickel, and chromium with embedded sub‐micron‐sized particles containing titanium, oxygen, and small amounts of aluminum. X‐ray photoelectron spectroscopy of damaged CoCrMo surfaces confirmed the presence of chromium (VI) following dry electrocautery contact in coagulation mode. The structural effects of electrocautery‐induced damage are becoming visible in retrieval analysis, but the long‐term physiological implications during the lifetime of the implant from this damage mode have yet to be defined.
The JOBS Act, underwriting costs, and voluntary disclosure
Authors: Yu Ji , Gao Lei , Rezaee Zabihollah , Han Shipeng
Published: April 2021

The 2012 Jumpstart Our Business Startups Act (JOBS Act) was enacted to enable emerging growth companies (EGCs) to raise capital without facing vigorous regulations. We investigate whether underwriting fees and indirect costs of initial public offerings (IPOs) change after the passage of the JOBS Act. Unlike recent studies that investigate the impact of post‐IPO voluntary disclosure, we investigate the role of the pre‐IPO voluntary disclosure of use‐of‐proceeds for EGCs. Using a sample of 492 IPOs from April 5, 2009 to April 5, 2015, we find that after the adoption of the JOBS Act, IPOs’ indirect costs increase while the underwriting commissions decrease and that the effects of the JOBS Act on IPOs’ indirect costs and underwriting commissions are weaker for firms that have a high level of voluntary disclosure of use‐of‐proceeds. Results suggest that the optimal level of voluntary disclosures within the mandatory framework benefit EGCs and their investors and have policy, practice, and educational implications.
The prostate of the bat Artibeus lituratus: Seasonal variations, abiotic regulation, and hormonal control
Authors: Albernaz Edna S. S. , Santiago Cornélio S. , Guerra Luiz H. A. , Santos Fernanda C. A. , Góes Rejane M. , Morielle‐Versute Eliana , Taboga Sebastião R. , Souza Carolina C. , Beguelini Mateus R.
Published: April 2021

The prostate is an important gland that contributes to the male reproductive process, producing secretions that are essential for maintaining ideal conditions for the survival of sperm. Studies indicate a wide variation in the occurrence, morphology, and physiology of this gland in mammals, especially in bats, with this variation being related not only to the number of regions and their degree of compaction/lobulation but also to fluctuations in their functioning throughout the year. Thus, the aim of this study was to evaluate the annual morphological and physiological variations of the male prostate of Artibeus lituratus and analyze their responses to annual abiotic variations and hormonal control. Sixty sexually adult males of A. lituratus were analyzed in this study, with five specimens collected monthly. Blood samples were submitted to serum hormone measurements and the prostates were morphologically, morphometrically, and immunohistochemically analyzed. The results indicated that the two prostatic regions (ventral and dorsal) of A. lituratus had different morphology, as well as different physiology and regulation. Annual fluctuations in abiotic factors seemed to influence the dorsal region more than the ventral region. Conversely, variations on testicular factors, such as testosterone and estradiol, influenced the ventral region more than the dorsal region. Despite these differences, both prostatic regions were strongly synchronized to the main reproductive peak of the species in September. The holocrine pattern of the ventral prostate was not directly affected by abiotic factors or by factors released by the testes.
Detecting precipitation trend using a multiscale approach based on quantile regression over a Mediterranean area
Authors: Treppiedi D. , Cipolla G. , Francipane A. , Noto L.V.
Published: April 2021

One of the most relevant and debated topics related to the effects of the climate change is whether intense rainfall events have become more frequent over the last decades. It is a crucial aspect, since an increase in the magnitude and frequency of occurrence of heavy rainfall events could result in a dramatic growth of floods and, in turn, human lives losses and economic damages. Because of its central position in the Mediterranean area, Sicily has been often screened with the aim to capture some trends in precipitation, potentially related to climate change. While Mann‐Kendall test has been largely used for the rainfall trend detection, in this work a different procedure is considered. Precipitation trends are here investigated by processing the whole rainfall time‐series, provided by the regional agency SIAS at a 10‐min resolution, through the quantile regression method by aggregating precipitation across a wide spectrum of durations and considering different quantiles. Results show that many rain gauges are characterized by an increasing trend in sub‐hourly precipitation intensity, especially at the highest quantiles, thus suggesting that, from 2002 to 2019, sub‐hourly events have become more intense in most of the island. Moreover, by analysing some spatial patterns, it has been revealed that the south and the east of Sicily are more interested in significant increasing rainfall trends, especially at the 10‐min duration. Finally, the comparison between the two procedures revealed a stronger reliability of the quantile regression in the trend analysis detection, mainly due to the possibility of investigating the temporal variation of the tails of precipitation distribution.
ACL injury prevention: Where have we come from and where are we going?
Authors: Arundale Amelia J. H. , Silvers‐Granelli Holly J. , Myklebust Grethe
Published: April 2021

Anterior cruciate ligament (ACL) injuries are one of the most common and severe knee injuries across sports. As such, ACL injury prevention has been a focus of research and sports medicine practice for the past three‐plus decades. Examining the current research and identifying both clinical strategies and research gaps, the aim of this review is to empower clinicians and researchers with knowledge of where the ACL injury prevention literature is currently and where it is going in the future. This paper examines the mechanism of ACL injury prevention, screening, implementation, compliance, adherence, coronavirus, and areas of future research. Clinical significance: The time lag between research and practical implementation in general healthcare settings can be as long as 17 years; however, athletes playing sports today are unable to wait that long. With effective programs already established, implementation and adherence to these programs is essential. Strategies such as coaching education, increasing awareness of free programs, identifying barriers, and overcoming implementation obstacles through creative collaboration are just a few ways that could help improve both ACL injury prevention implementation and adherence.