bluuebunny/crossref_metadata_2025 huggingface dataset:
As-Continuous-As-Possible Extrusion-Based Fabrication of Surface Models
Authors: Zhong Fanchao , Xu Yonglai , Zhao Haisen , Lu Lin
Published: December 2022

In this study, we propose a computational framework for optimizing the continuity of the toolpath in fabricating surface models on an extrusion-based 3D printer. Toolpath continuity is a critical issue that influences both the quality and the efficiency of extrusion-based fabrication. Transfer moves lead to rough and bumpy surfaces, where this phenomenon worsens for materials with large viscosity, like clay. The effects of continuity on the surface models are even more severe in terms of the quality of the surface and the stability of the model. We introduce a criterion called the
one–path patch
(OPP) to represent a patch on the surface of the shell that can be traversed along one path by considering the constraints on fabrication. We study the properties of the OPPs and their merging operations to propose a bottom-up OPP merging procedure to decompose the given shell surface into a minimal number of OPPs, and to generate the “as-continuous-as-possible” (ACAP) toolpath. Furthermore, we augment the path planning algorithm with a curved-layer printing scheme that reduces staircase defects and improves the continuity of the toolpath by connecting multiple segments. We evaluated the ACAP algorithm on ceramic and thermoplastic materials, and the results showed that it improves the fabrication of surface models in terms of both efficiency and surface quality.
Optimization of Sodium Bis(oxalato)borate (NaBOB) in Triethyl Phosphate (TEP) by Electrolyte Additives
Authors: Welch Jonas , Mogensen Ronnie , van Ekeren Wessel , Eriksson Henrik , J. Naylor Andrew , Younesi Reza
Published: December 2022

The electrolyte solution of NaBOB in TEP is a low-cost, fluorine-free and flame-retardant electrolyte with ionic conductivity of 5 mS cm−1, recently discovered to show promises for sodium-ion batteries. Here, the abilities of this electrolyte to effectively form a solid electrolyte interphase (SEI) was augmented with five common electrolyte additives of fluoroethylene carbonate (FEC), vinylene carbonate (VC), prop-1-ene-1,3-sultone (PES), 1,3,2-dioxathiolane 2,2-dioxide (DTD) and tris(trimethylsilyl)phosphite (TTSPi). Full-cells with electrodes of Prussian white and hard carbon and industrial mass loadings of >10 mg cm−2 and electrolyte volumes of <5 ml g−1 were used. X-ray photoelectron spectroscopy (XPS) and pressure analysis were also deployed to investigate parasitic reactions. Cells using electrolyte additives of PES, PES+DTD and PES+TTSPi (3 wt%) showed significantly increased performance in terms of capacity retention and initial Coulombic efficiency as compared to additive-free NaBOB–TEP. The best cell retained 80% discharge capacity (89 mAh g−1) after 450 cycles, which is also significantly better than reference cells using 1 M NaPF6 in EC:DEC electrolyte. This study sheds light on opportunities to optimize the NaBOB–TEP electrolyte for full-cell sodium-ion batteries in order to move from low-mass-loading lab-scale electrodes to high mass loading electrodes aiming for commercialization of sodium-ion batteries.
Enhancement of the Electrode Activity of the Vanadium Redox Flow Battery by Higher Crystallinity of Carbon Matrix Using Seamless and Consecutive-porous Carbon Materials
Authors: Ishitobi Hirokazu , Doki Honoka , Shiraishi Soshi , Tsukada Hidehiko , Hatakeyama Yoshikiyo , Obata Ryusuke , Nakagawa Nobuyoshi
Published: December 2022

The crystallinity of the carbon matrix and the surface oxygen groups of the electrode materials for vanadium redox flow batteries (VRFBs) are considered to be important for enhancing the activity of the electrochemical reactions. We applied seamless carbon materials with consecutive macropores as a novel electrode material for the VRFB. We heat-treated the seamless carbon materials from 1200 °C to 2200 °C in an Ar atmosphere, then oxidized them in air at the appropriate temperature. Although the number of surface oxygen groups, which are believed to be the active sites, decreased at the higher crystallinity of the carbon matrix, the electrode activity was simply increased at the higher crystallinity of the carbon matrix. This result suggests the increased π electron density enhanced the ion exchange between the active materials and protons at the active sites due to the higher pK
a value. Next, we examined the necessity of the surface oxygen groups for the material by the thermal decomposition in the Ar atmosphere. The current density significantly decreased after the thermal decomposition of the surface oxygen groups. Hence, the surface oxygen groups are believed to be essential for the electrochemical reactions.
Simulation Result of InGaN for Solar Cell Application
Authors: Wu Jin , Wen Tian
Published: December 2022

InGaN can reach all values of bandgap from 3.42 to 0.7eV, which covers almost the entire solar spectrum. This study is to understand the influence of each parameter of the solar cell for an improved optimization of performance. The yield obtained for a reference cell is 12.2 % for optimal values of doping of the layers. For generation and recombination, performance of the cell varies with these settings. III nitrides have a high absorption coefficient, a very thin layers of material are sufficient to absorb most of the light.
Characteristics, Management, and Outcomes of Community-Acquired Pneumonia Due to Human Rhinovirus—A Retrospective Study
Authors: Bahabri Ibrahim , Abdulaal Abdulaziz , Alanazi Thamer , Alenazy Sultan , Alrumih Yasser , Alqahtani Rakan , Bosaeed Mohammad , Al-Dorzi Hasan M.
Published: December 2022

Introduction. Human rhinovirus (HRV) can lead to a variety of respiratory illnesses; it is also an uncommon cause of community-acquired pneumonia (CAP). We described the characteristics and outcomes of patients hospitalized for CAP due to HRV. Methods. We retrospectively studied consecutive adult patients admitted to King Abdulaziz Medical City-Riyadh with CAP due to HRV between 2016 and 2019. The diagnosis was made by respiratory multiplex PCR within 48 hours of hospitalization. We compared patients requiring ICU admission to those who did not. Results. One-hundred-and-six patients were studied (peak hospitalization between November and January, median age 71.5 years, hypertension 59%, diabetes 50%, and chronic respiratory disease 44.3%); 16 (15.1%) patients required ICU admission. The median pneumonia severity index score (PSI) was 107, with no significant difference between ICU and nonICU patients. ICU patients had a higher prevalence of tachypnea (62.5% vs. 26.7%,

p
=
0.005

), hemoptysis (12.5% vs 0%,

p
=
0.001

), and lymphopenia (71.4% vs 26.3%,

p
=
0.01

). Chest X-ray on presentation showed bilateral infiltrates in 47/101 (46.5%) patients and unilateral infiltrates in 26/101 (25.7%) patients. Systemic corticosteroids were used in 54.7% of patients (the median initial dose was 120 mg of prednisone equivalent and was higher in nonICU patients). Most (69.2%) ICU patients received mechanical ventilation (median duration of 8 days). Bacterial coinfection (6.6%) and superinfection (3.8%) were rare. The overall hospital mortality was 9.4% (higher for ICU patients: 37.5% vs. 4.4%,

p
<
0.001

). Conclusions. Most patients with CAP due to HRV were elderly and had significant comorbidities. ICU admission was required in almost one in six patients and was associated with higher mortality.
On Random Dynamical Systems Generated by White Noise Time Change of Deterministic Dynamical Systems
Authors: Hmissi Mohamed , Mokchaha Farida
Published: December 2022

In this paper, we apply the random time change by the real white noise to deterministic dynamical systems. We prove that the obtained random dynamical systems are solutions of some stochastic differential equations whenever the deterministic dynamical systems are solutions of ordinary differential equations.
Design and Analysis of Ultralow Voltage Graphene on the Silicon Rich Nitride Tunable Ring Resonator-Based Add-Drop Filter for DWDM Systems
Authors: Rukerandanga Filston , Musyoki Stephen , Ataro Edwin O.
Published: December 2022

We propose and simulate a third-order 3D electro-optically highly tunable compact add-drop filter based on nonlinear microring resonators. The used tuning mechanism relies on enhanced Kerr nonlinearity in a graphene layer integrated on top of a two-photonabsorption-free and low loss silicon-rich nitride core material at telecommunication wavelengths. An ultrahigh tuning efficiency (150 pm/V) over a tuning range of 1.3 nm, ensuring ultralow voltage consumption, was achieved in this work. We used titanium oxide and silicon oxide as the upper-cladding and under-cladding materials, respectively, around the silicon-rich nitride core material, to come up with a polarization-insensitive, and the thermally resilient third-orderadd-drop optical filter in the L band (1565 nm–1625 nm) with a full wave at a half maximum bandwidth of 50 GHz (linewidth of 0.4 nm) around 1570 nm, a high-free spectral range of 18.5 nm, a quality factor of 2580, an extinction ratio of 60 dB, a finesse of 19, and a thermal stability of 0.3 pm/K. A three-dimensional multiphysics approach was used to simulate the propagation of transverse electric and transverse magnetic polarized waves through the filter, combining the electromagnetic features with thermo-optic and stress-optical effects. The contribution of this work to the existing literature is that the designed filter proposes a new and highly tunable material system compatible with the complementary metal-oxide-semiconductor fabrication technology while combining high tunability, polarization insensitivity, and high thermal stability features for an ultracompact and energy-efficienton-chip integrated photonic tunable filter for dense wavelength division multiplexing systems in the less occupied L band.
Feasibility and Safety of Sodium Glucose Cotransporter-2 Inhibitors in Adults with Heart Failure after the Fontan Procedure
Authors: Muneuchi Jun , Sugitani Yuichiro , Kobayashi Masaru , Ezaki Hiroki , Yamada Hiromu , Watanabe Mamie
Published: December 2022

Sodium glucose cotransporter-2 (SGLT-2) inhibitors have been widespread in patients with heart failure; however, there is little information regarding its feasibility and safety among patients after the Fontan procedure. We presented five adults after the Fontan procedure who were treated with SGLT-2 inhibitors. All patients reduced oedema and/or pleural effusion despite other conjunct medications were ineffective. Although we did not measure the urine volume in all patients, all patients themselves reported an increase in urinary output after the administration of a SGLT-2 inhibitor. In addition, administration of a SGLT-2 inhibitor resulted in weight loss (4/5), an increase in systemic oxygen saturation (4/5), an increase in serum albumin level (4/5), an increase in estimated glomerular filtration ratio (4/5), and a decrease in plasma brain natriuretic peptide level (4/5). Our case series supported the feasibility and safety of SGLT-2 inhibitors in patients with Fontan circulatory failure, although the exact changes in urinary output were unknown in all patients. Further investigation will be required to explore a diuretic effect by SGLT-2 in patients after the Fontan procedure.
Coincidence Fixed-Point Theorems for
p
-Hybrid Contraction Mappings in

G

b

-Metric Space with Application
Authors: Wangwe Lucas
Published: December 2022

By combining the notions of

G

-metric space and

b

-metric space, in this paper, we present coincidence fixed-point theorems for

p

-hybrid mappings in

G

b

-metric spaces. An example is given to demonstrate the novelty of our main results. Henceforth, the illustrative applications are given by using nonlinear fractional differential equations.
Social networks and tolerance differences associated to grouping patterns in Ateles geoffroyi
Authors: González-Ruiz Mariana , Cervantes Fernando A. , Mondragón-Ceballos Ricardo
Published: December 2022

Each species displays a certain level of social tolerance. However, within a species, individuals show differences in their ability to accept the presence of conspecifics around resources of mutual interest. Social structure research allows studying how social relationships arise within a group, how they survive or end through time, and how they are influenced by various factors such group composition, mating system, and habitat quality variations. Furthermore, it can help elucidate the tolerance of individuals to other group members and how changes in it may lead to changes in social stability. Social Network Analysis (SNA) is a tool that allows the assessment of social dynamics and interactions. Our goal was to evaluate and compare social tolerance in captive spider monkeys (Ateles geoffroyi) by examining social networks formed in social groups that varied in size and composition. We compared social networks of captive groups varying in sex ratio, group size, and age ratio. Results showed relationship between networks with similar size and composition. Smaller groups showed greater social distancing, while larger ones displayed shorter inter-individual distances and more affiliation. Agonism was infrequent in unisexual groups compared to groups formed by both sexes. Finally, groups with more males showed greater social distancing and greater agonism. Overall, largest groups (five members or more) and similar sex ratio (or unisexual) are better connected. Largest groups showed higher proximity levels and a more tolerance to conspecifics than small groups.
Revisiting Wansbrough’s Perspective on the Qurʾān’s Synoptic Problem
Authors: Moqbel Tareq
Published: December 2022

The occurrence of variant versions of the same story is not uncommon in the Qurʾān. In response to this phenomenon, different approaches have been developed; one of which was Wansbrough’s variant traditions hypothesis. The hypothesis, which emerged mainly from an analysis of three accounts of the prophet Shuʿayb’s story in the Qurʾān, posits that the different tellings of the same story existed as independent pericopes that later found their way into the text of the Qurʾān, a claim that has many implications on the authorship and composition of the Qurʾān. Consequently, the reactions to this hypothesis were varied. In this paper, I present one of the critiques to the hypothesis, that of Stewart. Then, I employ elements of textual criticism to provide further ways for viewing the variant traditions. I do this by drawing attention to empirical evidence from the Near East, pre-Islamic poetry, orality theory, and to some of the internal characteristics of the Qurʾān. The general conclusion is neither surprising nor new: Wansbrough’s findings regarding the genealogy of the variant traditions and the authorship of the Qurʾān are far from self-evident.
2. Let’s Go Shopping
Authors: Gutiérrez Fanny , Rodríguez Yael
Published: December 2022

“Let’s Go Shopping” is a landscape of investigation about economic and financial education framed by the sociocritical perspective of mathematical modelling. The landscape developed as a result of discussions among students from a school in Bogotá about high-interest charges and loans. Our aim was to identify possibilities and challenges in the use of a sociocritical

perspective on mathematical modelling when promoting citizenship education. To do this, we addressed the discussions by the students and considered students’ intentions, backgrounds, and foregrounds. The landscape included investigations of families’ economic conditions, as the students related the mathematics classroom activities to their families’ financial issues.
3. Media and Racism
Authors: de Britto Reginaldo Ramos
Published: December 2022

In this paper, I address the theme of racism in the mathematics classroom in order to investigate the invisibility of black people in printed media. To do this, I describe a pedagogical strategy called the Social Research Group (SRG), which largely originates from critical mathematics education. SRGs are research groups formed by students in basic education who develop thematic investigations. In this text, we describe how the theme of racism was problematised through one of the landscapes of investigation, built on the theme of the visibility of black characters in national magazines. This scenario, in addition to enabling reflection on an important topic for Brazilian society—racial democracy—served to promote the idea that mathematics not only colonises various social practices, but can also be an instrument that helps us to reveal social asymmetries.
5. Mathematics Embedded in Community-Based Practices
Authors: Bose Arindam
Published: December 2022

Low-income settlements with diverse income-generating work practices dispersed among households create opportunities and affordances for learning, which have mathematical elements embedded in them. Drawing from the community’s rich knowledge resource (funds of knowledge), children from the neighbourhood learn to assimilate knowledge, competence, and skills. Out-of-school mathematical knowledge equips them to handle complex situations calling for quick decision-making and optimising resources and profits. Deals are negotiated following several variables, and cases of unjust wages and payments are aplenty. This chapter argues that such backdrops could form landscapes of investigation, and that the handling of or limited access to diverse goods—as well as the optimising of resources and decision-making processes—create different possibilities for not just dealing with mathematical knowledge but also questioning unfair work deals and examining social injustice. Such landscapes of investigation provide direction beyond the exercise paradigm,

towards an enabling pattern of critical communication.
15. The Investigative Approach to Talking about Inclusion in Mathematics Teacher Education
Authors: Dias Barros Denner
Published: December 2022

Looking at the range of diversity in the classroom is a necessary task for the teacher who seeks to teach from an inclusive perspective. More and more educational legislation has been authorised so that all students can have access to quality education. The use of landscapes of investigation in mathematics teacher education could become a practice that helps prospective teachers to reflect on future practices by taking into consideration the diversity of school contexts. In this chapter, reflections are made on the practices of two research projects, one for a doctorate and another for a Master’s degree. Working with investigative projects allowed prospective teachers to think about practices that take into account the particularities of this diversity. Furthermore, the dialogic perspective is highlighted as being essential in this process, as well as the ideas and visions of the prospective teachers invited

to participate in their own professional education. It is hoped that this chapter can inspire prospective teachers to develop critical activities that allow for the participation of all students.
Measurement of effective penetration depth of line laser into wheat flour in Raman hyperspectral imaging system
Authors: Wang Xiaobin
Published: December 2022

The penetration depth of the same light source to different samples is determined by the physical properties of the samples, and the determination of the penetration depth is the basis for the effective detection of the samples using spectral technology. This paper aimed to determine
the effective penetration depth of line laser into wheat flour with different gluten in Raman hyperspectral imaging system. Double-layer samples were prepared using L-ascorbic acid (LAA) and wheat flour with different gluten, and Raman hyperspectral images of LAA, wheat flour with different
gluten, and double-layer samples were collected, respectively. The single-band image corresponding to the Raman characteristic peak of LAA was selected from the doublelayer sample image, and the threshold segmentation method was used to create a detection image to identify LAA pixels. The
penetration rate of the line laser into different thickness of wheat flour layer was calculated according to the identification results. The results showed that the Raman characteristic peak of LAA was located at 1658 cm−1, which had the highest intensity and did not coincide
with the Raman peak of wheat flour with different gluten. The maximum penetration depth of the line laser into the wheat flour layer was 4 mm in the average Raman spectrum of the double-layer sample. The penetration rate of the line laser into the 2 mm wheat flour layer in the detection image
of the double-layer sample was more than 99%, and this thickness was regarded as the effective penetration depth. The accuracy and reliability of 2 mm effective penetration depth were verified by tests on wheat flour of the same gluten and different brands. The results laid a foundation for
the subsequent effective identification of additives in wheat flour.
The effect of the temperature of heat treatment process and the concentration and duration of acid leaching on the size and crystallinity of nano-silica powders formed by the dissociation of natural diatom frustule
Authors: Ülker Sevkan , Güden Mustafa
Published: December 2022

The present study focused on the processing of nano-silica powders in varying sizes and crystallinities through heat treatment (900–1200 °C), hydrofluoric acid leaching (1–7 N), and ball milling (1 h, 500 rpm) of natural diatom frustules. The starting natural frustules
were determined to be composed of amorphous silica (88%) and quartz. The partially ordered crystalline low-quartz and or precursor to low-cristobalite started to form at ~900 °C. As the heat treatment temperature increased, the crystallinity of the frustules increased from 9.3% at 25 °C
to 46% at 1200 °C. Applying a ball milling reduced the mean particle sizes of the as-received and heat-treated frustules from 15.6–13.7 μm to 7.2–6.7 μm, respectively. Acid leaching of the as-received and heat-treated frustules resulted in a further increase
in the crystallinity. Furthermore, a ball milling applied after an acid leaching was very effective in reducing the particle size of the as-received and heat-treated frustules. The mean particle size of the acid-leached frustules decreased to 774–547 nm with a crystallinity varying between
12 and 48% after ball milling. A partially dissolved amorphous phase was observed in between crystalline silica grains after acid leaching, which resulted in a rapid fracture/separation of the frustules in ball milling.
Antibacterial surface coatings of fracture fixation implants
Authors: Yang Qiming , Chen Long
Published: December 2022

Infection after internal fixation of fractures is one of its most common complications, which can lead to delayed fracture healing, non-union of fractures and even bone infection and osteomyelitis, causing a heavy burden to patients’ families and society. In recent years, based
on the concept of topical antimicrobial agents, scholars have proposed the method of antimicrobial coating on the material surfaces for internal fixation to treat and prevent postoperative infections associated with internal fixation. The antimicrobial mechanisms of surface coatings can be
broadly classified into 3 categories, including antiadhesive coatings, silver (Ag) ion coatings, and antibiotic coatings. In this study, their advantages and disadvantages are described in detail to provide a novel insight and theoretical basis for the improvement of antimicrobial coatings
in the future.
Molecular simulation of the adsorption of the hydration inhibitor N1,N1’-(ethane-1,2-diethyl)bis(N1-(2-aminoethyl)ethane-1,2-diamine onto montmorillonite
Authors: Yuan Shi , Zhao Xin , Cheng Rongchao , Qu Yuanzhi , Xue Jiawen , Li Yiang , Sun Jinsheng , Xu Jiafang
Published: December 2022

Clay-swelling inhibitors are often used to prevent the hydration of clay minerals, which can reduce the risk of wellbore instability and reservoir damage. The molecular behaviour of clay-swelling inhibitors at the montmorillonite–water interface is crucial for revealing their inhibition mechanisms and for evaluating and designing inhibitor molecules. N1,N1'-(ethane-1,2-diyl)bis(N1-(2-aminoethyl)ethane-1,2-diamine) (NETS), a low-molecular-weight clay-swelling inhibitor, is used widely to prevent clay swelling. Herein, the adsorption mechanism of NETS on the surface of montmorillonite (Mnt) was investigated using molecular dynamics (MD) simulations. In particular, the effects of molecular conformation and temperature on adsorption ability were investigated. The results show that the adsorption ability of NETS on the Mnt surface was affected significantly by the molecular conformation. Specifically, the dihedral angle of NETS adsorbed on the surface of Mnt decreases by ~20° and tends to adsorb on the surface of Mnt in a plane state. In addition, the adsorption stability of NETS on the Mnt surface decreased with increasing temperature, as was found using MD simulations. Detailed analysis shows that increasing temperature can lead to more frequent conformational changes, which weaken the interaction between NETS and Mnt, thus reducing adsorption stability. These molecular insights into the interaction mechanism between NETS and Mnt are beneficial for the evaluation of inhibitory effects and for the selection and molecular design of new clay-swelling inhibitors for use in drilling fluids.
The histone methyltransferase MLL1/KMT2A in monocytes drives coronavirus-associated coagulopathy and inflammation
Authors: Sharma Sriganesh B. , Melvin William J. , Audu Christopher O. , Bame Monica , Rhoads Nicole , Wu Weisheng , Kanthi Yogendra , Knight Jason S. , Adili Reheman , Holinstat Michael A. , Wakefield Thomas W. , Henke Peter K. , Moore Bethany B. , Gallagher Katherine A. , Obi Andrea T.
Published: December 2022

Coronavirus-associated coagulopathy (CAC) is a morbid and lethal sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CAC results from a perturbed balance between coagulation and fibrinolysis and occurs in conjunction with exaggerated activation of monocytes/macrophages (MO/Mφs), and the mechanisms that collectively govern this phenotype seen in CAC remain unclear. Here, using experimental models that use the murine betacoronavirus MHVA59, a well-established model of SARS-CoV-2 infection, we identify that the histone methyltransferase mixed lineage leukemia 1 (MLL1/KMT2A) is an important regulator of MO/Mφ expression of procoagulant and profibrinolytic factors such as tissue factor (F3; TF), urokinase (PLAU), and urokinase receptor (PLAUR) (herein, “coagulopathy-related factors”) in noninfected and infected cells. We show that MLL1 concurrently promotes the expression of the proinflammatory cytokines while suppressing the expression of interferon alfa (IFN-α), a well-known inducer of TF and PLAUR. Using in vitro models, we identify MLL1-dependent NF-κB/RelA–mediated transcription of these coagulation-related factors and identify a context-dependent, MLL1-independent role for RelA in the expression of these factors in vivo. As functional correlates for these findings, we demonstrate that the inflammatory, procoagulant, and profibrinolytic phenotypes seen in vivo after coronavirus infection were MLL1-dependent despite blunted Ifna induction in MO/Mφs. Finally, in an analysis of SARS-CoV-2 positive human samples, we identify differential upregulation of MLL1 and coagulopathy-related factor expression and activity in CD14+ MO/Mφs relative to noninfected and healthy controls. We also observed elevated plasma PLAU and TF activity in COVID-positive samples. Collectively, these findings highlight an important role for MO/Mφ MLL1 in promoting CAC and inflammation.
Marginal zone B cells are responsible for the production of alloantibodies following platelet transfusion in mice
Authors: Couvidou Adèle , Angénieux Catherine , Ruch Laurie , Mangin Pierre H. , Gachet Christian , Maître Blandine
Published: December 2022

Alloimmunization against platelets remains a potentially serious adverse transfusion event. Alloantibodies produced by the recipient, mainly directed against human leukocyte antigen class I donor antigens, can compromise the therapeutic efficacy of subsequent transfusions, and may lead to refractoriness. Because the mechanism of anti-HLA alloantibody formation is poorly understood, this study aimed to identify the cells involved in the platelet immune response by focusing on the spleen, the main organ that orchestrates this alloimmune response. In the spleen, transfused allogeneic platelets are located in the marginal zone and interact with marginal zone B (MZB) cells, a specialized B-cell population implicated in the capture and follicular delivery of blood-borne antigens. To study the involvement of MZB cells in alloantibody production, we used a murine model reproducing major histocompatibility complex incompatibility between a donor (H2b) and recipient (H2d) that occurs during platelet transfusion. Following weekly H2b platelet transfusions, recipient H2d mice produced anti-H2b immunoglobulin G, which induced a refractory state upon subsequent transfusions. Specific immunodepletion of MZB cells or their displacement from the marginal zone to the B-cell follicles by treatment with an S1P1 antagonist before each transfusion prevented significant alloantibody formation. Under these conditions, transfused platelets were still circulating after 24 hours, whereas they were rapidly removed from circulation in alloimmunized mice. The identification of MZB cells as key players in the platelet alloimmune response opens up new perspectives for minimizing platelet alloimmunization and avoiding the associated refractory state in frequently transfused patients.
Antibodies and bispecifics for multiple myeloma: effective effector therapy
Authors: Cipkar Christopher , Chen Christine , Trudel Suzanne
Published: December 2022

The therapeutic landscape in multiple myeloma (MM) has changed dramatically over the last 2 decades. With the introduction of novel immunotherapies, patients with MM can expect deeper responses, longer remissions, and improved overall survival. Since its approval by the US Food and Drug Administration in 2015, the monoclonal antibody specific for CD38, daratumumab, has been incorporated into both frontline and relapsed treatment regimens. Its role as a maintenance therapy is currently being explored. Subsequently, a variety of novel antibody therapeutics have evolved from the success of daratumumab, using similar concepts to target the malignant plasma cell clone. Noteworthy naked monoclonal antibodies include isatuximab, another agent directed against CD38, and elotuzumab, an agent directed against SLAM family member 7. Antibody-drug conjugates, complex molecules composed of an antibody tethered to a cytotoxic drug, target malignant cells and deliver a lethal payload. The first to market is belantamab mafodotin, which targets B-cell maturation antigen (BCMA) on malignant plasma cells and delivers a potent microtubule inhibitor, monomethyl auristatin F. Additionally, bispecific T-cell antibodies are in development that engage the immune system directly by simultaneously binding CD3 on T cells and a target epitope—such as BCMA, G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5)—on malignant cells. Currently, teclistamab, an anti-BCMA bispecific, is closest to approval for commercial use. In this review, we explore the evolving landscape of antibodies in the treatment of MM, including their role in frontline and relapse settings.
Hitting the brakes on accelerated and blast-phase myeloproliferative neoplasms: current and emerging concepts
Authors: Bewersdorf Jan Philipp , Rampal Raajit K.
Published: December 2022

The BCR-ABL-negative myeloproliferative neoplasms (MPNs) have a variable risk of progressing to accelerated- or blast-phase MPN (MPN-AP/MPN-BP), defined by the presence of 10% to 19% and more than or equal to 20% myeloid blasts in the peripheral blood or bone marrow, respectively. The molecular processes underlying the progression to MPN-AP/MPN-BP are becoming increasingly understood with the acquisition of additional mutations in epigenetic modifiers (eg, ASXL1, EZH2, TET2), TP53, the Ras pathway, or splicing factors (eg, SRSF2, U2AF1), having been described as important steps in this evolutionary process. At least partially driven by the enrichment of these high-risk molecular features, the prognosis of patients with MPN-BP remains inferior to other patients with acute myeloid leukemia, with a median overall survival of 3 to 6 months. Allogeneic hematopoietic cell transplantation remains the only potentially curative therapeutic modality, but only a minority of patients are eligible. In the absence of curative intent, therapeutic strategies or palliative treatment with hypomethylating agents as monotherapy or in combination with ruxolitinib or venetoclax can be considered. Several novel agents are in various stages of clinical development but are not available for routine use at this point, highlighting the need for ongoing research and the prioritization of clinical trial enrollment when feasible.
Transplant for TP53-mutated MDS and AML: because we can or because we should?
Authors: Versluis Jurjen , Lindsley R. Coleman
Published: December 2022

TP53 mutations impair the cellular response to genotoxic stress and drive intrinsic resistance to conventional cytotoxic therapies. Clinical outcomes in patients with TP53-mutated myeloid malignancies are poor and marked by high-risk clinical features, such as complex karyotype and prior exposure to leukemogenic therapies, and short survival due to a high risk of relapse after allogeneic transplantation. TP53 mutations are thus included as adverse markers in clinical prognostic models, including European LeukemiaNet recommendations and the Molecular International Prognostic Scoring System for myelodysplastic syndromes (MDS). Recent data indicate that the TP53 allelic state, co-occurring somatic mutations, and the position of the TP53 mutation within the clonal hierarchy define genetic heterogeneity among TP53-mutated MDS and acute myeloid leukemia that may influence clinical outcomes, thereby informing the selection of patients most suitable for transplantation. Further, novel therapeutic methods such as antibody-based agents (monoclonals or dual-affinity retargeting antibodies), cellular therapies (natural killer cells, chimeric antigen receptor T cells), or targeted agents (eprenetapopt) may offer opportunities to modify the approach to pretransplant conditioning or posttransplant maintenance and improve clinical outcomes.
The consultant's guide to smoldering multiple myeloma
Authors: Thorsteinsdottir Sigrun , Kristinsson Sigurdur Yngvi
Published: December 2022

Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM). The prevalence of SMM is 0.5% in persons over 40 years old; it is higher in men than women and increases with age. When SMM is diagnosed, a thorough diagnostic workup is necessary to exclude myeloma-defining events and stratify patients according to risk of progression to MM. While close monitoring for progression remains the best management for most patients with SMM, in this article, we discuss if treatment initiation before myeloma-defining events occur might be relevant in selected high-risk cases. Two randomized clinical trials have shown a clinical benefit of initiating treatment at the SMM stage, whereof 1 showed an overall survival benefit for those receiving treatment. We discuss various risk stratification models in SMM, important treatment trials, and ongoing trials. Finally, we present how to approach the clinical management of patients with SMM.
Organ function indications and potential improvements following curative therapy for sickle cell disease
Authors: Hulbert Monica L. , King Allison A. , Shenoy Shalini
Published: December 2022

Curative therapies for sickle cell disease include allogeneic hematopoietic stem cell transplantation (HSCT) and gene-modified autologous stem cell transplantation. HSCT has been used for 30 years with success measured by engraftment, symptom control, graft-vs-host disease (GVHD) risk, organ toxicity, and immune reconstitution. While human leukocyte antigen–matched sibling donor (MSD) transplants have excellent outcomes, alternate donor transplants (unrelated/haploidentical) are just beginning to overcome GVHD and engraftment hurdles to match MSD. Gene therapy, a newly developed treatment, is undergoing careful evaluation in many trials with varying approaches. The risk/benefit ratio to the patient in relation to outcomes, toxicities, and mortality risk drives eligibility for curative interventions. Consequently, eligibility criteria for MSD transplants can be less stringent, especially in the young. Posttransplant outcome analysis after the “cure” with respect to organ function recovery is essential. While established damage such as stroke is irreversible, transplant can help stabilize (pulmonary function), prevent further deterioration (stroke), improve (neurocognition), and protect unaffected organs. Tracking organ functions postintervention uniformly between clinical trials and for adequate duration is essential to answer safety and efficacy questions related to curative therapies. Age-appropriate application/outcome analyses of such therapies will be the ultimate goal in overcoming this disease.
Acute pain episodes, acute chest syndrome, and pulmonary thromboembolism in pregnancy
Authors: Asare Eugenia Vicky , DeBaun Michael R. , Olayemi Edeghonghon , Boafor Theodore , Oppong Samuel A.
Published: December 2022

Pregnancy in women with sickle cell disease (SCD) is a life-threatening condition. In both high- and low-income countries, there is an 11-fold increased risk of maternal death and a 4-fold increased risk of perinatal death. We highlight the epidemiology of SCD-specific and obstetric complications commonly seen during pregnancy in SCD and propose definitions for acute pain and acute chest syndrome (ACS) episodes during pregnancy. We conducted a systematic review of the recent obstetric and hematology literature using full research articles published within the last 5 years that reported outcomes in pregnant women with SCD. The prevalence of acute pain episodes during pregnancy ranged between 4% and 75%. The prevalence of ACS episodes during pregnancy ranged between 4% and 13%. The estimated prevalence of pulmonary thromboembolism in women with SCD during pregnancy is approximately 0.5 to 1%. ACS is the most common cause of death and is often preceded by acute pain episodes. The most crucial time to develop these complications in pregnancy is during the third trimester and postpartum period. In a pooled analysis from studies in low- and middle-income settings, maternal death in women with SCD is approximately 2393 and 4300 deaths per 100 000 live births with and without multidisciplinary care, respectively. In comparison, in the US and northern Europe, the general maternal mortality rate is approximately 23.8 and 8 deaths per 100 000 live births, respectively. A multidisciplinary SCD obstetrics care approach reduces maternal and perinatal morbidity and mortality in low- and middle-income countries.
Thrombosis questions from the inpatient wards
Authors: Goshua George , Bendapudi Pavan K. , Lee Alfred Ian
Published: December 2022

The multifaceted pathophysiologic processes that comprise thrombosis and thromboembolic diseases take on a particular urgency in the hospitalized setting. In this review, we explore 3 cases of thrombosis from the inpatient wards: purpura fulminans, cancer-associated thrombosis with thrombocytopenia, and coronavirus disease 2019 (COVID-19) and the use of dose-escalated anticoagulation therapy and antiplatelet agents. We discuss the evaluation and management of purpura fulminans and the roles of plasma transfusion, protein C and antithrombin replacement, and anticoagulation in treating this disease. We present a framework for evaluating the etiologies of thrombocytopenia in cancer and review 2 strategies for anticoagulation management in patients with cancer-associated thrombosis and thrombocytopenia, including recent prospective data supporting the use of dose-modified anticoagulation based on platelet count. Last, we dissect the major clinical trials of therapeutic- and intermediate-dose anticoagulation and antiplatelet therapy in hospitalized patients with COVID-19, reviewing key recommendations from consensus guidelines while highlighting ways in which institutional and patient-tailored practices regarding antithrombotic therapies in COVID-19 may differ. Together, the cases highlight the diverse and dramatic presentations of macro- and microvascular thrombosis as encountered on the inpatient wards.
Long-term prophylaxis: what are our options and how to define success?
Authors: Manco-Johnson Marilyn Jean , Warren Beth Boulden
Published: December 2022

Currently, we are at an enviable place in hemophilia treatment. Although full prophylaxis with standard half-life recombinant or plasma-derived factor concentrates has been definitively shown to be inadequate for full protection against bleeding and arthropathy, a number of novel therapies with improved hemostatic enhancement are clinically available or in promising clinical trials. In order to compare outcomes among a number of very efficacious therapies, it is necessary to have sensitive tools employed in long-term follow-up for several years for participants with no or minimal joint disease. The tool kit must be comprehensive, with outcomes of bleeding, factor level restoration or hemostatic capacity, joint structure, joint function, pain, quality of life, and patient satisfaction. This article reviews the history of prophylaxis, the promise of emerging therapies, and the sensitive tools used to assess long-term efficacy for joint structure and function.
Evidence-Based Minireview: What is the optimal tyrosine kinase inhibitor for adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia?
Authors: Haddad Fadi G. , Short Nicholas J.
Published: December 2022

The incorporation of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy significantly improved the outcomes of patients with Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL). This was first shown with the addition of the first-generation TKI imatinib, which allowed more patients to be bridged to an allogeneic stem cell transplant (SCT) and led to superior long-term outcomes compared with chemotherapy alone. The use of second-generation TKIs (eg, dasatinib and nilotinib) has led to further improvement in outcomes of patients with Ph- positive ALL, with a long-term survival of 40% to 60% in several studies. Ponatinib is a third-generation, more potent TKI that results in high rates of molecular response and promising long-term survival even when allogeneic SCT is not routinely performed. While randomized data to support the TKI selection in Ph-positive ALL are lacking, data from single-arm studies suggest deeper molecular responses and superior survival outcomes with each successive generation of TKI. More recently, chemotherapy-free regimens with blinatumomab and TKIs have shown excellent results in the frontline setting and may represent an emerging paradigm shift in the treatment of Ph-positive ALL.
Pangenome and genomic taxonomy analyses of Leuconostoc gelidum and Leuconostoc gasicomitatum
Authors: Johansson Per , Säde Elina , Hultman Jenni , Auvinen Petri , Björkroth Johanna
Published: December 2022

Background

Leuconostoc gelidum and Leuconostoc gasicomitatum have dual roles in foods. They may spoil cold-stored packaged foods but can also be beneficial in kimchi fermentation. The impact in food science as well as the limited number of publicly available genomes prompted us to create pangenomes and perform genomic taxonomy analyses starting from de novo sequencing of the genomes of 37 L. gelidum/L. gasicomitatum strains from our culture collection. Our aim was also to evaluate the recently proposed change in taxonomy as well as to study the genomes of strains with different lifestyles in foods.

Methods

We selected as diverse a set of strains as possible in terms of sources, previous genotyping results and geographical distribution, and included also 10 publicly available genomes in our analyses. We studied genomic taxonomy using pairwise average nucleotide identity (ANI) and calculation of digital DNA-DNA hybridisation (dDDH) scores. Phylogeny analyses were done using the core gene set of 1141 single-copy genes and a set of housekeeping genes commonly used for lactic acid bacteria. In addition, the pangenome and core genome sizes as well as some properties, such as acquired antimicrobial resistance (AMR), important due to the growth in foods, were analysed.

Results

Genome relatedness indices and phylogenetic analyses supported the recently suggested classification that restores the taxonomic position of L. gelidum subsp. gasicomitatum back to the species level as L. gasicomitatum. Genome properties, such as size and coding potential, revealed limited intraspecies variation and showed no attribution to the source of isolation. The distribution of the unique genes between species and subspecies was not associated with the previously documented lifestyle in foods. None of the strains carried any acquired AMR genes or genes associated with any known form of virulence.

Conclusion

Genome-wide examination of strains confirms that the proposition to restore the taxonomic position of L. gasicomitatum is justified. It further confirms that the distribution and lifestyle of L. gelidum and L. gasicomitatum in foods have not been driven by the evolution of functional and phylogenetic diversification detectable at the genome level.
The draft genome of Andean Rhodopseudomonas sp. strain AZUL predicts genome plasticity and adaptation to chemical homeostasis
Authors: Guardia Aisha E. , Wagner Agustín , Busalmen Juan P. , Di Capua Cecilia , Cortéz Néstor , Beligni María V.
Published: December 2022

The genusRhodopseudomonascomprises purple non-sulfur bacteria with extremely versatile metabolisms. Characterization of several strains revealed that each is a distinct ecotype highly adapted to its specific micro-habitat. Here we present the sequencing, genomic comparison and functional annotation of AZUL, aRhodopseudomonasstrain isolated from a high altitude Andean lagoon dominated by extreme conditions and fluctuating levels of chemicals. Average nucleotide identity (ANI) analysis of 39 strains of this genus showed that the genome of AZUL is 96.2% identical to that of strain AAP120, which suggests that they belong to the same species. ANI values also show clear separation at the species level with the rest of the strains, being more closely related toR. palustris.Pangenomic analyses revealed that the genusRhodopseudomonashas an open pangenome and that its core genome represents roughly 5 to 12% of the total gene repertoire of the genus. Functional annotation showed that AZUL has genes that participate in conferring genome plasticity and that, in addition to sharing the basal metabolic complexity of the genus, it is also specialized in metal and multidrug resistance and in responding to nutrient limitation. Our results also indicate that AZUL might have evolved to use some of the mechanisms involved in resistance as redox reactions for bioenergetic purposes. Most of those features are shared with strain AAP120, and mainly involve the presence of additional orthologs responsible for the mentioned processes. Altogether, our results suggest that AZUL, one of the few bacteria from its habitat with a sequenced genome, is highly adapted to the extreme and changing conditions that constitute its niche.