bluuebunny/crossref_metadata_2025 huggingface dataset:
Precision medicine within health professions education: Defining a research agenda for emergency medicine using a foresight and strategy technique (FaST) review
Authors: Chan Teresa M. , Thoma Brent , Finnell John T. , Gordon Bradley D. , Farrell Susan , Pusic Martin , Cabrera Daniel , Gisondi Michael A. , Caretta‐Weyer Holly A. , Stave Christopher , Ankel Felix
Published: May 2024

Background

Precision medicine, sometimes referred to as personalized medicine, is rapidly changing the possibilities for how people will engage health care in the near future. As technology to support precision medicine exponentially develops, there is an urgent need to proactively improve our understanding of precision medicine and pose important research questions (RQs) related to its inclusion in the education and training of future emergency physicians.

Methods

A seven‐step process was employed to develop a research agenda exploring the intersection of precision and emergency medicine education/training. A literature search of articles about precision medicine was conducted first, which informed the creation of future four scenarios in which trainees and practicing physicians regularly discuss and incorporate precision medicine tools into their discussions and work. Based on these futurist narratives, potential education RQs were generated by an expert panel. A total of 59 initial questions were subsequently categorized and refined to a priority list through a nominal group voting method. The top/priority questions were presented at the 2023 SAEM Consensus Conference on Precision Medicine, Austin, Texas, for further input.

Results

Eight high‐value education RQs were developed, reflecting a holistic view of the challenges and opportunities for precision medicine education in the knowledge, skills, and attitudes relevant to emergency medicine. These questions contend with topics such as most effective pedagogical methods; intended resulting outcomes and behaviors; the generational differences between practicing emergency physicians, educators, and future trainees; and the desires and expectations of patients.

Conclusions

Emergency medicine and emergency physicians must be prepared to understand precision medicine and incorporate this information into their “toolbox” of thinking, problem solving, and communication with patients and colleagues. This research agenda on how best to educate future emergency physicians in the use of personalized data to provide optimal health care is the focus of this article.
Beyond subsistence? The role of rural cooperatives in driving smallholder commercialization in Ethiopia
Authors: Geffersa Abebayehu Girma , Islam Md. Monirul
Published: May 2024

The transition from subsistence to market‐oriented agriculture holds the potential to boost rural economic progress and improve the well‐being of the rural poor in developing countries. Despite this potential, there is limited understanding of the key drivers for smallholder commercialization. In this study, we utilize comprehensive three‐wave panel data collected from three major maize‐producing regions in Ethiopia to examine the role of agricultural cooperatives in promoting smallholder commercialization. Employing a double‐hurdle model, we model smallholder commercialization as a two‐step decision process involving market participation and the extent of participation (sales quantity), conditional on market participation. Unobserved heterogeneity is accounted for using a correlated random effect procedure, and the potential endogeneity of cooperative membership is addressed through a control function approach. The findings reveal that cooperative membership increases the probability of market participation and the intensity of sales. However, further analysis demonstrates a heterogeneous relationship between cooperative membership and commercialization, underscoring the importance of targeted interventions to boost the contribution of cooperatives to rural development through commercialization. The main findings highlight that promoting smallholder commercialization through farmer groups necessitates implementing policies to increase cooperative membership, coupled with allocating resources that enhance the contribution of agricultural cooperatives [EconLit Citations: Q12, Q13, Q18].
Parallel patterns of genetic diversity and structure in circumboreal species of the Sphagnum capillifolium complex
Authors: Imwattana Karn , Aguero Blanka , Nieto‐Lugilde Marta , Duffy Aaron , Jaramillo‐Chico Juan , Hassel Kristian , Afonina Olga , Lamkowski Paul , Jonathan Shaw A.
Published: May 2024

Premise

Shared geographical patterns of population genetic variation among related species is a powerful means to identify the historical events that drive diversification. The Sphagnum capillifolium complex is a group of closely related peat mosses within the Sphagnum subgenus Acutifolia and contains several circumboreal species whose ranges encompass both glaciated and unglaciated regions across the northern hemisphere. In this paper, we (1) inferred the phylogeny of subg. Acutifolia and (2) investigated patterns of population structure and genetic diversity among five circumboreal species within the S. capillifolium complex.

Methods

We generated RAD sequencing data from most species of the subg. Acutifolia and samples from across the distribution ranges of circumboreal species within the S. capillifolium complex.

Results

We resolved at least 14 phylogenetic clusters within the S. capillifolium complex. Five circumboreal species show some common patterns: One population system comprises plants in eastern North America and Europe, and another comprises plants in the Pacific Northwest or around the Beringian and Arctic regions. Alaska appears to be a hotspot for genetic admixture, genetic diversity, and sometimes endemic subclades.

Conclusions

Our results support the hypothesis that populations of five circumboreal species within the S. capillifolium complex survived in multiple refugia during the last glacial maximum. Long‐distance dispersal out of refugia, population bottlenecks, and possible adaptations to conditions unique to each refugium could have contributed to current geographic patterns. These results indicate the important role of historical events in shaping the complex population structure of plants with broad distribution ranges.
Plasmablastic lymphoma: 2024 update on diagnosis, risk stratification, and management
Authors: Ramirez‐Gamero Andres , Martínez‐Cordero Humberto , Beltrán Brady E. , Florindez Jorge , Malpica Luis , Castillo Jorge J.
Published: May 2024

Disease Overview

Plasmablastic lymphoma (PBL) is a rare CD20‐negative aggressive lymphoma with a poor prognosis under standard treatment options. Though PBL is associated with human immunodeficiency virus infection and other immunosuppressed states, it can also affect immunocompetent individuals.

Diagnosis

The diagnosis requires a high clinical suspicion and pathological confirmation. EBER expression and MYC gene rearrangements are frequently detected. The differential diagnosis includes EBV+ diffuse large B‐cell lymphoma, extracavitary primary effusion lymphoma, ALK+ DLBCL, and HHV8+ large B‐cell lymphoma, among others.

Risk Stratification

Age ≥60 years, advanced clinical stage, and high intermediate and high International Prognostic Index scores are associated with worse survival.

Management

Combination chemotherapy regimens, such as EPOCH, are recommended. The addition of bortezomib, lenalidomide, or daratumumab might improve outcomes. Including PBL patients and their participation in prospective clinical trials is warranted.
A rare case of uncharacterized autoinflammatory disease: Patient carrying variations in NLRP3 and TNFRSF1A genes
Authors: Kilinc Ozgur Can , Gayibova Konul , Onen Merve Ozkilinc , Onat Umut Inci , Bülbül Alper , Timucin Ahmet Can , Ugurlu Serdal , Turanli Eda Tahir
Published: May 2024

Tumor necrosis factor type 1A receptor‐associated periodic syndrome (TRAPS) and cryopyrin‐associated autoinflammatory syndrome (CAPS) are rare monogenic autoinflammatory diseases (AIDs) mainly caused by pathogenic variations in the TNFRSF1A and NLRP3 genes, respectively. Here, we describe a unique patient presenting with symptoms overlapping both TRAPS and CAPS, without known pathogenic variants in the respective genes. The patient harbored the p.Val200Met variation in NLRP3 and the p.Ser226Cys variation in TNFRSF1A, prompting us to delve deeper into the functional analysis due to conflicting or inconclusive pathogenicity interpretations of the variants across various databases. Molecular dynamics analysis of the p.Val200Met variation in NLRP3 revealed a rigid conformation in the helical domain 2 subdomain of the NACHT domain. This increased rigidity suggests a potential mechanism by which this variation supports the assembly of the NLRP3 inflammasome. Notably, the patient's peripheral mononuclear blood cells demonstrated an elevated IL‐1β response upon lipopolysaccharides (LPS) induction. Subsequent initiation of anti‐IL‐1β therapy resulted in a significant alleviation of the patient's symptoms, further supporting our hypothesis. We interpret these findings as suggestive of a potential pathophysiological role for the NLPR3 p.Val200Met variation in shaping the patient's clinical phenotype, which was also supported by clinical and genetic analysis of the family. This case underscores the complexity of the genetic landscape in AIDs and highlights the value of combining family genetic and functional data to refine the understanding and management of such challenging cases.
Simpson–Golabi–Behmel syndrome
Authors: Vaisfeld Alessandro , Neri Giovanni
Published: May 2024

The Simpson–Golabi–Behmel syndrome (SGBS; OMIM 312870) is an overgrowth/multiple congenital anomalies/dysplasia condition, inherited as an X‐linked semi‐dominant trait, with variable expressivity in males and reduced penetrance and expressivity in females. The clinical spectrum is broad, ranging from mild manifestations in both males and females to multiple malformations and neonatal death in the more severely affected cases. An increased risk of neoplasia is reported, requiring periodical surveillance. Intellectual development is normal in most cases. SGBS is caused by a loss‐of‐function mutation of the GPC3 gene, either deletions or point mutations, distributed all over the gene. Notably, GPC3 deletion/point mutations are not found in a significant proportion of clinically diagnosed SGBS cases. The protein product GPC3 is a glypican functioning as a receptor for Hh at the cell surface, involved in the Hh‐Ptc‐Smo signaling pathway, a regulator of cellular growth.
An eosinophil peroxidase activity assay predicts acute exacerbations in post‐operative chronic rhinosinusitis
Authors: Massey Conner J. , Oakley Gretchen M. , Orlandi Richard R. , Ashby Shaelene , Alt Jeremiah A. , Smith Kristine A. , Pulsipher Abigail
Published: May 2024

Key points

EPX activity has been correlated with eCRS diagnosis and baseline disease severity.

Herein, EPX activity is shown to correlate with post‐operative antibiotic and steroid use in CRS.

EPX activity has potential to act as a prognostic biomarker of CRS disease severity and control.
Surface‐Based Multimeric Aptamer Generation and Bio‐Functionalization for Electrochemical Biosensing Applications
Authors: Hamidi Seyed Vahid , Jahromi Arash Khorrami , Hosseini Imman I. , Moakhar Roozbeh Siavash , Collazos Cesar , Pan Qinghua , Liang Chen , Mahshid Sara
Published: May 2024

Multimeric aptamers have gained more attention than their monomeric counterparts due to providing more binding sites for target analytes, leading to increased affinity. This work attempted to engineer the surface‐based generation of multimeric aptamers by employing the room temperature rolling circle amplification (RCA) technique and chemically modified primers for developing a highly sensitive and selective electrochemical aptasensor. The multimeric aptamers, generated through surface RCA, are hybridized to modified spacer primers, facilitating the positioning of the aptamers in the proximity of sensing surfaces. These multimeric aptamers can be used as bio‐receptors for capturing specific targets. The surface amplification process was fully characterized, and the optimal amplification time for biosensing purposes was determined, using SARS‐CoV‐2 spike protein (SP). Interestingly, multimeric aptasensors produced considerably higher response signals and affinity (more than 10‐fold), as well as higher sensitivity (almost 4‐fold) compared to monomeric aptasensors. Furthermore, the impact of surface structures on the response signals was studied by utilizing both flat working electrodes (WEs) and nano‐/microislands (NMIs) WEs. The NMIs multimeric aptasensors showed significantly higher sensitivity in buffer and saliva media with the limit of detection less than 2 fg/ml. Finally, the developed NMIs multimeric aptasensors were clinically challenged with several saliva patient samples.
Dialumene‐Mediated Production of Phosphines through P4 Reduction
Authors: Xu Huihui , Roy Matthew M. D. , Kostenko Arseni , Kelly John A. , Fujimori Shiori , Inoue Shigeyoshi
Published: May 2024

The formation of phosphorus‐rich alanes featuring butterfly‐like geometries is achieved. The two‐electron reduction products feature a unique P42− structure and can act as a source of P3−. The treatment of these phosphorus containing products with electrophiles under mild conditions results in the formation of different phosphines. This approach eliminates the need for high temperatures and/or high pressures, which are commonly required in industrial processes for the preparation of useful phosphines.The activation and further functionalization of white phosphorus (P4) by main group complexes has become an increasingly studied topic in recent times. Herein, we report the controlled formation of phosphorus‐rich alanes featuring butterfly‐like geometries from the selective reaction of P4 with dialumenes, ([L(IiPr)Al]2) (1: L=Tripp=2,4,6‐iPr3C6H2; 2: L=tBu2MeSi; IiPr=[MeCN(iPr)]2C)). The two‐electron‐reduction product of P4 features a P42− structure and is shown to be able to act as a source of P3−. Treatments of different electrophiles (e.g., chlorotrimethylsilane (Me3SiCl), iodotrimethylsilane (Me3SiI), HCl, or acetyl chloride (CH3COCl)) with these alanes under mild conditions gave the corresponding phosphines (e.g., P(SiMe3)3, PH3, or P(COCH3)3).
Triply Interlocked [2]catenanes: Rational Synthesis, Reversible Conversion Studies and Unprecedented Application in Photothermal Responsive Elastomer
Authors: Dang Li‐Long , Zheng Jie , Zhang Ju‐Zhong , Chen Tian , Chai Yin‐Hang , Fu Hong‐Ru , Aznarez Francisco , Liu Shui‐Ren , Li Dong‐Sheng , Ma Lu‐Fang
Published: May 2024

Triply interlocked [2]catenane complexes featuring two identical, mechanically interlocked units are extraordinarily rare chemical compounds, whose properties and applications remain open to detailed studies. Herein, we introduce the rational design of a new ligand precursor, L1, suitable for the synthesis of six triply interlocked [2]catenanes by coordination‐driven self‐assembly. The interlocked compounds can be reversibly converted into the corresponding simple triangular prism metallacage by addition of H2O or DMF solvents to their CH3OH solutions, thereby demonstrating the importance of π⋅⋅⋅π stacking and hydrogen bonding interactions in the formation of triply interlocked [2]catenanes. Moreover, extensive studies have been conducted to assess the remarkable photothermal conversion performance. Complex 6 a, exhibiting outstanding photothermal conversion performance (conversion efficiency in solution : 31.82 %), is used to prepare novel photoresponsive elastomer in combination with thermally activated liquid crystal elastomer. The resultant material displays robust response to near‐infrared (NIR) laser and the capability of completely reforming the shape and reversible actuation, paving the way for the application of half‐sandwich organometallic units in photo‐responsive smart materials.
Stereoinvertive SN1 Through Neighboring Group Participation
Authors: Suresh Rahul , Orbach Noam , Marek Ilan
Published: May 2024

Neighboring group participation, the assistance of non‐conjugated electrons to a reaction center, is a fundamental phenomenon in chemistry. In the framework of nucleophilic substitution reactions, neighboring group participation is known to cause rate acceleration, first order kinetics (SN1), and retention of configuration. The latter phenomenon is a result of double inversion: the first one when the neighboring group displaces the leaving group, and the second when a nucleophile substitutes the neighboring group. This powerful control of stereoretention has been widely used in organic synthesis for more than a century. However, neighboring group participation may also lead to inversion of configuration, a phenomenon which is often overlooked. Herein, we review this unique mode of stereoinversion, dividing the relevant reactions into three classes with the aim to introduce a fresh perspective on the different modes of stereoinversion via neighboring group participation as well as the factors that control this stereochemical outcome.
The language of nature in Murray Bowen's writings: how connection to nature informs Bowen theory and is essential to human survival
Authors: Collier Carrie E. , Mader Ashley
Published: May 2024

The human is a product of nature, and the same emotional process at work in families is at work in the relationship of the human to nature. Current global concerns and environmental changes highlight the need for humans to revisit their relationships with the natural world. The purpose of this study was to survey Murray Bowen's professional letters to reify the constructs of Bowen theory. Qualitative methodology with a narrative research design was employed. A sample (N = 250) of Dr Bowen's professional letters from the archives dating from 1965 to 1990 was analysed. Results from this analysis reveal that Bowen's writings are grounded in the language of nature and that Bowen's thinking about the human species and the family offers ways in which to see the family and humans as part of a larger system. Relating more maturely to the natural world is essential for human survival.
Diaminodiphenylmethane modified zirconium phosphate: A new strategy for trace addition to improve flame retardancy, smoke inhibition, and compatibility of epoxy resins
Authors: Wang Feiyue , Li Weixuan , Long Miaotian , Liu Hui , Yan Long
Published: May 2024

High‐efficient flame retardants (ZrP‐DDM) were synthesized successfully via ion‐exchange method, using diaminodiphenylmethane (DDM) modified layered zirconium phosphate (α‐ZrP). Trace addition of ZrP‐DDM in epoxy resins (EP) can enhance the flame‐retardant, smoke‐inhibition, mechanical, and thermal stability properties of EP composites. As shown in the results, ZrP‐DDM exhibits a better synergistic effect than α‐ZrP, and the EP composites containing 0.5 wt% ZrP‐DDM (EP/0.5ZrP‐DDM) show excellent flame‐retardant and smoke‐inhibition properties. Especially, EP/0.5ZrP‐DDM possesses a limiting oxygen index (LOI) of 33.7% with UL94 V‐1 rating, while the EP composites containing 0.5 wt% ZrP (EP/0.5ZrP) has a LOI of 30.1% and fails to achieve the UL94 rating. Furthermore, the peak heat release rate (PHRR), total heat release rate (THR), and smoke density rating of EP/0.5ZrP‐DDM decrease by 10.2%, 3.7%, and 8.2% compared with EP/0.5ZrP. Based on condensed‐phase product analysis, EP/ZrP‐DDM sample provides a gas source for intumescent char layer, and produces a stable phosphorus‐rich crosslinking structures during combustion, thus decreasing the fire hazard of the composite material. Meanwhile, the introduction of ZrP‐DDM has a less impact on tensile strength of EP composites compared with α‐ZrP, suggesting the addition of ZrP‐DDM effectively enhances the compatibility with the EP matrix, thereby maintaining excellent mechanical properties of the EP matrix.
Preparation and performance evaluation of intelligent plugging agent for thermo‐sensitive water‐based drilling fluid
Authors: Luo Yumei , Wu Lianci , Yan Yancheng , Shang Qingguo , Huang Min , Pu Kefu , Bai Xiaodong
Published: May 2024

In the process of unconventional oil and gas exploitation, the invasion of a large amount of drilling fluid into the formation is one of the most critical reasons leading to wellbore instability. A temperature‐sensitive polymer (AOS) was synthesized from acrylamide, oligo (ethylene glycol) methyl ether methacrylate (OEGMA), and sodium p‐styrene sulfonate by emulsion polymerization. The material is a solid‐free fluid with good fluidity at room temperature, after injection into the formation, the fluid is gradually transformed into hard gel above the lower critical solution temperature (LCST) (90°C), thus blocking micro‐fractures and improving wellbore stability. Infrared and NMR characterization confirmed the successful preparation of the target product. The transmittance of AOS with ambient temperature was measured by UV–vis spectrophotometer, and the LCST behavior of AOS was verified by rheological and viscoelastic measurements. The interaction mechanism between AOS and sodium bentonite was evaluated according to the American Petroleum Institute standard. The results show that after aging at 180°C, the filtration loss is reduced by 93%, and the medium permeability (100, 200 mD) formation is effectively plugged, with a plugging efficiency is as high as 74.7%.
A novel and biocompatible photopolymerizable resin based on cyclohexanedimethanol‐dimetacrylate designed to light‐print microneedles
Authors: dos Santos Edielen F. , Maciel Larissa G. , Araujo‐Neto João H. , Nascimento Dayane K. D. , Barros‐Junior Wilson , dos Anjos Janaína V. , Alves‐Junior Severino
Published: May 2024

Microneedles offer a promising avenue for painless drug delivery through micro‐perforation, and additive manufacturing, particularly stereolithography, has proven effective for their fabrication. This study focuses on developing a novel biocompatible resin for 3D printing microneedles. Spectroscopic methods are employed to confirm the structures of all intended resin monomers, with a specific analysis of the crystallographic structure of cyclohexanedimethanol methacrylate (CDMM) using x‐ray diffraction. The results indicate that CDMM crystallizes in the monoclinic system, aligning with the P21/c space group. The fabricated conical microneedles, standing at approximately 655 μm in height, underwent thorough mechanical and thermal characterization. Depth analyses of micro‐perforations in Parafilm M and pig skin were performed using optical coherence tomography and histological sections, demonstrating successful penetration through the stratum corneum and epidermal layers into the superficial dermal layer (1.5–4 mm thickness) without affecting nerve endings. Cytocompatibility tests affirm the biocompatibility of the microneedles. This work highlights the potential of the newly developed biocompatible material for printable drug delivery systems, emphasizing microneedles and other implant forms.
ALKBH5 modulates bone cancer pain in a rat model by suppressing NR2B expression
Authors: Song Kun , Cao Qionghua , Yang Yanping , Zuo Yuefen , Wu Xianping
Published: May 2024

Currently, the clinical treatment of bone cancer pain (BCP) is mainly related to its pathogenesis. The aim of the present study was to elucidate the potential role of N6‐methyladenosine (m6A) in BCP in the spinal cord dorsal root ganglia (DRG) of BCP rats and its specific regulatory mechanism in N‐methyl‐d‐aspartate receptor subunit 2B (NR2B). A rat model of BCP was constructed by tibial injection of Walker256 cells, and ALKBH5 and NR2B expression in the spinal cord DRG was detected. ALKBH5 was silenced or overexpressed in PC12 cells to verify the regulatory effect of ALKBH5 on NR2B. The specific mechanism underlying the interaction between ALKBH5 and NR2B was investigated using methylated RNA immunoprecipitation and dual‐luciferase reporter gene assays. The results showed increased expression of m6A, decreased expression of ALKBH5, and increased expression of NR2B in the DRG of the BCP rat model. Overexpression of ALKBH5 inhibited NR2B expression, whereas interference with ALKBH5 caused an increase in NR2B expression. In NR2B, interference with ALKBH5 caused an increase in m6A modification, which caused an increase in NR2B. Taken together, ALKBH5 affected the expression of NR2B by influencing the stability of the m6A modification site of central NR2B, revealing that ALKBH5 is a therapeutic target for BCP.
Tourism's circular economy: Opportunities and challenges from an integrated theoretical perspective
Authors: Jain Nikunj Kumar , Panda Abinash , Arghode Vishal
Published: May 2024

This study explored circular economy (CE) performance in small‐ and medium‐sized enterprises (SMEs) in the tourism sector. The study's theoretical framework comprised value–belief–norm theory, institutional theory, upper echelon theory (UET), and the dynamic capabilities (DCs) approach. Empirical data from 286 Indian SMEs were analyzed using partial least squares structural equation modeling. The results indicated that personal norms, coercive pressures (CP), mimetic pressures (MP), and top management commitment toward the environment influenced CE performance through DCs. However, normative pressures (NP) did not significantly influence CE performance. DCs were a catalyst enabling individual beliefs, organizational factors, and external pressures to push SMEs toward a CE. Nevertheless, possibly due to insufficient resources, SMEs were reluctant in improving their CE performance. Policymakers and SME owners should therefore develop DCs in their organizations to achieve CE performance through appropriate resource assessment and design.
Resource recombination perspective on open eco‐innovation: Open innovation type, strategic orientation, and green innovation
Authors: Kim Younghuk , Roh Taewoo , Boroumand Raphaël Homayoun
Published: May 2024

This study aims to investigate the missing links in open eco‐innovation by focusing on the following questions, which existing studies have limited attention in the existing literature: (1) Given the level of breadth and depth of a firm's open eco‐innovation, how can open innovation types be distinguished? (2) In what way does the open innovation type differ in implementing an open eco‐innovation strategy? and (3) How do open innovation strategic differences affect green innovation performance? Drawing upon the knowledge‐based view and dynamic capability perspective, this study provides theoretical grounds for a firm's breadth and depth of an open eco‐innovation strategy. It suggests a 2
 2 resource recombination framework to differentiate between four open innovation types for green innovation: Maverick, Best friend, True, and Cherry‐picker. Using data from 2496 manufacturing firms in South Korea, we applied a k‐means cluster analysis to generate four groups and conducted regression analyses to confirm hypotheses. Our findings supported the influence of open innovation type on strategic orientation; however, the effect was not observed in Best Friend. Additionally, ambidextrous strategic orientation significantly influenced green innovation compared to either exploitative or explorative strategic orientations.
Integrative analyses identified gap junction beta‐2 as a prognostic biomarker and therapeutic target for breast cancer
Authors: Zhang Di , Li Lixi , Ma Fei
Published: May 2024

Background

Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene expression patterns, prognostic values, and potential mechanisms of connexins in breast cancer.

Methods

We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution. Connexin mRNA expressions in breast cancer and matched normal tissues were compared, and multiomics studies were performed.

Results

Gap junction beta‐2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes, and its high expression was associated with poor prognosis. The tumor membrane of the gap junction beta‐2 mutated group was positive, and the corresponding protein was expressed. Somatic mutation and copy number variation of gap junction beta‐2 are rare in breast cancer. The gap junction beta‐2 transcription level in the p110α subunit of the phosphoinositide 3‐kinase mutant subgroup was higher than that in the wild‐type subgroup. Gap junction beta‐2 was associated with the phosphoinositide 3‐kinase‐Akt signaling pathway, extracellular matrix–receptor interaction, focal adhesion, and proteoglycans in cancer. Furthermore, gap junction beta‐2 overexpression may be associated with phosphoinositide 3‐kinase and histone deacetylase inhibitor resistance, and its expression level correlated with infiltrating CD8+ T cells, macrophages, neutrophils, and dendritic cells.

Conclusions

Gap junction beta‐2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.
Grape Pomace Polyphenols Reduce Acute Inflammatory Response Induced by Carrageenan in a Murine Model
Authors: Nery‐Flores Sendar Daniel , Castro‐López Cristina Marisela , Martínez‐Hernández Lucía , García‐Chávez Clara Victoria , Palomo‐Ligas Lissethe , Ascacio‐Valdés Juan Alberto , Flores‐Gallegos Adriana Carolina , Campos‐Múzquiz Lizeth Guadalupe , Rodríguez‐Herrera Raúl
Published: May 2024

Grape pomace (GP), a by‐product of wine production, contains bioactive polyphenols with potential health benefits. This study investigates the anti‐inflammatory properties of a polyphenolic fraction derived from GP, obtained by ultrasound‐microwave hybrid extraction and purified using ion‐exchange chromatography. In the inflammation model, mice were divided into six groups: intact, carrageenan, indomethacin, and three GP polyphenols treatment groups. Paw edema was induced by subplantar injection of carrageenan, and the GP polyphenols were administered intraperitoneally at doses of 10, 20, and 40 mg/kg. The anti‐inflammatory effect was evaluated by measuring paw volume, and expression of inflammatory markers: cyclooxygenase‐2 (COX‐2), myeloperoxidase (MPO), and cytokines (IL‐1β and IL‐6), along with lipid peroxidation levels. The GP polyphenols significantly reduced paw edema and expression levels of COX‐2, MPO, and cytokines in a dose‐dependent manner effect, with the highest dose showing the greatest reduction. Additionally, lipid peroxidation levels were also decreased by GP polyphenols treatment at doses of 10 and 20 mg/kg. These findings suggest that ultrasound‐microwave extraction combined with amberlite purification proved to be effective in obtaining a polyphenolic‐rich fraction from GP. Thus, GP polyphenols may serve as a natural anti‐inflammatory and antioxidant agent for treating inflammation and oxidative stress‐related diseases.
Discovery of Photoexcited 2‐Chloro‐3,5‐Dinitrobenzoic Acid as a Chemical Deprenylase of i6A RNA
Authors: Sun Xin , Hui Tian‐He , Liu Li , Cheng Liang
Published: May 2024

RNA modifications play crucial roles in regulating gene expression and cellular homeostasis. Modulating RNA modifications, particularly by targeting the enzymes responsible for their catalysis, has emerged as a promising therapeutic strategy. However, limitations, such as the lack of identified modifying enzymes and compensatory mechanisms, hinder targeted interventions. Chemical approaches independent of enzymatic activity offer an alternative strategy for RNA modification modulation. Here, we present the identification of 2‐chloro‐3,5‐dinitrobenzoic acid as a highly effective photochemical deprenylase of i6A RNA. This method demonstrates exceptional selectivity towards i6A, converting its substituent into a “N‐doped” ozonide, which upon hydrolysis releases natural adenine. We believe that this chemical approach will pave the way for a better understanding of RNA modification biology and the development of novel therapeutic modalities.
Clinical journey for patients with aortic regurgitation: A retrospective observational study from a multicenter database
Authors: Amoroso Nicholas S. , Sharma Rahul P. , Généreux Philippe , Pinto Duane S. , Dobbles Michael , Kwon Michelle , Thourani Vinod H. , Gillam Linda D.
Published: May 2024

Background

Data using real‐world assessments of aortic regurgitation (AR) severity to identify rates of Heart Valve Team evaluation and aortic valve replacement (AVR), as well as mortality among untreated patients, are lacking. The present study assessed these trends in care and outcomes for real‐world patients with documented AR.

Methods

Using a deidentified data set (January 2018–March 2023) representing 1,002,853 patients >18 years of age from 25 US institutions participating in the egnite Database (egnite, Inc.) with appropriate permissions, patients were classified by AR severity in echocardiographic reports. Rates of evaluation by the Heart Valve Team, AVR, and all‐cause mortality without AVR were examined using Kaplan–Meier estimates and compared using the log‐rank test.

Results

Within the data set, 845,113 patients had AR severity documented. For moderate‐to‐severe or severe AR, respectively, 2‐year rates (95% confidence interval) of evaluation by the Heart Valve Team (43.5% [41.7%–45.3%] and 65.4% [63.3%–67.4%]) and AVR (19.4% [17.6%–21.1%] and 46.5% [44.2%–48.8%]) were low. Mortality at 2 years without AVR increased with greater AR severity, up to 20.7% for severe AR (p < 0.001). In exploratory analyses, 2‐year mortality for untreated patients with left ventricular end‐systolic dimension index > 25 mm/m2 was similar for moderate (34.3% [29.2%–39.1%]) and severe (37.2% [24.9%–47.5%]) AR.

Conclusions

Moderate or greater AR is associated with poor clinical outcomes among untreated patients at 2 years. Rates of Heart Valve Team evaluation and AVR were low for those with moderate or greater AR, suggesting that earlier referral to the Heart Valve Team could be beneficial.
Balloon predilation or direct valve implantation in TAVI for women: Insights from the DIRECTAVI study
Authors: Robert Pierre , Akodad Mariama , Lattuca Benoit , Gandet Thomas , Meunier Pierre Alain , Macia Jean‐Christophe , Schmutz Laurent , Steinecker Matthieu , Roubille Francois , Cayla Guillaume , Leclercq Florence
Published: May 2024

Background

The randomized DIRECTAVI trial demonstrated safety and feasibility of transcatheter aortic valve implantation (TAVI) without balloon aortic valvuloplasty (BAV) using SAPIEN 3 balloon‐expandable devices. However, the female population with smaller anatomy may have potential higher risk of residual gradient and/or mismatch.

Purpose

We assessed the impact of BAV on the procedural success rate and clinical outcomes in the female population of the DIRECTAVI trial.

Methods

Between May 2016 and May 2018, 91 of the 250 patients included in the DIRECTAVI trial were women (38.6%), 45 of them (49.5%) were enrolled in the BAV group and 46 of them (50.5%) in the direct TAVI group. The primary endpoint was procedural success rate in women (Valve Academic Research Consortium‐2 criteria). The secondary endpoint included evaluation of PPM and 1‐month major adverse events according to the implantation stategy in women and comparison between men and women regarding major endpoints.

Results

The primary endpoint occurred in 29 women (64.4%) in the BAV group and in 34 women (73.9%) in the direct TAVI group (mean difference 9.47%; 95% confidence interval: 6.5%–25.4%; p = 0.045 for non‐inferiority of the direct strategy). One‐month major adverse events were similar between the 2 women groups. Procedural success was lower in women vs men (p = 0.01) due to higher incidence of moderate mismatches in women (p = 0.001) but with no significant difference regarding the implantation strategy (p = 0.4).

Conclusion

Direct implantation of the balloon‐expandable SAPIEN 3 valve was non‐inferior to predilatation on procedural success in women. Incidence of moderate mismatch was higher in women but was not related to the implantation strategy.
Hypokalemic paralysis following intramuscular betamethasone injection: A case report and review of literature
Authors: Ebrahimi Pouya , Taheri Homa , Mousavinejad Seyed Ali , Nazari Pedram
Published: May 2024

Key Clinical Message

Acute neuromuscular paralysis is a relatively common condition in emergency rooms (ERs). They can be caused by several reasons, including adverse drug reactions. Betamethasone is a glucocorticoid commonly used for various conditions, such as allergic conditions. One of the rare but known side effects of glucocorticoids is hypokalemia. Rare cases of hypokalemia following high‐ and low‐dose glucocorticoid injections have been reported. This study presents the history of a young, healthy male without significant past medical history who presented with an inability to stand and walk due to four‐limb paralysis (more prominent in the lower limbs) following an intramuscular injection of a 4 mg betamethasone, which was prescribed for the treatment of allergic rhinitis. The patient was stabilized with an intravascular injection of potassium chloride diluted in 1000 mL of normal saline and monitored for 24 h, ruling out any other endocrine condition. Hypokalemia and its severe form are defined as the serum level of lower than 3.5 and 2.5 mEq/Lit, respectively. One of the etiologies of drug‐induced hypokalemic paralysis is systemic glucocorticoid administration. In severe cases, it can cause quadriplegia and other neuromuscular, respiratory, and cardiac complications. Therefore, it is an urgent condition that should be managed carefully. Pregnant women who are receiving these medications are a specific group at risk of hypokalemic paralysis. There are several safer treatments for seasonal allergic rhinitis compared to systemic glucocorticoids, which should be considered by physicians. Moreover, paralysis in patients receiving these medications should be approached attentively since it might be caused by hypokalemia, which can be life threatening if not treated. It is advisable that the blood level of electrolytes, especially potassium, be checked for patients who present with paralysis or weakness after glucocorticoid injections.
Protecting‐Group‐Free Synthesis of ADP‐Ribose and Dinucleoside Di‐/Triphosphate Derivatives via P(V)‐P(V) Coupling Reaction
Authors: Hagino Rui , Kuwabara Ryo , Komura Naoko , Imamura Akihiro , Ishida Hideharu , Ando Hiromune , Tanaka Hide‐Nori
Published: May 2024

Biomolecules containing adenosine di‐ or triphosphate (ADP or ATP) are crucial for diverse biological processes. Synthesis of these biomolecules and development of their chemical probes are important to elucidate their functions. Enabling reproducible and high‐yielding access to these ADP‐ and ATP‐containing molecules via conventional P(III)‐P(V) and P(V)‐P(V) coupling reactions is challenging owing to water content in highly polar phosphate‐containing substrates. Herein, we report an efficient and reliable method for protecting‐group‐free P(V)‐P(V) coupling reaction through in situ activation of phosphates using hydrolysis‐stable 2‐[N‐(2‐methylimidazoyl)]‐1,3‐dimethylimidazolinium chloride (2‐MeImIm‐Cl), providing the corresponding electrophilic P(V) intermediates for subsequent nucleophilic attack using their coupling partners. This P(V)‐P(V) coupling reaction proceeded even in a wet reaction medium and showed a broad substrate scope, accommodating protecting‐group‐free synthesis of ADP‐ribose and nicotinamide adenine diphosphate analogs, ATP‐containing biomolecules, and ADP‐ribosyl peptides.
Determination of benzophenone derivatives in wastewater by GC–MS/MS combined with in‐port derivatization
Authors: Tüzün Serenay Ceren , Karapinar Ilgi , Yücel Cemile , Ertaş Fatma Nil , Ertaş Hasan
Published: May 2024

The analysis of UV filters (UVFs) in water has become increasingly important due to their adverse effects on aquatic organisms and humans. This study describes a method for the determination of benzophenone derivatives UVF in wastewater samples. The selected UVFs are 2‐hydroxy‐4‐methoxybenzophenone (BP‐3), 2,4‐dihydroxybenzophenone (BP‐1), 4‐hydroxybenzophenone (4HB), 2,2′‐dihydroxy‐4‐methoxybenzophenone (DHMB) and lastly, 4,4′‐dihydroxybenzophenone (4DHB). The method includes solid‐phase extraction (SPE) of analytes from wastewater followed by on‐line derivatization with bis(trimethylsilyl)trifluoroacetamide (BSTFA) and analysis with GC‐MS/MS. Method validation studies resulted in good recoveries (86–112%), relative standard deviation RSD = 0.8 and 7.3%, the limits of detection LODs = 1.00–10.8 ng/L, and the limits of quantification LOQs = 3.00–32.3 ng/L. The method was successfully applied to domestic wastewater samples collected from influent and effluent of touristic hotels’ biological wastewater treatment plants. BP‐3 (24–1765 ng/L), BP‐1 (8–703 ng/L), 4HB (26–96 ng/L), and 4DHB (20–22 ng/L) were the common benzophenone derivatives in the influent wastewater while effluent contained mainly BP‐1 (8–32 ng/L), 4HB (12–57 ng/L) and 4DHB (20–102 ng/L). These results indicate that BP‐3 and BP‐1 are biodegraded in the treatment processes. However, 4HB and 4DHB are resistant to degradation and they are the main benzophenone metabolites discharged to receiving media.
TNF‐alpha promotes cilia elongation via mixed lineage kinases signaling in mouse fibroblasts and human RPE‐1 cells
Authors: Kumari Amrita , Caliz Amada D. , Yoo Hyung‐Jin , Kant Shashi , Vertii Anastassiia
Published: May 2024

The primary cilium is a characteristic feature of most non‐immune cells and functions as an environmental signal transduction sensor. The defects in primary cilium have profound effects on the developmental program, including the maturation of retinal epithelium. The ciliary length is tightly regulated during ciliogenesis, but the impact of inflammation on ciliary length remains elusive. The current study investigates the outcome of inflammatory stimuli for the primary cilium length in retinal epithelium cells and mouse embryonic fibroblasts. Here, we report that exposure to the pro‐inflammatory cytokine TNF‐alpha elongates cilia in a mixed‐lineage kinase (MLK)‐dependent manner. Pro‐inflammatory stimuli such as bacterial LPS and interferon‐gamma have similar effects on ciliary length. In contrast, febrile condition‐mimicking heat stress dramatically reduced the number of ciliated cells regardless of TNF‐alpha exposure but did not shorten TNF‐induced elongation, suggesting distinct but rapid effects of inflammatory stresses on ciliogenesis.
High‐dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience
Authors: Richardson Noah H. , Taza Fadi , Abonour Rafat , Althouse Sandra K. , Ashkar Ryan , Abu Zaid Mohammad , Hanna Nassar H. , Kesler Kenneth A. , Adra Nabil , Einhorn Lawrence H.
Published: May 2024

Background

Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high‐dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University.

Methods

The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first‐line cisplatin‐based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression‐free survival and overall survival were analyzed using the Kaplan–Meier method. Medians with 95% conﬁdence intervals were also calculated along with 2‐year probabilities.

Results

The median age at HDCT was 30 years (range, 18–61 years). With a median follow‐up of 4.7 years (range, 1–14 years), the 2‐year progression‐free survival rate was 31% (95% confidence interval, 16%–47%), and the 2‐year overall survival rate was 35% (95% confidence interval, 19%–52%). At last follow‐up, nine patients (28%) remained without evidence of disease, including two platinum‐refractory patients and two patients who were receiving HDCT as third‐line therapy. There were three treatment‐related deaths.

Conclusions

Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum‐refractory and third‐line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.
Treatment intensity affects immune reconstitution even after childhood cancer not treated with hematopoietic stem cell transplantation
Authors: Antikainen Ella , Grönroos Marika , Huurre Anu , Korhonen Laura , Peltola Ville , Lähteenmäki Päivi , Schuez‐Havupalo Linnea
Published: May 2024

Background

Only a few previous studies examine immune system recovery after completed cancer treatment.

Aims

The aim of this study was to analyze immune reconstitution after childhood cancer therapy in a non‐hematopoietic stem cell transplantation setting.

Methods and results

We analyzed children (N = 79) who received chemotherapy with/without irradiation for cancer diagnosed between 2014 and 2019 at Turku University Hospital, Finland. We retrospectively collected data on baseline parameters and post‐treatment immunological recovery, namely neutrophil and lymphocyte counts, IgG levels, CD19, CD4 and natural killer cell counts. Immunological parameters were followed until their normalization. Treatment intensity was stratified according to the Intensity of Treatment Rating Scale (ITR‐3). We analyzed the effects of treatment intensity on normalization of immunological parameters across the entire treatment range. Treatment intensity had a major effect on immune system recovery after completion of treatment. Most patients had normal immunological parameters 1–4 months post‐treatment both in high‐ and low‐intensity treatment groups, but patients classified in the high‐intensity group had low parameters more often than patients in the low‐intensity group.

Conclusion

Our data suggest a fast recovery of studied immunological parameters after the majority of current pediatric oncologic treatments. Treatment for high‐risk acute lymphoblastic leukemia, acute myeloid leukemia, medulloblastoma, and mature B‐cell lymphoma was associated with prolonged recovery times for a substantial proportion of cases. High treatment intensity was associated with prolonged immunological recovery.