bluuebunny/crossref_metadata_2025 huggingface dataset:
Timing of hydrocarbon charge in the Axial Zone of the Eastern Cordillera, Colombia
Authors: Pacheco-Mendoza Jael Yanine , Tesón-Del Hoyo Eliseo , García-González Mario , Mora Andrés , Ketcham Richard
Published: April 2024

The petroleum potential of onshore basins in Colombia has been partly controlled by the Andean Orogeny since the end of the Cretaceous. Its Axial Zone has at least one understudied active petroleum system with a rather low petroleum potential and few commercial medium to heavy oil accumulations, raising questions about how the Andean deformation influenced the petroleum system and the possible undiscovered accumulations. We examine the timing of this petroleum system in the Axial Zone through oil–source correlations and two 2D petroleum system models across the Boyacá and Soápaga faults based on cross-sections.

Modelling reveals the direct control of deformation on generation–accumulation in the Axial Zone, where the Lower Cretaceous source rocks, due to high heat flows during the synrift phase, started generation so early (100 to 60 Ma) that no reservoirs or traps were yet available to allow hydrocarbon entrapment and accumulation. Equally, for the younger Upper Cretaceous source rocks, the tectonic inversion of the basin between 33 and 23 Ma along the Boyacá and Soápaga faults interrupted burial and the maturation in most parts of the basin, leaving only local pods of active source rocks where maturation continues today due to the tectonic overburden along the footwall of the Soápaga Fault. The latter is thus the major kitchen, contributing more than 50% of the liquid hydrocarbons trapped mainly in Upper Cretaceous and Paleocene sandstones. Hydrocarbons migrate upwards where biodegradation and water washing occurred in the near-surface, giving rise to the many tar sand occurrences in the Eocene sandstones.
The 1st Hanrahan Lecture: Geotechnical properties of Irish glacial and interglacial soils
Authors: Farrell Eric Raymond
Published: April 2024

This paper reviews the current state of the art in relation to geotechnical design in unsorted till deposits, commonly called boulder clays by engineers or diamictons by geologists, generally taking the topics discussed by Professor Eamon Hanrahan in his seminal work of 1977 on Irish tills. These topics include the permeability, stiffness and consolidation characteristics of these deposits, together with their undrained and drained behaviour. The geological background to the deposition of these tills is discussed and the available information on the presence of interglacial soils around the country is presented. Where possible, practical experience from working with these deposits is compared with predictions made from field or laboratory test results: for example, in settlement assessment of foundations, slope stability and in earthworks.

Whilst most of Ireland is covered with stony boulder clays, which is the main topic of this paper, the geotechnical parameters of a fine-grained till encountered on the east coast, known as Irish Sea Till or colloquially as Macamore Clay, are discussed and the implications of this on slope stability is investigated.
Inferring the evolutionary history of the Sino-Himalayan biodiversity hotspot using a Bayesian birth–death skyline model
Authors: Allen Bethany J. , Vaughan Timothy G. , du Plessis Louis , Schouten Thomas L. A. , Yuan Zili , Willett Sean D. , Stadler Tanja
Published: April 2024

The current status of the Sino-Himalayan region as a biodiversity hotspot, particularly for flora, has often been linked to the uplift of the Sino-Tibetan Plateau and Himalayan and Hengduan Mountains. However, the relationship between the topological development of the region and the onset of diversification is yet to be confirmed. Here, we apply Bayesian phylodynamic methods to a large phylogeny of angiosperm species from the Sino-Himalayas to infer changes in their rates of evolution through time. We find strong evidence for high diversification rates in the Paleocene, late Miocene and Pliocene, and for negative diversification rates in the Quaternary driven by an increase in extinction rates. Our analyses suggest that changes in global palaeotemperatures are unlikely to be a driving force for these rate shifts. Instead, the collision of the Indian continent with Eurasia and coeval topographic change in the Sino-Himalayas, the Miocene Grassland Expansion and the impact of Pleistocene glaciations on this altitudinally variable region may have driven these rates. We also demonstrate the strong influence of the choice of change times on the shape of inferred piecewise-constant trajectories in Bayesian phylodynamics, and advocate for the use of prior information when making this decision.
Electrochemical Biosensing Strategy for Ultrasensitive Detection of Aquaporin-4 Antibody as Neuromyelitis Optica Autoimmune Disease Biomarker Using Aquaporin-4 Extracellular Loop
Authors: Hoseynidokht Farzaneh , Mazloum-Ardakani Mohammad , Moshtaghioun Seyed Mohammad , Farbod Fatemeh , Behnam Rad Mohammad
Published: April 2024

Neuromyelitis optica (NMO) is a severe and disabling neurodegenerative disorder of the central nervous system (CNS). Neuromyelitis optica-Immunoglobulin G (NMO-IgG) is a serum IgG autoantibody almost exclusively present in NMO patients, which helps to differentiate NMO from other CNS disorders. Developing standardized and user-friendly assays remains a significant challenge in making NMO-IgG testing widely available. Label-free methods are simpler and faster, without additional reagents and procedures. Here, we present a peptide-based label-free electrochemical biosensor for detecting aquaporin-4 antibodies (AQP4-Abs) using extracellular AQP4 to diagnose NMO disease via the DPV electrochemical method. We have developed a novel approach in which the E loop of extracellular AQP4 is bemployed to detect NMO. 3 phenylalanines (Phe) were annexed to the C terminal, and because phenylalanine has a benzene ring, it can have π-π interaction with the benzene ring of carbon nanotube (CNT). In the designated platform, instead of using functional groups with complex and multi-step processes for immobilizing on the electrode surface, we used Nickel-Metal−organic framework /CNT as a novel modifier for measuring AQP4 antibodies with a simple, cheap, and accessible synthesis method. The developed sensor can detect antibodies with detection limit and quantification of 6.2 and 10.0 pg ml−1, respectively (S/N = 3). Also, superb sensitivity of the biosensor was attained as 28.8 μA mL ng−1 cm−2, confirming that the sensor has great potential for clinical application as a diagnostic test.
Effect of Sulfide Addition on the Corrosion Mechanism of Copper in Saline Groundwater Solution
Authors: Bojinov Martin , Goel Sneha , Ikäläinen Tiina , Saario Timo
Published: April 2024

The interaction of copper with sulfide-containing simulated saline groundwater is studied by electrochemical techniques (voltammetry, current-time transients, and electrochemical impedance spectroscopy, EIS) complemented with surface and cross-sectional microscopic observations and energy dispersive spectroscopic analyses. Both experimental findings and quantitative interpretation of EIS data using previously published kinetic models indicate that no continuous adherent barrier-type layer is formed on Cu in sulfide-containing groundwater, thus precluding the possibility of the development of localized corrosion modes.
The Effect of Bi0.5Li0.5ZrO3-SrSnO3 Composite Doping on the Construction of Polymorphic Phase Boundaries and Enhanced Electrical Properties of K0.45Na0.55Nb0.965Sb0.035O3 Piezoelectric Ceramics
Authors: Zheng Ruihua , Yin Qiyi , Lin Fei , Zhang Yulin , Zhang Quanzheng , Hu Kunhong , Yang Kejie , Zhu Yangyang , Zou Wangzu
Published: April 2024

In this experiment, a new lead-free piezoelectric ceramics (1−x)K0.45Na0.55Nb0.965Sb0.035O3−x(0.9Bi0.5Li0.5ZrO3−0.1SrSnO3) were prepared by the conventional solid-phase method, and the effects of the doping amount of 0.9Bi0.5Li0.5ZrO3−0.1SrSnO3 on the K0.45Na0.55Nb0.965Sb0.035O3 ceramics on the crystal structure, microstructure, microscopic structure and electrical properties. All the doping ions entered the KNN lattice and formed a dense solid solution with a single-phase structure, and the phase structure of the ceramics coexisted from orthorhombic (O) to orthorhombic-tetragonal (O-T) phases in the range of 0 ≤ x ≤ 0.03, and transitioned to rhombohedral-tetragonal (R-T) phase coexistence when 0.035 ≤ x ≤ 0.05. The electrical properties of the ceramics were analyzed and the polymorphic phase boundary (PPB) region was obtained at x = 0.035 and had the best overall properties: d
33 = 324pC/N, k
p = 49%, ε
r = 1479, tanδ = 3.21%, P
r = 31.98 μC/cm2, E
c = 16.83 kV cm−1 and T
C = 293°C. By The microstructural analysis of the ceramics showed that the appropriate amount of compound doping of the second element enhances the denseness of the ceramics as well as makes the grains uniformly distributed. These results indicate that the ceramics of this system have great prospects for future applications in the field of lead-free piezoelectric ceramics.
Synaptic inputs to motor neurons underlying muscle coactivation for functionally different tasks have different spectral characteristics
Authors: Borzelli Daniele , Vieira Taian M. M. , Botter Alberto , Gazzoni Marco , Lacquaniti Francesco , d’Avella Andrea
Published: April 2024

The characterization of the pathways underlying force generation or stiffness modulation are still unknown. In this study, we demonstrated that the common input to motor neurons of antagonist muscles shows a high-frequency component when muscles are coactivated to modulate stiffness but not to generate force. Our results provide novel insights on the neural strategies for the recruitment of multiple muscles by identifying specific spectral characteristics of the synaptic inputs underlying functionally different tasks.
Factors Influencing Pain Scores and Opioid Demand after Robotically Assisted Cardiac Surgery
Authors: Hasan Irsa , Seese Laura , Deitz Rachel , Ashraf Faaz , Ogami Takuya , Subramaniam Kathirvel , Boisen Michael , Yoon Pyongsoo , West David , Kaczorowski David , Sultan Ibrahim , Bonatti Johannes
Published: April 2024

Objective. Introduction of minimally invasive cardiac surgery anticipated the reduction in postoperative pain but little quantitative data are available on this effect. This study investigated factors influencing pain scores and opioid demand after robotically assisted cardiac procedures. Methods. Using data derived from prospective robotic cardiac surgery and anesthesia databases, we analyzed 75 patients undergoing robotic cardiac surgery between July 2021 and December 2022. Study endpoints were mean cumulative pain scores measured on a 0–10 scale and opioid use on postoperative days (PODs) 1 to 4. Pain scores and oral morphine equivalent (OME) were correlated with perioperative variables. Results. Postoperatively, 39/75 (52%) of patients were extubated in the operating room (OR) and 34/75 (45.3%) were extubated within 24 hours of surgery. Mean pain scores declined from 5.8 (SD 1.5) on POD 1 to 3.8 (SD 1.6) on POD 4 and OME fell from 34.9 (SD 29) mg to 8.2 (SD 11.8) mg. OME use correlated significantly with pain scores (p < 0.01). Higher pain scores on postoperative day (POD) 1 were associated with diabetes (p = 0.006), tobacco use (p = 0.006), and extubation in the OR (p = 0.017). Opioid utilization was higher in younger patients (p < 0.001), heavier patients (p = 0.033), active tobacco users (p = 0.01), longer procedure times (p = 0.002), and those extubated in the OR (p < 0.001). Conclusion. Pain and opioid consumption after robotically assisted cardiac surgery are moderate but decline steadily within the first four postoperative days. Tobacco use and extubation in the OR were associated with increased pain and opioid consumption.
An In-Depth Overview of the Structural Properties, Health Benefits, and Applications of Resistant Dextrin
Authors: Wu Xiuli , Zhang Jianwen , Yan Xiangxuan , Wu Xuexu , Zhang Qing , Luan Mingran
Published: April 2024

With the escalating prevalence of diabetes and obesity, resistant dextrin, renowned for its prebiotic properties and blood glucose-lowering physiological activity, has garnered significant attention. Resistant dextrin, a low-calorie, indigestible water-soluble dietary fiber processed from starch, has high solubility, low molecular weight, and good thermal stability. The established method for its preparation involves a combination of acid heat treatment and enzymatic purification. Within the human body, resistant dextrin confers numerous health benefits. It promotes a balanced intestinal microbiome, regulates blood glucose and lipid metabolism, and enhances satiety. Additionally, it exerts positive influences on the intestinal environment, aids in weight management, and alleviates chronic conditions, particularly diabetes. In the food industry, resistant dextrin is widely employed as a functional food additive to enhance the nutritional value and health benefits of various food products. However, there is a need for greater clarity regarding the structural characteristics of resistant dextrin and the potential interplay between its structure and physiological activity. This paper comprehensively reviews the preparation methods, structural properties, health benefits, and application areas of resistant dextrin. Additionally, it anticipates future trends in its development. The primary objective of this review is to offer theoretical guidance and fresh perspectives for further research, the innovation of functional products, and the expanded utilization of resistant dextrin.
Characteristic Flavor Substances of Guizhou Black Tea and the Environmental Factors Influencing Their Formation Using Stable Isotopes and Headspace Gas Chromatography-Ion Mobility Spectrometry
Authors: Ge Yonghui , Huang Yongji , Wang Ling , Jia Luyu , Wang Jinhua
Published: April 2024

Guizhou is one of the most important black tea producing areas in China. The purpose of this study was to explore the characteristic flavor compounds of Guizhou black tea and investigate the influence of environmental factors on the formation of black tea flavor components. In this study, HS-GC-IMS was used to identify 143 compounds from black tea samples. OPLS-DA was employed to analyze the data, effectively distinguishing black tea from different origins. A total of 83 significant flavor compounds were selected as potential markers using the VIP variable selection method and OAV screening. Cluster analysis was used to identify the characteristic flavor compounds in black tea samples from different origins. In addition, by investigating the climate environment of various production regions and analyzing the volatile components along with stable C and N isotope ratios of samples, it was discovered that the development of volatile components in black tea could be significantly influenced by ambient temperature and light. In regions with higher temperatures, the concentration of volatile components with floral, fruity, and sweet aromas is higher, resulting in a more intense aroma in black tea. In regions with low ambient temperatures but strong sunlight, black tea contains higher levels of components that give it a fresh and nutty aroma. As a result, the aroma of black tea is relatively elegant and fresh. At the same time, it was found that the stable isotope ratios of C and N in black tea were also significantly affected by ambient temperature and were positively correlated. This study introduces a fresh perspective for the comprehensive examination of Guizhou black tea, offering theoretical guidance for optimizing planting conditions and enhancing product quality. Its positive influence on promoting the development of the Guizhou black tea industry is noteworthy.
Overcoming Osimertinib Resistance with AKT Inhibition in EGFRm-Driven Non–Small Cell Lung Cancer with PIK3CA/PTEN Alterations
Authors: Grazini Ursula , Markovets Aleksandra , Ireland Lucy , O’Neill Daniel , Phillips Benjamin , Xu Man , Pfeifer Matthias , Vaclova Tereza , Martin Matthew J. , Bigot Ludovic , Friboulet Luc , Hartmaier Ryan , Cuomo Maria E. , Barry Simon T. , Smith Paul D. , Floc’h Nicolas
Published: April 2024

Purpose:

Osimertinib is an EGFR tyrosine kinase inhibitor indicated for the treatment of EGFR-mutated (EGFRm)–driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line–treated patients with EGFRm advanced non–small cell lung cancer (NSCLC). Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression.

Experimental Design:

ctDNA profiling analysis of on-progression plasma samples from patients treated with osimertinib in both first- (phase III, FLAURA trial) and second-line trials (phase III, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR-engineered NSCLC cell lines and patient-derived xenograft (PDX) models supports a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance.

Results:

These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be resensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alterations, and in these double-mutant models, capivasertib and osimertinib combination elicits an improved antitumor effect versus osimertinib alone.

Conclusions:

Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC who have a suboptimal response or develop resistance to osimertinib through PIK3CA/AKT/PTEN alterations.

See related commentary by Vokes et al., p. 3968
Efficacy of Pembrolizumab and Biomarker Analysis in Patients with WGS-Based Intermediate to High Tumor Mutational Load: Results from the Drug Rediscovery Protocol
Authors: Geurts Birgit S. , Zeverijn Laurien J. , Leek Lindsay V.M. , van Berge Henegouwen Jade M. , Hoes Louisa R. , van der Wijngaart Hanneke , van der Noort Vincent , van de Haar Joris , van Ommen-Nijhof Annemiek , Kok Marleen , Roepman Paul , Jansen Anne M.L. , de Leng Wendy W.J. , de Jonge Maja J.A. , Hoeben Ann , van Herpen Carla M.L. , Westgeest Hans M. , Wessels Lodewyk F.A. , Verheul Henk M.W. , Gelderblom Hans , Voest Emile E.
Published: April 2024

Purpose:

To evaluate the efficacy of pembrolizumab across multiple cancer types harboring different levels of whole-genome sequencing–based tumor mutational load (TML; total of nonsynonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234).

Patients and Methods:

Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer cohort harboring a TML of 140 to 290, cohort B: tumor-agnostic cohort harboring a TML of 140 to 290, and cohort C: tumor-agnostic cohort harboring a TML >290. Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint was clinical benefit [CB; objective response or stable disease (SD) ≥16 weeks]. Pretreatment tumor biopsies were obtained for whole-genome sequencing and RNA sequencing.

Results:

Seventy-two evaluable patients with 26 different histotypes were enrolled. The CB rate was 13% in cohort A [3/24 with partial response (PR)], 21% in cohort B (3/24 with SD; 2/24 with PR), and 42% in cohort C (4/24 with SD; 6/24 with PR). In cohort C, neoantigen burden estimates and expression of inflammation and innate immune biomarkers were significantly associated with CB. Similar associations were not identified in cohorts A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, whereas in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated.

Conclusions:

Although pembrolizumab lacked activity in cohort A, cohorts B and C met the study’s primary endpoint. Further research is warranted to refine the selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.

See related commentary by Hsu and Yen, p. 3652
Melanoma Clonal Heterogeneity Leads to Secondary Resistance after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes
Authors: König David , Sandholzer Michael T. , Uzun Sarp , Zingg Andreas , Ritschard Reto , Thut Helen , Glatz Katharina , Kappos Elisabeth A. , Schaefer Dirk J. , Kettelhack Christoph , Passweg Jakob R. , Holbro Andreas , Baur Katharina , Medinger Michael , Buser Andreas , Lardinois Didier , Jeker Lukas T. , Khanna Nina , Stenner Frank , Kasenda Benjamin , Homicsko Krisztian , Matter Matthias , Rodrigues Mantuano Natalia , Zippelius Alfred , Läubli Heinz
Published: April 2024

Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in patients with melanoma, although long-term responses seem restricted in patients who have complete remissions. Many patients develop secondary resistance to TIL-ACT but the involved mechanisms are unclear. In this study, we describe a case of secondary resistance to TIL-ACT possibly due to intratumoral heterogeneity and selection of a resistant tumor cell clone by the transferred T cells. To the best our knowledge, this is the first case of clonal selection of a pre-existing nondominant tumor cell clone; this report demonstrates the mechanism involved in secondary resistance to TIL-ACT that can potentially change current clinical practice because it advocates for T-cell collection from multiple tumor sites and analysis of tumor heterogeneity before treatment with TIL-ACT.
Disruption of KLHL6 Fuels Oncogenic Antigen Receptor Signaling in B-Cell Lymphoma
Authors: Meriranta Leo , Sorri Selma , Huse Kanutte , Liu Xiaonan , Spasevska Ivana , Zafar Sadia , Chowdhury Iftekhar , Dufva Olli , Sahlberg Eerika , Tandarić Luka , Karjalainen-Lindsberg Marja-Liisa , Hyytiäinen Marko , Varjosalo Markku , Myklebust June H. , Leppä Sirpa
Published: April 2024

Pathomechanisms that activate oncogenic B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma (DLBCL) are largely unknown. Kelch-like family member 6 (KLHL6) encoding a substrate-adapter for Cullin-3-RING E3 ubiquitin ligase with poorly established targets is recurrently mutated in DLBCL. By applying high-throughput protein interactome screens and functional characterization, we discovered that KLHL6 regulates BCR by targeting its signaling subunits CD79A and CD79B. Loss of physiologic KLHL6 expression pattern was frequent among the MCD/C5-like activated B-cell DLBCLs and was associated with higher CD79B levels and dismal outcome. Mutations in the bric-a-brac tramtrack broad domain of KLHL6 disrupted its localization and heterodimerization and increased surface BCR levels and signaling, whereas Kelch domain mutants had the opposite effect. Malfunctions of KLHL6 mutants extended beyond proximal BCR signaling with distinct phenotypes from KLHL6 silencing. Collectively, our findings uncover how recurrent mutations in KLHL6 alter BCR signaling and induce actionable phenotypic characteristics in DLBCL.

Significance: Oncogenic BCR signaling sustains DLBCL cells. We discovered that Cullin-3-RING E3 ubiquitin ligase substrate-adapter KLHL6 targets BCR heterodimer (CD79A/CD79B) for ubiquitin-mediated degradation. Recurrent somatic mutations in the KLHL6 gene cause corrupt BCR signaling by disrupting surface BCR homeostasis. Loss of KLHL6 expression and mutant-induced phenotypes associate with targetable disease characteristics in B-cell lymphoma.

See related commentary by Leveille et al.

See related commentary by Corcoran et al.
LP-184, a Novel Acylfulvene Molecule, Exhibits Anticancer Activity against Diverse Solid Tumors with Homologous Recombination Deficiency
Authors: Kulkarni Aditya , Zhou Jianli , Biyani Neha , Kathad Umesh , Banerjee Partha P. , Srivastava Shiv , Prucsi Zsombor , Solarczyk Kamil , Bhatia Kishor , Ewesuedo Reginald B. , Sharma Panna
Published: April 2024

Homologous recombination (HR)-related gene alterations are present in a significant subset of prostate, breast, ovarian, pancreatic, lung, and colon cancers rendering these tumors as potential responders to specific DNA damaging agents. A small molecule acylfulvene prodrug, LP-184, metabolizes to an active compound by the oxidoreductase activity of enzyme prostaglandin reductase 1 (PTGR1), which is frequently elevated in multiple solid tumor types. Prior work demonstrated that cancer cell lines deficient in a spectrum of DNA damage repair (DDR) pathway genes show increased susceptibility to LP-184. Here, we investigated the potential of LP-184 in targeting multiple tumors with impaired HR function and its mechanism of action as a DNA damaging agent. LP-184 induced elevated DNA double-strand breaks in HR deficient (HRD) cancer cells. Depletion of key HR components BRCA2 or ataxia telangiectasia mutated (ATM) in cancer cells conferred up to 12-fold increased sensitivity to the LP-184. LP-184 showed nanomolar potency in a diverse range of HRD cancer models, including prostate cancer organoids, leiomyosarcoma cell lines, and patient-derived tumor graft models of lung, pancreatic, and prostate cancers. LP-184 demonstrated complete, durable tumor regression in 10 patient-derived xenograft (PDX) models of HRD triple-negative breast cancer (TNBC) including those resistant to PARP inhibitors (PARPi). LP-184 further displayed strong synergy with PARPi in ovarian and prostate cancer cell lines as well as in TNBC PDX models. These preclinical findings illustrate the potential of LP-184 as a pan-HRD cancer therapeutic. Taken together, our results support continued clinical evaluation of LP-184 in a large subset of HRD solid tumors.

Significance:

New agents with activity against DDR-deficient solid tumors refractory to standard-of-care therapies are needed. We report multiple findings supporting the potential for LP-184, a novel alkylating agent with three FDA orphan drug designations, to fill this void clinically: strong nanomolar potency; sustained, durable regression of solid tumor xenografts; synthetic lethality with HR defects. LP-184 adult phase IA trial to assess safety in advanced solid tumors is ongoing.
Morphological and Immunohistochemical Differentiation of Neuronal and Glial Cells of the Vascular and Avascular Regions of the Donkey’s Paurangiotic Retina
Authors: Gaber Wafaa , Hussein Manal T. , Aly Khaled H. , Abdel-Maksoud Fatma M.
Published: April 2024

Introduction: Ocular diseases pose a significant health concern for donkeys. However, studies examining the microanatomy and cell populations of the donkey retina are scarce. The current study aimed to describe the vascular pattern of the donkey retina and document its cellular components. Methods: The donkey retina specimens were obtained from different retinal regions and prepared for semithin sectioning and immunohistochemistry. Results: The donkey has a paurangiotic retina in which retinal vessels are confined to a narrow area around the optic disc. Glial cells coexist with the blood vessels being very numerous in the vascular region and become scanty in the avascular ones. S-100-positive astrocytes could be observed in these avascular areas. Ganglion cells are organized in a single layer with the least population existing in the peripheral retina. Acidic fibroblast growth factor (AFGF) is immunoreactive in amacrine and ganglion cells. A subpopulation of amacrine cells reacted strongly to tyrosine hydroxylase (TH), and others reacted positively to S-100 protein. Ganglion cell nuclei exhibited a strong immunoreactivity to S-100 protein as well. Furthermore, glial fibrillary acidic protein (GFAP) is used to identify Müller cells that extend their processes across the retina from the inner to the outer limiting membrane. Conclusions: In conclusion, our findings provide novel insights into the normal retinal organization. The donkey retina shows the characteristic expression of immunohistochemical markers for the major cell types. In addition, the distribution of glial cells is comparable between the vascular and avascular regions.
The Effects of Environmental Pollutants and Exposures on Hair Follicle Pathophysiology
Authors: Samra Tara , Lin Rachel R. , Maderal Andrea D.
Published: April 2024

Background: Environmental exposures profoundly impact cutaneous physiology, with hair follicles (HFs) being particularly vulnerable due to their high levels of proliferation and perfusion. HFs are exposed directly to contaminants that are absorbed transcutaneously and exposed indirectly to ingested and inhaled pollutants via the bloodstream. Summary: Some pollutants, such as particulate matter, trigger inflammatory responses and have been associated with alopecia areata. Others, like tobacco smoke and phthalates, exert endocrine effects with unclear ramifications for HF function. Pesticides and heavy metals have both been linked to alopecia areata and acute anagen effluvium, while polyaromatic hydrocarbons – ligands of aryl hydrocarbon receptors – are linked to androgenetic alopecia. Finally, UV exposure, which has increased due to anthropogenic ozone depletion, causes oxidative damage and perifollicular mast cell degranulation. Key Messages: Pollutants have far-reaching consequences for hair pathology, which remain incompletely characterized. The effects of environmental exposures on HFs are an active area of research that deserve further attention.
Exogenous Hydrogen Sulfide Prevents Necroptosis by Inhibiting p38MAPK Pathway Activation in JEG-3 Trophoblast Cells: A Role in Preeclampsia
Authors: Zhang Caihong , Chen Zixi , Shao Huijing , Ma Ziwen , Guan Rui , Yu Xiaomin , Sun Qianqian , Gu Hang
Published: April 2024

Objectives: Necroptosis, a form of programmed cell death, can occur in the placenta of patients with preeclampsia (PE). Hydrogen sulfide (H2S) can inhibit necroptosis of human umbilical vein endothelial cells under the high glucose-induced injury. Whether H2S can protect trophoblasts against necroptosis underlying PE has not been elucidated. This study aimed to explore the protective role of H2S in trophoblast cells against necroptosis underlying PE. Design: This is an in vitro experimental study. Participants: A total of 10 pregnant women with severe PE and 10 matched control normotensive pregnant women were included. The placenta tissues were extracted from participators. The human JEG-3 trophoblasts were commercially available. Methods: The expression and localization of necrotic proteins were assayed in human placenta samples, and the effect of necrotic cell death on the proliferation and apoptosis of human JEG-3 trophoblasts was evaluated. The component expressions of inflammatory cytokine and p38MAPK signaling pathway were measured in samples pretreated with or without NaHS (H2S donor) and SB203580 (p38 inhibitor). Results: RIPA1, RIPA3, and p-p38 levels were significantly higher in PE placental tissue, whereas cystathionine β-synthase expression was decreased. In JEG-3 trophoblasts, necroptosis increased apoptotic cell numbers, suppressed cell proliferation, increased inflammatory cytokine expression, and increased p38MAPK activation, which can be prevented by NaHS. Limitations: In the present study, we did not provide sufficient evidence that necroptosis was a part of the pathogenesis of PE. Conclusions: We proposed the putative role of necroptosis in early-onset PE, reflected by the blockage of caspase-8/3 and increased expression of RIPA1 and RIPA3 in PE placenta tissues. Furthermore, we demonstrated that exogenous H2S protected cytotrophoblasts against ceramide-induced necroptosis via the p38MAPK pathway.
Prevalence and Correlates of Night Eating Syndrome, Insomnia, and Psychological Distress in Primary Care Patients with Obesity: A Cross-Sectional Study
Authors: Sayed Ahmed Hazem A. , Abo El-Ela Sohila G. , Joudeh Anwar I. , Moawd Sally M. , El Hayek Samer , Shah Jaffer , Eldahshan Nahed Amen
Published: April 2024

Introduction: Management of obesity is challenging for both patients and healthcare workers. Considering the low success rate of current interventions, this study aimed to explore the prevalence and associated factors of night eating syndrome (NES), insomnia, and psychological distress among individuals with obesity in order to plan comprehensive obesity management interventions. Methods: A cross-sectional study on a convenient sample from five primary healthcare centers in Port Said, Egypt, was conducted from November 2020 to March 2021. Sociodemographic and clinical characteristics were collected in addition to the assessment of NES, insomnia, and psychological distress using the Arabic versions of the Night Eating Diagnostic Questionnaire (NEQ), the Insomnia Severity Index (ISI), and the Patient Health Questionnaire-4 (PHQ-4) scales, respectively. Associations of NES, insomnia, and psychological distress were assessed by multiple regression analysis. We performed Bonferroni adjustments for multiple comparisons. Results: We included 425 participants with obesity with a mean age of 45.52 ± 6.96 years. In all, 54.4% were females and the mean body mass index (BMI) was 35.20 ± 4.41 kg/m2. The prevalence rates of NES, insomnia, and psychological distress were 21.6% (95% CI: 17.7–25.6%), 15.3% (95% CI: 11.9–18.7%), and 18.8% (95% CI: 15.1–22.6%), respectively. NES was significantly associated with younger age (OR 0.974, p = 0.016), physical inactivity (OR 0.485, p = 0.010), insomnia (OR 2.227, p = 0.014), and psychological distress (OR 2.503, p = 0.002). Insomnia showed strong associations with NES (OR 2.255, p = 0.015) and psychological distress (OR 5.990, p < 0.001). Associated factors of psychological distress symptoms included insomnia (OR 6.098, p < 0.001) and NES (OR 2.463, p = 0.003). Conclusion: The prevalence rates of NES, insomnia, and psychological distress were high among primary care patients with obesity, and these conditions were interrelated. Optimal obesity management necessitates individualized and targeted multidisciplinary care plans that take into consideration individual patients’ mental, behavioral, and dietary habits needs.
In vitro Activity of Dalbavancin and Fourteen Other Antimicrobial Agents against Toxigenic Clostridioides difficile Clinical Isolates in a Greek Tertiary-Care Hospital
Authors: Maraki Sofia , Mavromanolaki Viktoria Eirini , Stafylaki Dimitra , Iliaki-Giannakoudaki Evangelia , Kasimati Anna
Published: April 2024

Objective: Clostridioides difficile is a major cause of healthcare-associated diarrhea worldwide. For years, metronidazole and vancomycin were considered the standard treatment for C. difficile infection. However, they are increasingly being associated with treatment failure and recurrence. In this study, we investigated the in vitro activity of dalbavancin and fourteen other antimicrobials against 155 toxigenic C. difficile isolates originating from patients with C. difficile-associated diarrhea. Materials and Methods: Antimicrobial susceptibility was evaluated by the MIC Test Strip, and the results were interpreted using both the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. Results: C. difficile isolates were fully susceptible to metronidazole, vancomycin, amoxicillin/clavulanate, piperacillin/tazobactam, and tigecycline. All isolates were dalbavancin susceptible by the CLSI breakpoint (≤0.25 μg/mL) compared with 97.4% susceptibility by the EUCAST breakpoint (≤0.125 μg/mL). Dalbavancin demonstrated significantly lower MIC50 and MIC90 values compared to vancomycin (0.047 vs. 0.38 and 0.125 vs. 0.5, respectively, p < 0.001). Resistance rates to penicillin, ampicillin, cefoxitin, imipenem, meropenem, clindamycin, moxifloxacin, chloramphenicol, and tetracycline were 20%, 14.2%, 100%, 75.5%, 0.6%, 51%, 36.1%, 3.2%, and 14.8%, respectively. Multidrug-resistant phenotypes were detected among 41.3% of the isolates. Conclusion: Dalbavancin exhibited potent activity against the isolates tested. As C. difficile is an important healthcare-associated pathogen, continued surveillance is required to monitor for development of resistance.
Association between Sense of Coherence and Caries Activity and Caries Experience among Male Adolescents from Southern Brazil: A Cross-Sectional Study
Authors: Lock Nicássia Cioquetta , Gazola Maria Laura , Marquezan Patrícia Kolling , Zenkner Julio Eduardo do Amaral , Alves Luana Severo
Published: April 2024

Introduction: This cross-sectional study assessed the association between sense of coherence (SoC) and caries activity (number of active caries lesions) and caries experience (DMFT index) among 18–19-year-old male adolescents who joined the Brazilian Army as draftees for mandatory military service (n = 507). Methods: Data collection included a questionnaire (level of education, family income, and tooth brushing frequency), the Brazilian short version of the SoC scale (SOC-13), and clinical caries examination (noncavitated/cavitated, inactive/active). The main predictor variable was SoC, categorized as low, moderate, or high. Poisson regression models were used for statistical analysis. Results: A high SoC was significantly associated with a lower number of active lesions (adjusted rate ratio = 0.85; 95% CI = 0.74–0.98). No association between SoC and DMFT was detected. Conclusion: A high SoC was found to be a protective factor to caries activity in this population.
Discordance in Phenotypic and Genotypic Susceptibility Testing for Streptomycin Due to Nonsynonymous/Nonsense/Deletion Frame-Shift Mutations in gidB among Clinical Mycobacterium tuberculosis Isolates in Kuwait
Authors: Al-Mutairi Noura M. , Ahmad Suhail , Mokaddas Eiman
Published: April 2024

Objective: Increasing reports of resistance to newer antituberculosis drugs have prompted the search for other alternative drugs. Streptomycin (STR) could be used for the treatment of drug-resistant tuberculosis if susceptibility of Mycobacterium tuberculosis isolate to STR could be accurately detected. We performed phenotypic and genotypic drug susceptibility testing (DST) of 118 M. tuberculosis isolates for STR. Materials and Methods: Fifty pansusceptible and 68 multidrug-resistant M. tuberculosis (MDR-TB) isolates were used. Phenotypic DST for STR, rifampicin, isoniazid, and ethambutol was performed by mycobacteria growth indicator tube 960 System. Genotypic DST was done by GenoTypeMTBDRplus assay for rifampicin and isoniazid and by PCR-sequencing of rpsL, rrs, and gidB genes for STR. MDR-TB isolates were genotyped by spoligotyping. Results: Phenotypic DST identified 50 isolates susceptible to all four drugs (pansusceptible). Sixty-one of 68 MDR-TB isolates were resistant to STR. Genotypic testing for rifampicin and isoniazid yielded expected results. Fifty pansusceptible and 7 STR-susceptible MDR-TB isolates contained no mutation in rpsL or rrs, while 47, 2, and 1 STR-resistant isolate contained rpsL, rrs, and rpsL + rrs mutations, respectively. Of the remaining 11 STR-resistant MDR-TB, 9 isolates contained deletion frame-shift/nonsynonymous mutations in gidB. Surprisingly, 13 pansusceptible isolates also contained deletion frame-shift/nonsense/nonsynonymous mutations in gidB. Also, 30 of 68 MDR-TB but only 2 of 50 pansusceptible isolates belonged to the Beijing genotype. Conclusions: Our data show that, like rifampicin, ethambutol, and pyrazinamide, STR also exhibits discordant phenotypic and genotypic DST results for some M. tuberculosis isolates. Hence, STR should be included in therapy regimens only if both phenotypic and genotypic resistance testing indicate susceptibility to avoid amplification of resistance and drug toxicity.
Pain Scores after Open Fetal Spina Bifida Repair and Caesarean Section: A Longitudinal Cohort Study
Authors: Zepf Julia , Vonzun Ladina , Rüegg Ladina , Strübing Nele , Krähenmann Franziska , Meuli Martin , Mazzone Luca , Moehrlen Ueli , Moehrlen Theres , Kandler Lukas ,   Spina Bifida Study Group Zurich, Ochsenbein-Kölble Nicole
Published: April 2024

Introduction: In fetal surgery, successful pain management is crucial for postoperative mobilization, prophylaxis of contractions, and fast recovery. This study analyzed patient’s pain experience after open fetal spina bifida (fSB) repair in comparison to pain scores after the subsequent Caesarean section (C-section). Materials and Methods: Data were collected with a questionnaire given to 91 women, who had fSB repair and then C-section at our center between 2019 and 2022. It comprised 12 questions covering different aspects of pain experience and satisfaction with pain therapy and was answered by 67 women after fSB repair and 53 after C-section. Postoperative pain was rated on a Likert scale from 0 (slight/rarely) to 100 (strongest/always). Outcomes after fSB repair were compared to those after C-section. Additionally, subgroup analysis compared outcomes of women with different pain levels (group 1–5) after fSB repair. Results: Compared to women after C-section women after fSB repair reported significantly higher maximum pain scores (MPS) (p = 0.03), higher sleep disturbance due to pain (p = 0.03), and sedation rates (p = 0.001) as side effect from pain therapy. No differences were found regarding feelings of insecurity (p = 0.20) or helplessness (p = 0.40), as well as involvement in (p = 0.3) and satisfaction with pain therapy (p = 0.5). Subgroup analysis revealed that women with higher MPS after fSB repair were significantly more often non-Caucasians (p = 0.003) and more often affected by pain while lying in bed (p = 0.007) and during mobilization (p = 0.005). Additionally, they reported higher rates of dizziness (p = 0.02) and lower satisfaction rates with pain therapy (p = 0.03). Postoperative complication rate did not differ among groups. Conclusion: Although women after fSB repair reported higher MPS compared to after C-section, the current pain management was generally perceived as satisfactory.
Outcome of Colorectal Robotic Surgery in Newly Established Robotic Surgery Center: A Case Series
Authors: Alkhamis Ahmed A. , Soliman Diaa M. , Alsadder Khaled A. , Busalha Hashem M. , Alrashed Ahmad S. , Alshaban Bader H. , Alsafran Salman K. , Almazeedi Sulaiman M.
Published: April 2024

Introduction: The robotic platform compared to laparoscopy has proven to have similar postoperative outcomes; however, its adoption in the Middle East has been slow and there are limited data regarding outcomes with its use in small newly established robotic colorectal programs. Our aim was to report our experience and outcomes of robotic colorectal surgery performed by fellowship-trained robotic colorectal surgeons and compare them to larger, more experienced centers. Methods: This is retrospective review of data collected between November 2021 and March 2023 from a tertiary health care referral center. The series included 51 patients who had elective or urgent robotic colorectal surgery. Patients who had emergency surgery were excluded. The outcomes were overall morbidity, serious morbidity, mortality, conversion to open, length of hospital stay, and quality of oncological specimen. Results: The overall morbidity was 31.4% (n = 16 patients). Only 9.8% (n = 5) had serious morbidity of which three required interventions under general anesthesia. The median length of hospital stay was 6 days (IQR = 4), and there was no mortality. Of 17 rectal cancer resections, 88% had complete mesorectal excision, 15 of them were R0 resections, median lymph node harvested was 14 (IQR = 7) and two cases were converted to open. All the colon cancer resections had R0 resection, median lymph nodes harvested was 21 (IQR = 4) and none were converted to open. Conclusions: The implementation and integration of robotic colorectal surgery at a newly established center in a small country, when led by fellowship-trained robotic colorectal surgeons, is safe and effective in terms of morbidity, mortality, conversion to open and specimen pathological quality.
Additive Effects of Citrus Juice Flavonoid Naringenin and Statins on Human Ether-a-go-go-Related Gene Channels Expressed in Xenopus Oocytes
Authors: Isaev Dmytro , Yang Keun-Hang Susan , Oz Murat
Published: April 2024

Objective: Naringenin, a major flavonoid found in citrus juice, has been shown to inhibit human ether-a-go-go-related gene (HERG) channels and cause QT prolongation. Statins, the most commonly used class of cholesterol reducing drugs, have also been reported to inhibit HERG channels and prolong QT interval in patients using these drugs. However, the interaction between naringenin and statins on the function of HERG channels has not been studied. Materials and Methods: In the present study, we expressed HERG channels in Xenopus oocytes, tested the effects of naringenin and statins separately, and combined on HERG channels. Results: When 30 µm naringenin was added to statins (1 µm rosuvastatin or 3 µm atorvastatin), significantly greater inhibition of HERG was demonstrated, compared to the inhibition caused by statins alone. Conclusions: The results indicate that an additive interaction occurs between naringenin and statins; this could pose an increased risk of arrhythmias by decreasing repolarization reserve.
Estimating the Prevalence of Cerebral Palsy in a Semi-Urban City in Benin: A Door-to-Door Community-Based Study
Authors: Sogbossi Emmanuel Segnon , Baba-Tadja Adjoua , Nouatin Emilienne , Agbetou Mendinatou , Adoukonou Thierry , Kossi Oyéné
Published: April 2024

Introduction: Cerebral palsy (CP) is the most common cause of pediatric motor disability. While epidemiological data are widespread in high-income countries, corresponding data in low-income countries in sub-Saharan Africa are still rare. This study aimed to estimate the prevalence of CP in Northern Benin, a French-speaking low-income country in sub-Saharan Africa. Methods: This study was a community-based door-to-door study involving children younger than 18 years old, in Parakou, a semi-urban city in Benin. We used a two-stage procedure. The first one consisted on children screening to identify potential cases of CP. During the second stage, suspected children were examined by neurologists with high experience with CP. Results: In total, 2,630 children were screened with 10 confirmed cases of CP, resulting in a crude prevalence (95% confidence interval) of 3.8 (1.4, 6.15) per 1,000 children. Of the 10 confirmed cases, six were younger than 5 years old, and five were male. Eight children over ten were spastic with six bilateral spastic subtype according to the Surveillance of Cerebral Palsy in Europe classification system. Seven children had a Gross Motor Function Classification System level III–V, and six were classified level III to V of the manual ability classification system. Conclusion: CP is highly prevalent in semi-urban area in Northern Benin. Large studies on potential risk factors are needed for the development of effective preventive strategies.