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Ling Peng,1,2,&ast; Hong You,2,&ast; Mei-yu Xu,2 Zhou-yu Dong,2 Min Liu,2 Wen-jing Jin,2 Chao Zhou2 1Department of Critical Care Medicine, Qiannan Buyi and Miao Autonomous Prefecture People’s Hospital, Guizhou, People’s Republic of China; 2Department of Respiratory Medicine, Guangming Traditional Chinese Medicine Hospital of Pudong New Area, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chao Zhou, Department of Respiratory Medicine, Guangming Traditional Chinese Medicine Hospital of Pudong New Area, No. 43 DongMen Street. Pudong new District, Shanghai, 201399, People’s Republic of China, Tel +86-21-68019069, Email zhou2000sh@163.comBackground: Chronic obstructive pulmonary disease (COPD) has higher mortality when developing to acute exacerbation (AECOPD); hence, the early intervention of COPD is critical for preventing AECOPD. Exploring the serum metabolites associated with acute exacerbation in patients with COPD will contribute to the early intervention of COPD.Methods: In the study, a non-targeted metabolomics strategy combined with multivariate statistical methods was performed to explore the metabolic profiling of COPD developing acute exacerbation, to screen the potential metabolites associated with AECOPD and to analyze the potential value of these metabolites in predicting the development of COPD.Results: Serum lysine, glutamine, 3-hydroxybutyrate, pyruvate and glutamate levels were significantly higher, while 1-methylhistidine, isoleucine, choline, valine, alanine, histidine and leucine levels were significantly lower in AECOPD patients, compared with stable COPD patients after normalization based on the healthy controls. Moreover, eight metabolic pathways were significantly altered (P< 0.05) in the serum of AECOPD patients compared with the stable COPD population, including purine metabolism, glutamine and glutamate metabolism, arginine biosynthesis, butyrate metabolism, ketone body synthesis and degradation, and linoleic acid metabolism. In addition, the correlation analysis between metabolites and AECOPD patients demonstrated that an M-score based on a weighted sum of concentrations of four metabolites including pyruvate, isoleucine, 1-methylhistidine and glutamine were significantly associated with the acute exacerbation of pulmonary ventilation function in COPD patients.Conclusion: Altogether, the metabolite score based on a weighted sum of concentrations of four serum metabolites was associated with an increased risk of COPD developing acute exacerbation, which will provide a new insight for the understanding of COPD development.Keywords: COPD, AECOPD, acute exacerbation, metabolomics, metabolites

Physico-chemical characteristics of groundwater are often impacted by agricultural practices such as land use, fertilizer types, and groundwater pumping. This study aimed to identify contaminant sources and redox processes controlling the hydrogeochemistry of groundwater in riparian zones influenced by intensive agricultural activities, focusing on sulfur species. Groundwater samples were collected bimonthly from March 2014 to March 2015 from groundwater wells in two zones in South Korea with different agricultural systems. The water isotopic compositions of the groundwater indicated that all groundwater originated from the same meteoric water. Groundwater samples affected by periodic groundwater pumping exhibited wide variations in Mn 2+ (47.8 ± 18.2 μM) and Fe 2+ (123 ± 61.0 μM) and elevated SO 4 2- , while NO 3 - was below the detection limit. Groundwater chemistry was affected by fertilizer and manure, and denitrification. The oxidation of reduced sulfur compounds by oxygen and nitrate did not fully account for the elevated SO 4 2- concentrations and isotopic composition of sulfate (δ 34 S and δ 18 O) in the investigated aquifers. Therefore, we postulate that water level change due to periodic groundwater pumping and recharge enabled oxidants (MnO 2 and Fe 3+ ) to also contribute to oxidation of reduced sulfur. Additionally, fertilizers with distinct δ 34 S values and bacterial sulfate reduction (BSR) affected groundwater chemistry and its sulfur species, including δ 34 S SO4 and δ 18 O SO4 . Removal of sulfate from the aquifer during pumping limited BSR. Consequently, the agricultural practices may further increase sulfate concentrations in the groundwater. This environmental impact should be thoroughly managed because high sulfate concentrations in drinking water cause ingestion problems in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Geminal bromofluoroalkenes are an important subclass of versatile organic interhalide, which can serve as useful synthetic precursors to monofluoroalkenes that are valuable amide group isosteres. Nonetheless, despite the vast advancement of olefination methodologies, the broadly applicable stereoselective synthesis remained elusive for geminal bromofluoroalkenes before our work. In particular, the seemingly straightforward Wittig-type approach with interhalogenated phosphorus ylide has been unsuccessful because of the difficulty in the diastereoselective oxaphosphetane formation. Here, we describe a conceptually distinctive strategy, by which the stereoselectivity is gained via the selective decomposition of the oxaphosphetane intermediates. The suitably identified phosphorus(III) reagent and reaction medium enabled efficient kinetic differentiation, which was supported by nuclear magnetic resonance analysis and density functional theory calculation. Through our method, the highly diastereoselective synthesis of geminal E -bromofluoroalkenes was accomplished in one step. Furthermore, the generality was demonstrated by accommodating a wide range of readily available carbonyl compounds, including ketones and pharmaceutical substrates.

Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade, but understanding of the prognostic and predictive value of TLS and the circumstances of their resolution is incomplete. Here we show that in hepatocellular carcinoma treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse-free survival. In areas of tumor regression, we identify a noncanonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell-mature dendritic cell interactions and increased expression of T cell memory markers. Collectively, these data suggest that TLS can serve as both a prognostic and predictive marker of response to immunotherapy in hepatocellular carcinoma and that late-stage TLS may support T cell memory formation after elimination of a viable tumor., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

A two-step procedure, combining a SmI 2 -mediated transannular pinacol coupling reaction with an acid-catalyzed pinacol rearrangement process, was employed to prepare a diverse range of 1-substituted bicyclo[2.1.1]hexan-5-ones from cyclobutanedione derivatives. To underscore the significance of these bicyclic ketones in drug synthesis, an sp 3 -rich analog of nitazoxanide, a well-known antiparasitic and antiviral agent, was synthesized.

Background: The prevalence of hypertension and uncontrolled hypertension may differ by age and sex., Methods: We included participants in the Atherosclerosis Risk in Communities study at seven study visits over 33 years (visit 1: 15 636 participants; mean age, 54 years; 55% women), estimating sex differences in prevalence of hypertension (systolic blood pressure ≥130 mm Hg; diastolic blood pressure ≥80 mm Hg; or self-reported antihypertension medication use) and uncontrolled hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) using unadjusted and comorbidity-adjusted models., Results: The prevalence of hypertension increased with age from 40% (ages, 43-46 years) to 93% (ages, 91-94 years). Within hypertensive individuals, the prevalence of uncontrolled hypertension was higher in men (33%) than women (23%) at ages 43 to 46 years but became higher in women than men starting at ages 61 to 64, with 56% of women and 40% men having uncontrolled hypertension at ages 91 to 94. This sex difference was not explained by differences in coronary heart disease, diabetes, body mass index, estimated glomerular filtration rate, number of antihypertension medications, classes of medications, or adherence to medications. In both sexes, uncontrolled hypertension was associated with a higher risk for chronic kidney disease progression (hazard ratio, 1.5 [1.2-1.9]; P =4.5×10 -4 ), heart failure (hazard ratio, 1.6 [1.4-2.0]; P =8.1×10 -7 ), stroke (hazard ratio, 2.1 [1.6-2.8]; P =1.8×10 -8 ), and mortality (hazard ratio, 1.5 [1.3-1.6]; P =6.2×10 -19 )., Conclusions: Sex differences in the prevalence of hypertension and uncontrolled hypertension vary by age, with the latter having implications for health throughout the life course., Competing Interests: The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US government. USRDS data were used for Table 3. The opinions presented do not necessarily represent those of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health, the Department of Health and Human Services, or the US Government. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US Government.

Background and Objective: The incidence of facial fractures is on the rise globally, yet limited studies are addressing the diverse forms of facial fractures present in 3D images. In particular, due to the nature of the facial fracture, the direction in which the bone fractures vary, and there is no clear outline, it is difficult to determine the exact location of the fracture in 2D images. Thus, 3D image analysis is required to find the exact fracture area, but it needs heavy computational complexity and expensive pixel-wise labeling for supervised learning. In this study, we tackle the problem of reducing the computational burden and increasing the accuracy of fracture localization by using a weakly-supervised object localization without pixel-wise labeling in a 3D image space., Methods: We propose a Very Fast, High-Resolution Aggregation 3D Detection CAM (VFHA-CAM) model, which can detect various facial fractures. To better detect tiny fractures, our model uses high-resolution feature maps and employs Ablation CAM to find an exact fracture location without pixel-wise labeling, where we use a rough fracture image detected with 3D box-wise labeling. To this end, we extract important features and use only essential features to reduce the computational complexity in 3D image space., Results: Experimental findings demonstrate that VFHA-CAM surpasses state-of-the-art 2D detection methods by up to 20% in sensitivity/person and specificity/person, achieving sensitivity/person and specificity/person scores of 87% and 85%, respectively. In addition, Our VFHA-CAM reduces location analysis time to 76 s without performance degradation compared to a simple Ablation CAM method that takes more than 20 min., Conclusion: This study introduces a novel weakly-supervised object localization approach for bone fracture detection in 3D facial images. The proposed method employs a 3D detection model, which helps detect various forms of facial bone fractures accurately. The CAM algorithm adopted for fracture area segmentation within a 3D fracture detection box is key in quickly informing medical staff of the exact location of a facial bone fracture in a weakly-supervised object localization. In addition, we provide 3D visualization so that even non-experts unfamiliar with 3D CT images can identify the fracture status and location., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 ZIOVISION co. ltd. Published by Elsevier B.V. All rights reserved.)

Prurigo nodularis (PN) is a chronic, inflammatory skin condition that disproportionately affects African Americans and features intensely pruritic, hyperkeratotic nodules on the extremities and trunk. PN is understudied compared with other inflammatory skin diseases, with the spatial organization of the cutaneous infiltrate in PN yet to be characterized. In this work, we employ spatial imaging mass cytometry to visualize PN lesional skin inflammation and architecture with single-cell resolution through an unbiased machine learning approach. PN lesional skin has increased expression of caspase 3, NF-kB, and phosphorylated signal transducer and activator of transcription 3 compared with healthy skin. Keratinocytes in lesional skin are subdivided into CD14+CD33+, CD11c+, CD63+, and caspase 3-positive innate subpopulations. CD14+ macrophage populations expressing phosphorylated extracellular signal-regulated kinase 1/2 correlate positively with patient-reported itch (P = .006). Hierarchical clustering reveals a cluster of patients with PN with greater atopy, increased NF-kB+ signal transducer and activator of transcription 3-positive phosphorylated extracellular signal-regulated kinase 1/2-positive monocyte-derived myeloid dendritic cells, and increased vimentin expression (P < .05). Neighborhood analysis finds interactions between CD14+ macrophages, CD3+ T cells, monocyte-derived myeloid dendritic cells, and keratinocytes expressing innate immune markers. These findings highlight phosphorylated extracellular signal-regulated kinase-positive CD14+ macrophages as contributors to itch and suggest an epithelial-immune axis in PN pathogenesis., (Copyright © 2024. Published by Elsevier Inc.)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS., (© 2024 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Objective: Expand genetic screening for atypical Type I sialidosis (ST-1) could address its underdiagnosed in both progressive myoclonic ataxia (PMA) and ataxia patients. To evaluate the potential founder effect of mutation in the population., Methods: We enrolled 231 patients with PMA or ataxia from the First Affiliated Hospital of Fujian Medical University. Through Whole Exome Sequencing and Sanger sequencing, we identified the causative gene in patients. Haplotype analysis was employed to explore a potential founder effect of the NEU1 c.544A>G mutation., Results: A total of 31 patients from 23 unrelated families were genetically diagnosed with ST-1. A significant 80.6% of these patients were homozygous for the c.544A>G mutation. We discovered six different NEU1 variants, including two novel mutations: c.951&#95;968del and c.517T>G. The mean age of onset was 18.0 ± 7.1 years. The clinical spectrum of ST-1 featured ataxia and myoclonus as the most common initial symptoms. Over 40% suffered from controlled generalized tonic-clonic seizures. Mobility and independence varied greatly across the cohort. Cherry-red spots were rare, occurring in just 9.5% (2/21) of patients. Brain MRIs were typically unremarkable, except for two patients with unusual findings. EEGs showed diffuse paroxysmal activity in 17 patients. The c.544A>G mutation in NEU1 is a founder variant in Fujian, with a unique haplotype prevalent in East Asians., Interpretation: ST-1 should be suspected in patients with PMA or ataxia in Southeast China, even without macular cherry-red spots and seizures, and the premier test could be a variant screening of the founder variant NEU1 c.544A>G., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background/aims: Proton pump inhibitors (PPIs) play a crucial role in managing laryngopharyngeal reflux (LPR), but the optimal dosing regimen remains unclear. We aim to compare the effectiveness of the same total PPI dose administered twice daily versus once daily in LPR patients., Methods: We conducted a prospective randomized controlled trial at a tertiary referral hospital, enrolling a total of 132 patients aged 19 to 79 with LPR. These patients were randomly assigned to receive either a 10 mg twice daily (BID) or a 20 mg once daily (QD) dose of ilaprazole for 12 weeks. The Reflux Symptom Index (RSI) and Reflux Finding Score (RFS) were assessed at 8 weeks and 16 weeks. The primary endpoint was the RSI response, defined as a reduction of 50% or more in the total RSI score from baseline. We also analyzed the efficacy of the dosing regimens and the impact of dosing and duration on treatment outcomes., Results: The BID group did not display a higher response rate for RSI than the QD group. The changes in total RSI scores at the 8-week and 16- week visits showed no significant differences between the 2 groups. Total RFS alterations were also comparable between both groups. Each dosing regimen demonstrated significant decreases in RSI and RFS., Conclusions: Both BID and QD PPI dosing regimens improved subjective symptom scores and objective laryngoscopic findings. There was no significant difference in RSI improvement between the 2 dosing regimens, indicating that either dosing regimen could be considered a viable treatment option.

Background: The cost of endoscopic carpal tunnel release (ECTR) has historically been shown to be significantly higher than the cost of open carpal tunnel release (OCTR). Setting and anesthetic technique drive costs in hand surgery; ambulatory surgical center (ASC) settings demonstrate lower costs when compared to hospital-based settings and local-only anesthetic techniques demonstrate savings over general anesthesia. The purpose of this study is to compare wide awake local-only anesthesia technique (WALANT) to monitored anesthetic care (MAC) for ECTR performed in an ASC setting., Methods: This study includes 481 ECTR under WALANT and 405 ECTR under MAC, performed between January 2019 and December 2021 in an ASC. Utilizing previously reported direct operating room costs, overhead, and material costs, we calculated a final cost for each procedure. We also report our complication rates: intraoperative conversion to OCTR and late revision to OCTR., Results: Intraoperative times were shortest for ECTR performed under WALANT (22 min) versus ECTR under MAC (25 min). The total cost for ECTR under WALANT was most cost-effective at $1341.28 versus ECTR under MAC at $1634.00. Both techniques demonstrated a low complication profile., Conclusions: Our intraoperative process flow, staffing model, and ASC setting resulted in cost savings making ECTR an economically feasible option., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Mycobacterium tuberculosis (MTB) is a pathogenic bacterium, belonging to the family Mycobacteriaceae , that causes tuberculosis (TB). Toxoplasma gondii macrophage migration inhibitory factor (TgMIF), a protein homolog of macrophage migration inhibitory factor, has been explored for its potential to modulate immune responses during MTB infections. We observed that TgMIF that interacts with CD74, antizyme inhibitor 1 (AZIN1), and signal transducer and activator of transcription 1 (STAT1) modulates endocytosis, restoration of mitochondrial function, and macrophage polarization, respectively. These interactions promote therapeutic efficacy in mice infected with MTB, thereby presenting a potential route to host-directed therapy development. Furthermore, TgMIF, in combination with first-line TB drugs, significantly inhibited drug-resistant MTB strains, including multidrug-resistant TB. These results demonstrate that TgMIF is potentially a multifaceted therapeutic agent against TB, acting through immune modulation, enhancement of mitochondrial function, and dependent on STAT1 and AZIN1 pathways.

The aim of this study was to propose a novel method to identify individuals by recognizing dentition change, along with human identification process using deep learning. Recent and past images of adults aged 20-49 years with more than two dental panoramic radiographs (DPRs) were assumed as postmortem (PM) and antemortem (AM) images, respectively. The dataset contained 1,029 paired PM-AM DPRs from 2000 to 2020. After constructing a database of AM dentition, the degree of similarity was calculated and sorted in descending order. The matched rank of AM identical to an unknown PM was measured by extracting candidate groups (CGs). The percentage of rank was calculated as the success rate, and similarity scores were compared based on imaging time intervals. The matched AM images were ranked in the CG with success rates of 83.2%, 72.1%, and 59.4% in the imaging time interval for extracting the top 20.0%, 10.0%, and 5.0%, respectively. The success rates depended on sex, and were higher for women than for men: the success rates for the extraction of the top 20.0%, 10.0%, and 5.0% were 97.2%, 81.1%, and 66.5%, respectively, for women and 71.3%, 64.0%, and 52.0%, respectively, for men. The similarity score differed significantly between groups based on the imaging time interval of 17.7 years. This study showed outstanding performance of convolutional neural network using dental panoramic radiographs in effectively reducing the size of AM CG in identifying humans., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Choi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The impact of blood-brain barrier (BBB) leakage on white matter hyperintensity (WMH) subtypes (location) and its association with clinical factors and cognition remains unclear., Purpose: To investigate the relationship between WMH volume, permeability, clinical factors, and cognition in older individuals across the cognitive spectrum., Study Type: Prospective, cross-sectional., Subjects: A total of 193 older adults with/without cognitive impairment; 128 females; mean age 70.1 years (standard deviation 6.8)., Field Strength/sequence: 3 T, GE Dynamic contrast-enhanced, three-dimensional (3D) Magnetization-prepared rapid gradient-echo (MPRAGE T1WI), 3D fluid-attenuated inversion recovery (FLAIR)., Assessment: Periventricular WMH (PWMH), deep WMH (DWMH), and normal-appearing white matter (NAWM) were segmented using FMRIB automatic segmentation tool algorithms on 3D FLAIR. Hippocampal volume and cortex volume were segmented on 3D T1WI. BBB permeability (Ktrans) and blood plasma volume (Vp) were determined using the Patlak model. Vascular risk factors and cognition were assessed., Statistical Tests: Univariate and multivariate analyses were performed to identify factors associated with WMH permeability. Logistic regression analysis assessed the association between WMH imaging features and cognition, adjusting for age, sex, apolipoprotein E4 status, education, and brain volumes. A P-value <0.05 was considered significant., Results: PWMH exhibited higher Ktrans (0.598 ± 0.509 × 10 -3  minute -1 ) compared to DWMH (0.496 ± 0.478 × 10 -3  minute -1 ) and NAWM (0.476 ± 0.398 × 10 -3  minute -1 ). Smaller PWMH volume and cardiovascular disease (CVD) history were significantly associated with higher Ktrans in PWMH. In DWMH, higher Ktrans were associated with CVD history and cortical volume. In NAWM, it was linked to CVD history and dyslipidemia. Larger PWMH volume (odds ratio [OR] 1.106, confidence interval [CI]: 1.021-1.197) and smaller hippocampal volume (OR 0.069; CI: 0.019-0.253) were independently linked to worse global cognition after covariate adjustment., Data Conclusion: Elevated BBB leakage in PWMH was associated with lower PWMH volume and prior CVD history. Notably, PWMH volume, rather than permeability, was correlated with cognitive decline, suggesting that BBB leakage in WMH may be a consequence of CVD rather than indicate disease progression., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 3., (© 2024 The Author(s). Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Various sources associated with mining activities adversely affect water quality in aquatic ecosystems. This study aimed to estimate the sources of dissolved trace elements (DTEs: Al, As, B, Ba, Cd, Co, Cr, Cs, Cu, Fe, Li, Mn, Mo, Ni, Pb, Rb, Sb, U, and Zn) affecting water chemistry in the upper Nakdong River (UNR) catchment and determine the hydrological processes associated with the inflow from anthropogenic sources. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) were employed to estimate main sources affecting water chemistry and its spatiotemporal variability in the four tributaries and main channel of the UNR. Water samples were classified into four groups based on their chemistry. The spatiotemporal variations of DTEs were driven by the presence of anthropogenic sources (including smelters, AMD, mining-related sources), while running toward downstream. The correlations among PCA (and HCA), Zn as smelter impact, and deuterium excess (d-excess = δ 2 H - 8 × δ 18 O) indicated that smelters had a strong influence on water chemistry in the main channel after passing through the smelter. In the dry season, d-excess < ~12 ‰ was observed with increasing Zn levels and factor score for PC2, especially samples influenced by DTEs from smelter, indicating that groundwater affected by the smelters recharged mainly by summer rainwater impacted the spatiotemporal variability of DTEs. This multivariate study suggests that the spatiotemporal variation in DTEs is associated with the complex contributions of natural and anthropogenic sources to water chemistry, which are strongly influenced by hydrological processes and seasonality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationship that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The aim of this study is to propose and evaluate a novel method for measuring the central ray direction and detecting the rotation center of panoramic radiography using the panorama phantom., Methods: To determine the central ray direction, two points passing through the same x-coordinate in a panoramic radiograph were identified and connected. The angles formed by the central ray with the midline and the angle to the arch form were measured using mathematical calculations. Further, by analyzing the continuous changes in the central ray obtained in this manner, the movement of the rotation center was detected and visualized., Results: The angle between the central ray and the midline exhibited a progressive decrease from the anterior to the posterior direction. With regards to the arch form, the angle of the central ray exhibited an increasing pattern as it moved from the anterior to the posterior direction, culminating in its peak value at the lower second premolar cusp region, followed by a consistent decrease. The rotation center approximately started from the distolateral aspect of the coronoid process and then anteromedially moved to the midline in a curved line passing between the mandibular notch and coronoid process., Conclusions: By using the panorama phantom, we successfully obtained the central ray direction and detected the rotation center of the panoramic radiography., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology and the International Association of Dentomaxillofacial Radiology.)

Lymphoma is one of the most common malignant tumors in dogs. Combination chemotherapy with vincristine, cyclophosphamide, doxorubicin, and prednisolone (CHOP) is the most effective treatment for multicentric lymphoma. Previous studies have evaluated the response of large dogs to CHOP treatment and identified prognostic factors; however, studies on small dogs are lacking. In this study, we investigated the outcomes and prognostic factors for small dogs with multicentric lymphoma treated with CHOP. The responses of patients to CHOP treatment were assessed, and 54.3% were evaluated as being in complete remission (CR), 31.4% in partial remission (PR), and 14.3% in no remission (NR). The overall response rate was 85.7%. The median survival times for CR, PR, and NR patients were 683 days (85-1496 days), 241 days (15-777 days), and 119 days (61-308 days), respectively. Among the CR patients, survival was longer under the following conditions: age under 10 years ( p = 0.011), no cardiovascular heart disease ( p = 0.046), and no history of hospitalization due to side effects from chemotherapy ( p = 0.002). These results might help clinicians build treatment plans for multicentric lymphoma in small breed dogs.

Objective: Unilateral vocal fold paralysis (UVFP) following open thoracic aortic surgery increases pulmonary complications and hospital stays. An intervention protocol with early injection laryngoplasty (IL) and swallowing maneuvers was developed for acute UVFP following thoracic aortic surgery. This study aimed to compare the incidence of complications and length of medical care between the non-VFP and the IL-UVFP group managed under this protocol., Methods: Patients who underwent open thoracic aortic surgery from March 2020 to February 2023 were included, excluding those with preoperative VFP or postoperative bilateral VFP. Under the protocol, patients with UVFP and incomplete glottic closure received IL and swallowing maneuvers within one week after diagnosis, while those without a glottic gap started a soft diet along with swallowing maneuvers. Postoperative complications, including reintubation, ICU re-transfer, pneumonia, stroke, delirium, wound infection, and bleeding, as well as hospital and ICU stay, were assessed., Results: Of the 355 patients included in the study, 51 (14.4%) developed postoperative UVFP, while 304 (85.6%) had normal VF function. In the UVFP group, 42 patients underwent IL, while 9 patients without a glottic gap did not undergo IL. The incidence of complications and length of medical care were analyzed in the non-VFP and the IL-UVFP groups. The IL-UVFP group had a longer median hospital stay compared to the non-VFP group (20.5 vs. 16.0 days), though this difference was not statistically significant (P = .0681). ICU stay (P = .5396) and ICU re-transfer rates (P = 1.00) were also comparable between the groups. There was no significant difference in the incidence of pneumonia between the IL-UVFP group (4.8%) and the non-VFP group (9.5%) (P = .4003). Additionally, no significant differences were observed in the incidence of stroke, delirium, wound infection, or bleeding between the groups. No IL-related complications were reported., Conclusions: The protocol with early IL appears to help reduce complication rates in acute UVFP patients following thoracic aortic surgery to levels comparable to those in patients without VFP. This protocol could serve as a guideline for otolaryngologists in managing UVFP patients., Level of Evidence: 2b/Individual cohort study., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

The wastewater produced during coffee cherry pulping is known for containing harmful pollutants, particularly organic compounds containing carbon, which pose significant risks to the environment and human health. This research aimed to evaluate the effectiveness of Tamarindus indica L. seed polysaccharides in treating coffee effluent. Varying doses (ranging from 0.05 to 0.30 g) of the isolated polysaccharides were added to samples of the effluent to determine their ability to remove contaminants, especially those of organic carbon origin. Notably, a dosage of 0.10 g demonstrated optimal efficacy, resulting in a 55% decrease in total dissolved solids and an 80% decrease in chemical oxygen demand. Additionally, Fourier-transform infrared and zeta potential analysis of both the polysaccharides and the treated effluent samples revealed the presence of functional groups potentially pivotal for the pollutant removal activity of the isolated polysaccharides. This provides insights into the coagulation mechanism of Tamarindus indica L. seed polysaccharides in eliminating organic carbon-based pollutants. These findings highlight the potential of Tamarindus polysaccharides as a sustainable alternative to chemical agents for removing pollutants, thus promoting environmental sustainability and human well-being., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This study aimed to assess the safety and feasibility of a 3-month flushing interval for totally implantable venous access ports (TIVAPs), particularly regarding intraluminal clot formation., Methods: Between May 2017 and September 2018, we established a single-center cohort of 151 patients who were referred for TIVAP removal and categorized them into three flushing-interval groups: A (⩽1 month), B (1-2 months), and C (2-3 months). Odds ratios (OR) with 95% confidence intervals (CI) were computed using logistic regression to determine the risk of intraluminal clot occurrence. To compare clot lengths among the groups, we employed linear regression. Restricted cubic splines were used to model the flushing interval as a continuous variable., Results: Compared to Group A, Groups B and C had adjusted ORs of 0.82 (0.35-1.92) and 0.78 (0.29-2.11) for intraluminal clot risk. Occlusion was rare (1/151; 0.7%) and successfully treated with mechanical recanalization. Adjusted differences in clot length compared to Group A were 0.01 (-0.85 to 0.87) for Group B and -0.23 (-1.21 to 0.76) for Group C. Spline regression analysis showed no significant association between the flushing interval and clot length ( p for trend = 0.84)., Conclusion: The incidence and burden of intraluminal clots did not increase significantly within the first 3 months. Occlusion was rare, even in the presence of clots, and was successfully treated. Therefore, a 3-month flushing interval appears to be a safe and practical option, aligning with the common recommendation for surveillance intervals in patients with cancer., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

One-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimers (IAJDs) were discovered in our laboratories in 2021 to represent a new class of synthetic vectors for the targeted delivery of messenger RNA (mRNA). They coassemble with mRNA by simple injection of their ethanol solution into a pH 4 acetate buffer containing the nucleic acid into monodisperse dendrimersome nanoparticles (DNPs) with predictable dimensions. DNPs are competitive with 4-component lipid nanoparticles (LNPs), which are used in commercial COVID-19 vaccines, except that IAJDs are prepared in fewer reaction steps than each individual component of the LNPs. This simple methodology for the synthesis of IAJDs and their coassembly with mRNA into DNPs, together with the precise placement of their individual components and indefinite stability at room temperature in air, make them attractive candidates for the development of nanomedicine-based targeted mRNA delivery. Access to the large-scale synthesis of IAJDs without the need for sophisticated technologies, instrumentation, and synthetic skills is expected to open numerous new opportunities worldwide in nanomedicine. The goal of this publication is to report an accelerated ten-gram-scale synthesis of IAJD97 from inexpensive food additives obtained from renewable plant phenolic acid starting materials by methodologies accessible to any laboratory. This accelerated synthesis can be accomplished in 4 days. We expect that the work reported here will impact the field of nanomedicine in both developed and less developed countries.

Background: Aesthetic neuromodulator injections of the upper face are frequently performed to temporarily block muscular actions of the periorbital muscles to ultimately reduce skin rhytids. However, the adverse event rate in the literature for toxin-induced blepharoptosis ranges from 0.51% to 5.4%., Objective: To identify access pathways by which injected neuromodulator product can travel from extra- to intra-orbital and therefore affect the levator palpebrae superioris muscle., Methods: Nine non-embalmed human body donors were investigated in this study with a mean age at death of 72.8 (16.1) years. The 18 supraorbital regions were injected in 28 times (14 for supratrochlear and 14 for supraorbital) with 0.5 cc, whereas eight cases (four for supratrochlear and four supraorbital) were injected with 0.1 cc of colored product. Anatomic dissections were conducted to identify structures stained by the injected color., Results: The results of this injection- and dissection-based study revealed that both the supratrochlear and the supraorbital neurovascular bundles are access pathways for injected neuromodulator products to reach the intra-orbital space and affect the levator palpebrea superioris muscle. Out of 36 conducted injection passes, seven (19.44%) resulted in affection of the sole elevator of the eyelid of which 100% occurred only at an injection volume of 0.5 cc and not at 0.1 cc., Conclusion: Clinically, the results indicate that a low injection volume, a superficial injection for the supraorbital location, and angling the needle tip away from the supratrochlear foramen (toward the contralateral temple) when targeting the corrugator supercilii muscles, can increase the safety profile of an aesthetic toxin glabellar treatment., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

The rhizosphere, where plant roots interact intensely with the soil, is a crucial but understudied area in terms of the impact of virus infection. In this study, we investigated the effects of lily symptomless virus (LSV) and cucumber mosaic virus (CMV) on the Lanzhou lily (Lilium davidii var. unicolor) rhizosphere using metagenomics and bioinformatics analysis. We found that virus infection significantly altered soil pH, inorganic carbon, nitrate nitrogen, and total sulfur. Co-infection with LSV and CMV had a greater influence than single infections on the α- and β-diversity of the rhizosphere viral community in which the absolute abundance of certain virus families (Siphoviridae, Podoviridae, and Myoviridae) increased significantly, whereas bacteria, fungi, and archaea remained relatively unaffected. These altered virus populations influenced the rhizosphere microbial carbon and nitrogen cycles by exerting top-down control on bacteria. Co-infection potentially weakened rhizosphere carbon fixation and promoted processes such as methane oxidation, nitrification, and denitrification. In addition, the co-occurrence network of bacteria and viruses in the rhizosphere revealed substantial changes in microbial community composition under co-infection. Our partial-least-squares path model confirmed that the diversity of the rhizosphere viral community indirectly regulated the carbon and nitrogen cycling functions of the microbial community, thus affecting the accumulation of carbon and nitrogen nutrients in the soil. Our results are the first report of the effects of virus infection on the lily rhizosphere, particularly for co-infection; they therefore complement research on the plant virus pathogenic mechanisms, and increase our understanding of the ecological role of rhizosphere soil viruses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The optimal diameter for endoscopic dilatation of anastomotic strictures after esophagectomy has not been elucidated. This study aimed to determine the optimal target diameter for endoscopic dilatation for anastomotic stricture after esophagectomy., Methods: The medical records of patients who underwent endoscopic dilatation for anastomotic stricture after esophagectomy between January 2009 and June 2024 at Pusan National University Yangsan Hospital were reviewed. The stricture recurrence rate, dilatation-free period, and complications according to the dilatation diameter were collected and included in the analysis., Results: We analyzed 149 endoscopic dilatations (diameters from 10 to 18 mm) in 43 patients. The median follow-up period was 47 months (range, 5-157). The stricture recurrence rate was 72.5%, and the median dilatation-free period was 60 days. The stricture recurrence rate was the lowest (41.7%, p = 0.022), and the overall dilatation-free period was the longest (median 490 days, p = 0.171) in dilations up to 16.5 mm. The stricture recurrence rate was higher in dilations up to 18 mm than in those up to 16.5 mm (54.5% vs. 41.7%, p = 0.331). Moreover, the bleeding rate was higher in patients with dilations up to 18 mm (18.2% vs. 4.2%, p = 0.205)., Conclusion: In patients with anastomotic strictures after esophagectomy, dilation up to 16.5 mm showed a lower stricture recurrence rate, longer dilation-free period, and less postprocedural bleeding than those of dilation up to 18 mm., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Binaural beat (BB) has been investigated as a potential modality to enhance sleep quality. In this study, we introduce a new form of BB, referred to as dynamic BB (DBB), which incorporates dynamically changing carrier frequency differences between the left and right ears. Specifically, the carrier frequency of the right ear varied between 100 and 103 Hz over a period, while the left ear remained fixed at 100 Hz, yielding a frequency difference range of 0 to 3 Hz. The objective of this study was to examine the effect of DBB on sleep quality. Ten healthy participants were included in a cross-over design, where they experienced both DBB and a SHAM (absence of sound) condition across two consecutive nights, with polysomnography evaluation. DBB was administrated during pre-sleep initiation, sleep onset, and transition from rapid eye movement (REM) to non-REM stage. DBB significantly reduced sleep latency compared to the SHAM condition. Electrocardiogram analysis revealed that exposure to DBB led to diminished heart rate variability during the pre-sleep initiation and sleep onset periods, accompanied by a decrease in low-frequency power of heart rate during the sleep onset period. DBB might be effective in improving sleep quality, suggesting its possible application in insomnia treatments., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Meniere's disease (MD) is a chronic inner ear disorder characterized by tinnitus, ear fullness, episodic vertigo, and fluctuating hearing loss, which significantly impacts quality of life and poses management challenges. Recent evidence suggests that upper respiratory infections (URIs) may contribute to MD's onset. This study examines the potential link between URIs and MD using data from the Korean National Health Insurance Service-National Sample Cohort (2002-2019). We analyzed 19,721 individuals with MD and 78,884 matched controls, adjusting for demographic factors and comorbidities using propensity score matching. Our results showed that individuals with a URI within one year prior to the index date exhibited a 2.01-fold greater likelihood of developing MD (95% confidence interval [CI] = 1.91-2.11, p < 0.001), while those with URIs within two years demonstrated a 1.54-fold higher probability (95% CI = 1.50-1.59, p < 0.001). Furthermore, we found that even remote URIs occurring up to two years before the index date significantly increased the risk of developing MD, underscoring the need for long-term patient follow-up. Overall, our study suggests that individuals with a history of URI may have an elevated risk of developing MD over multiple time frames, regardless of demographic or health profiles.

Introduction: Particulate matter (PM) air pollution is associated with an increased incidence of lung diseases, but the underlying mechanisms have not been fully elucidated. In this study, a mouse model of subacute lung inflammation was employed to investigate the cellular responses and gene expression changes induced by exposure to natural ambient air pollution., Methods: C57BL/6J mice were exposed to road dust (primarily PM10) at 150 µg/m³ for 21 days (8 h/day) through a nose-only inhalation exposure system. Lung tissues were analyzed for the expression of proinflammatory signaling, oxidative stress, and fibrosis markers. RNA-sequencing analysis was conducted to identify differentially expressed genes (DEGs). A gene ontology over-representation analysis was performed to identify the altered genetic pathways., Results: Elevated levels of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, and an increase in phosphorylated MAPK were determined in the road dust exposure group compared to the control group. Histopathological examinations revealed more severe lung inflammation and damage in the exposed mice, including fibrosis and bronchiolar hyperplasia. Gene expression profiling identified 108 DEGs, with decreases in most except genes such as Krt15 and Reg3g. The protein-protein interaction network analysis together with text-mining identified 18 key hub genes, associated with fatty acid oxidation, lipid metabolism, and peroxisomes., Conclusion: This study identified key genes, signaling pathways, and cellular responses in mouse lung affected by road dust exposure. These findings contribute to a deeper understanding of the transcriptional and cellular responses induced by subacute exposure to the PM in road dust.

Primary familial brain calcification (PFBC) is a genetic neurological disease, yet no effective treatment is currently available. Here, we identified five novel intronic variants in SLC20A2 gene from six PFBC families. Three of these variants increased aberrant SLC20A2 pre-mRNA splicing by altering the binding affinity of splicing machineries to newly characterized cryptic exons, ultimately causing premature termination of SLC20A2 translation. Inhibiting the cryptic-exon incorporation with splice-switching ASOs increased the expression levels of functional SLC20A2 in cells carrying SLC20A2 mutations. Moreover, by knocking in a humanized SLC20A2 intron 2 sequence carrying a PFBC-associated intronic variant, the SLC20A2-KI mice exhibited increased inorganic phosphate (Pi) levels in cerebrospinal fluid (CSF) and progressive brain calcification. Intracerebroventricular administration of ASOs to these SLC20A2-KI mice reduced CSF Pi levels and suppressed brain calcification. Together, our findings expand the genetic etiology of PFBC and demonstrate ASO-mediated splice modulation as a potential therapy for PFBC patients with SLC20A2 haploinsufficiency., Competing Interests: Declaration of interests W.-J.C., Z.-Q.X., X.C., M.Z., Y.-H.Z., and L.C. have filed patents (CN2023113708968) to protect the application of CRACE therapy for the treatment of brain calcification., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This study aimed to investigate the association of the grit scale, a personality trait characterized by perseverance and passion, with both the presence and the severity of insomnia in the Korean adult population., Methods: A nationwide population-based cross-sectional survey was conducted through face-to-face interviews using structured questionnaires between September and December 2018 in Korea. Grit was assessed by using the 8-item Short Grit Scale. Participants were categorized into insomnia and non-insomnia groups based on a threshold of 10 on the Insomnia Severity Index (ISI). The association between girt and insomnia was analyzed using multiple linear regression and multivariable logistic regression, controlling for sociodemographic factors, lifestyles, and comorbidities., Results: A total of 2453 participants (49.9 % male; aged 19-92 years) were enrolled in the study. Individual grit scores ranged from 1.75 to 5.00 points (mean [SD], 3.27 [0.42]), and insomnia was present in 16.5 % of the population. The insomnia group exhibited lower grit score compared to the non-insomnia group (3.11 [0.40] vs. 3.30 [0.42], p < 0.001, Cohen's d = 0.46). Grit was negatively associated with ISI scores (β = -0.15, 95 % CI = -0.19, -0.11, p < 0.001) and with having insomnia (OR 0.40, 95 % CI = 0.30, 0.55, p < 0.001), after controlling for covariates., Conclusions: Individuals with higher grit were less likely to have insomnia. Clinicians should consider personality traits, such as grit, in the evaluation and the management of insomnia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The neuropsychiatric symptoms are common in Wilson's disease (WD) patients. However, it remains unclear about the associated functional brain networks. In this study, source localization-based functional connectivity analysis of close-eye resting-state electroencephalography (EEG) were implemented to assess the characteristics of functional networks in 17 WD patients with neurological involvements and 17 healthy controls (HCs). The weighted phase-lag index (wPLI) was subsequently calculated in source space across five different frequency bands and the resulting connectivity matrix was transformed into a weighted graph whose structure was measured by five graphical analysis indicators, which were finally correlated with clinical scores. Compared to HCs, WD patients revealed disconnected sub-networks in delta, theta and alpha bands. Moreover, WD patients exhibited significantly reduced global clustering coefficients and small-worldness in all five frequency bands. In WD group, the severity of neurological symptoms and structural brain abnormalities were significantly correlated with disrupted functional networks. In conclusion, our study demonstrated that functional network deficits in WD can reflect the severity of their neurological symptoms and structural brain abnormalities. Resting-state EEG may be used as a marker of brain injury in WD., Competing Interests: Declaration of competing interest None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Post-transplant HCC recurrence significantly impacts survival, yet its management is challenging due to limited evidence. With recent advancements in HCC treatment, updated data on managing recurrent disease is needed., Methods: In this retrospective study across six centers (2000-2022), we employed Cox proportional-hazards regression and log-rank tests to assess survival differences. A prognostic score model was developed to categorize patient survival. Efficacy of tyrosine kinase inhibitors was evaluated through propensity score matching., Results: In our study, 431 of 3349 (14%) transplanted HCC patients developed recurrence within a median interval of 18 (IQR:9-32) months. 147 (34%) underwent curative-intent treatments, 207 (48%) received palliative treatments, and 77 (18%) were given best-supportive care. Patients undergoing curative-intent treatments had better survival from the time of recurrence with median survival of 45 (95%CI:36-63) months and 1/3/5-year survival of 90%/56%/43% compared to those receiving non-curative treatments (median: 11 (95%CI:10-13) months, 1/3/5-year survival of 46%/10%/7%, log-rank p<0.001). Patients with recurrence diagnosed in the era 2018-2022 showed improved survival over previous era (HR 0.64 (95%CI:0.47-0.86)). Multivariable analysis identified 5 prognostic factors: ineligibility for curative-intent treatment (HR 3.5 (95%CI:2.7-4.6)), recurrence within 1-year (HR 1.7 (95%CI:1.3-2.1)), poor tumor differentiation (HR 1.5 (95%CI:1.1-1.9)), RETREAT score ≥3 (HR 1.4 (95%CI:1.1-1.8)) and AFP at recurrence ≥400 ng/mL (HR 1.4 (95%CI:1.1-1.9)). These factors contributed to a prognostic scoring system (0-9) that stratified patients into three prognosis groups. Both propensity score-matched analysis and multivariable regression indicated that lenvatinib was not statistically superior to sorafenib in terms of efficacy., Conclusion: Curative-intent treatments should be advocated for patients with post-transplant recurrence whenever possible. Prognostic factors linked to aggressive tumor biology significantly influence survival. Advancements in HCC management have improved survival outcomes over the past five years., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Importance: Existing clinical trials favor neoadjuvant chemoradiation therapy (NCRT) followed by surgery alone for locally advanced esophageal cancer (EC) and perioperative chemotherapy as the preferred modality for esophageal adenocarcinoma (EAC). However, it is unclear whether these trial findings are reflected in the patterns of care and survival outcomes among patients in the clinical setting., Objective: To investigate survival outcomes in the clinical setting among patients with EC after various treatment modalities., Design, Setting, and Participants: This retrospective cohort study examined data from the National Cancer Database maintained by the American College of Surgeons and focused on patients with clinical stage II or III EC, excluding those with gastroesophageal junction cancer, who underwent trimodality therapy (NCRT followed by esophagectomy), definitive chemoradiation therapy (DCRT), radiotherapy (RT) alone, or perioperative chemotherapy from January 2006 to December 2020. Analyses were conducted from December 2023 to August 2024., Exposures: Perioperative chemotherapy, trimodality therapy, DCRT, and single-modality RT., Main Outcomes and Measures: A Cox proportional hazards regression model was used to compare overall survival (OS) between treatment groups in the entire cohort, among patients with squamous cell carcinoma or adenocarcinoma, and among those older than 65 years. Landmark survival analysis at 6 months was performed to reduce survivorship bias., Results: The study included 57 116 patients (median age, 64 [IQR, 57-72] years; 45 410 [79.5%] male); 21 619 patients (37.9%) received trimodality therapy, 32 493 (57.1%) received DCRT, 2692 (4.7%) received single-modality RT, and 312 (0.5%) received perioperative chemotherapy. In the overall study population, 37 698 patients (66.0%) had EAC, and of the 312 patients that received perioperative chemotherapy, 283 (90.7%) had EAC. In adjusted survival analysis, perioperative chemotherapy (adjusted hazard ratio [AHR], 0.33; 95% CI, 0.28-0.39; P <.001) and trimodality therapy (AHR, 0.45; 95% CI, 0.44-0.46; P < .001) were associated with improved OS compared with DCRT. In contrast, RT alone was associated with worse outcomes compared with DCRT (AHR, 1.37; 95% CI, 1.30-1.45; P < .001). The median OS for perioperative chemotherapy of 66.2 months (95% CI, 43.1-111.9 months; P < .001) was longer compared with that for DCRT alone (18.1 months; 95% CI, 17.8-18.4 months; P < .001). Trimodality therapy was associated with a median OS of 43.9 months (95% CI, 42.8-45.5 months; P < .001), which was shorter than that for perioperative chemotherapy but improved compared with DCRT and RT alone, which was associated with a median OS of 13.5 months (95% CI, 12.8-14.0 months; P < .001). In the subgroup of patients older than 65 years, those who received perioperative chemotherapy had longer median OS (56.7 months; 95% CI, 36.4-115.2 months; P < .001) compared with those receiving other treatment modalities (eg, trimodality therapy: 40.1 months; 95% CI, 38.1-42.0 months; P < .001). Patients who received RT alone had the worst median OS (13.6 months; 95% CI, 12.8-14.4 months; P < .001)., Conclusions and Relevance: In this cohort study of patients with stage II to III EC, trimodality therapy was associated with improved OS compared with DCRT or RT alone for locally advanced EC and perioperative chemotherapy was associated with improved OS for adenocarcinoma.

Purpose: Although laparoscopic distal gastrectomy has rapidly replaced open distal gastrectomy, laparoscopic total gastrectomy (LTG) is less frequently performed owing to technical difficulties. Robotic surgery could be an appropriate minimally invasive alternative to LTG because it alleviates the technical challenges posed by laparoscopic procedures. However, few studies have compared the oncological safety of robotic total gastrectomy (RTG) with that of LTG, especially for advanced gastric cancer (AGC). Herein, we aimed to assess the oncological outcomes of RTG for AGC and compare them with those of LTG., Materials and Methods: We retrospectively reviewed 147 and 204 patients who underwent RTG and LTG for AGC, respectively, between 2007 and 2020. Long-term outcomes were compared using inverse probability of treatment weighting (IPTW)., Results: After IPTW, the 2 groups exhibited similar clinicopathological features. The 5-year overall survival was comparable between the 2 groups (88.5% [95% confidence interval {CI}, 79.4%-93.7%] after RTG and 87.3% [95% CI, 80.1%-92.0%]) after LTG; log-rank P=0.544). The hazard ratio (HR) for death after RTG compared with that after LTG was 0.73 (95% CI, 0.40-1.33; P=0.304). The 5-year relapse-free survival was also similar between the 2 groups (75.7% [95% CI, 65.2%-83.4%] after RTG and 76.4% [95% CI, 67.9%-83.0%] after LTG; log-rank P=0.850). The HR for recurrence after RTG compared with that after LTG was 0.93 (95% CI, 0.60-1.46; P=0.753)., Conclusions: Our findings revealed that RTG and LTG for AGC had similar long-term outcomes. RTG is an oncologically safe alternative to LTG and has technical advantages., Competing Interests: H.W.J. reports receiving research grants from Medtronic and GC Pharma and is a stockholder and chief executive officer of Hutom. He provided consultancy services to Ethicon and SK Hynix (Wuxi) outside of the submitted work. The other authors have no disclosures to report., (Copyright © 2024. Korean Gastric Cancer Association.)

Background: Low energy availability (LEA) occurs when athletes' energy intake fails to match the energy expended during exercise, resulting in insufficient energy to support essential functions for optimal health, a condition known as relative energy deficiency in sports (REDs)., Objective: This study aims to explore the prevalence of LEA among Malaysian national athletes and its associations with health-related outcomes., Methods: A total of 43 athletes (51.2% males, aged 18-40) identified previously as having moderate or high risk of REDs through a questionnaire underwent comprehensive clinical assessments. Resting metabolic rate (RMR) was measured using indirect calorimetry, with an RMR ratio of <0.90 indicating LEA. Weight and height were measured, and fasting blood samples were analysed for ferritin, free triiodothyronine (fT3), follicle-stimulating hormone (FSH), luteinising hormone (LH), estradiol (female athletes) and testosterone (male athletes). Bone mineral density (BMD) of the lumbar spine and total left hip, as well as body composition, were measured using dual-energy X-ray absorptiometry (DXA)., Results: Out of the 43 athletes, 12 showed evidence of LEA, exhibiting at least one of the following characteristics: low estradiol levels (87.5%), low testosterone (75.0%), low fT3 (66.7%), low LH (58.3%), low FSH (58.3%), low ferritin (25.0%) and low BMD (8.3%). Notably, fT3, estradiol and testosterone were significant predictors for LEA., Conclusions: A low but noteworthy incidence of LEA among Malaysian national athletes was associated with hormone imbalances. Awareness about LEA among athletes and sports personnel is essential for early detection and appropriate intervention., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: I am supported by a grant from the National Research Foundation of Korea and Korean Government (Ministry of Science and ICT, research grant 2023-00208314).

Li-rich Mn-based cathode materials (LRMO) are promising for enhancing energy density of all-solid-state batteries (ASSBs). Nonetheless, the development of efficient Li + /e - pathways is hindered by the poor electrical conductivity of LRMO cathodes and their incompatible interfaces with solid electrolytes (SEs). Herein, we propose a strategy of in - situ bulk/interfacial structure design to construct fast and stable Li + /e - pathways by introducing Li 2 WO 4 , which reduces the energy barrier for Li + migration and enhances the stability of the surface oxygen structure. The reversibility of oxygen redox was improved, and the voltage decay of the LRMO cathode was addressed significantly. As a result, the bulk structure of the LRMO cathodes and the high-voltage solid-solid interfacial stability are improved. Therefore, the ASSBs achieve a high areal capacity (∼3.15 mAh/cm 2 ) and outstanding cycle stability of ≥1200 cycles with 84.1% capacity retention at 1 C at 25 °C. This study offers new insights into LRMO cathode design strategies for ASSBs, focusing on ultrastable high-voltage interfaces and high-loading composite electrodes.

Background: /purpose In cases where oral squamous cell carcinoma (OSCC) invades the jawbone, clinicians frequently observe abnormal attenuation on computed tomography (CT) and pathologic signal intensity (SI) on magnetic resonance (MR) imaging of the affected underlying bone marrow. This study introduced a concept of "underlying bone change" to examine its association with clinicopathological features and prognosis of OSCC, as well as its correlation with medullary invasion., Materials and Methods: We enrolled 93 consecutive patients diagnosed with OSCC, who underwent mandibulectomy between 2010 and 2016. CT and MR images, along with electronic medical records, were reviewed to evaluate correlations between underlying bone changes, clinicopathological features, five-year overall survival, and medullary invasion., Results: Of the 93 patients, 69 (74.2%) exhibited underlying bone sclerosis on CT, and 74 (79.6%) displayed pathological SI on MR images. These underlying bone changes correlated with the T stage and recurrence, but not with overall survival.Medullary invasion, observed in 61 (65.6%) patients, was strongly associated with T and TNM stages and was linked to poorer overall survival.The underlying bone changes on CT and MR images were positively associated with medullary invasion; however, no significant differences were found in the occurrence of underlying bone changes between the subtypes based on the extent of medullary invasion., Conclusion: Underlying bone changes on CT and MR images can provide valuable insights into the aggressiveness of bone invasion by OSCC. Accurate interpretation of these imaging findings might be crucial for correctly delineating surgical margins and preventing the overestimation of tumor extent., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2024 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Miltefosine is the first and only drug approved for the treatment of leishmaniasis. It is also known as a PI3K/AKT signaling pathway inhibitor utilized in anti-cancer or anti-viral therapies. However, the impact of miltefosine on male fertility has not been fully understood. Therefore, this study was performed to investigate the effects of miltefosine on sperm function during capacitation. Duroc spermatozoa were exposed to 0, 2.5, 5, 10, 20, 40, and 80 μM miltefosine and induced for capacitation. Our results showed that miltefosine dramatically increased the expression of PI3K/AKT signaling pathway-associated proteins. Sperm motility, motion kinetics, capacitation, and tyrosine phosphorylation were significantly suppressed by miltefosine. However, intracellular ATP levels and cell viability were not significantly affected. Our findings suggest that miltefosine may disrupt sperm function by abnormally increasing the levels of PI3K/AKT signaling pathway-associated proteins. Therefore, the harmful effects of miltefosine on male reproduction should be considered when using this drug., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Sentinel node navigation (SNN) has been known as the effective treatment for stomach-preserving surgery in early gastric cancer; however, SNN presents several technical difficulties in real practice., Objective: This study aimed to evaluate the feasibility of regional lymphadenectomy omitting SNN, using the post hoc analysis of a randomized controlled trial., Methods: Using data from the SENORITA trial that compared laparoscopic standard gastrectomy with lymphadenectomy and laparoscopic SNN, 237 patients who underwent SNN were included in this study. Tumor location was divided into longitudinal and circumferential directions. According to the location of the tumor, the presence or absence of lymph node (LN) metastases between sentinel and non-sentinel basins were analyzed. Proposed regional LN stations were defined as the closest area to the primary tumor. Sensitivities, specificities, positive predictive values, and negative predictive values (NPV) of SNN and regional lymphadenectomy were compared., Results: Metastasis to non-sentinel basins with tumor-free in sentinel basins was observed in one patient (0.4%). The rate of LN metastasis to non-regional LN stations without regional LN metastasis was 2.5% (6/237). The sensitivity and NPV of SNN were found to be significantly higher than those of regional lymphadenectomy (96.8% vs. 80.6% [p = 0.016] and 99.5% vs. 97.2% [p = 0.021], respectively)., Conclusions: This study showed that regional lymphadenectomy for stomach-preserving surgery, omitting SNN, was insufficient; therefore, SNN is required in stomach-preserving surgery., (© 2024. The Author(s).)

Anatomical airway labeling is crucial for precisely identifying airways displaying symptoms such as constriction, increased wall thickness, and modified branching patterns, facilitating the diagnosis and treatment of pulmonary ailments. This study introduces an innovative airway labeling methodology, BranchLabelNet, which accounts for the fractal nature of airways and inherent hierarchical branch nomenclature. In developing this methodology, branch-related parameters, including position vectors, generation levels, branch lengths, areas, perimeters, and more, are extracted from a dataset of 1000 chest computed tomography (CT) images. To effectively manage this intricate branch data, we employ an n-ary tree structure that captures the complicated relationships within the airway tree. Subsequently, we employ a divide-and-group deep learning approach for multi-label classification, streamlining the anatomical airway branch labeling process. Additionally, we address the challenge of class imbalance in the dataset by incorporating the Tomek Links algorithm to maintain model reliability and accuracy. Our proposed airway labeling method provides robust branch designations and achieves an impressive average classification accuracy of 95.94% across fivefold cross-validation. This approach is adaptable for addressing similar complexities in general multi-label classification problems within biomedical systems., (© 2024. International Federation for Medical and Biological Engineering.)

Rationale & Objective: Biomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease., Study Design: Prospective metabolome-wide association study., Setting & Participants: Persons with CKD enrolled in the GCKD (German CKD) study with metabolite measurements, with external validation within the ARIC (Atherosclerosis Risk in Communities) Study., Exposures: 1,513 urine and 1,416 plasma metabolites (Metabolon Inc) measured at study entry using untargeted mass spectrometry., Outcomes: Main end points were kidney failure (KF) and a composite kidney end point (CKE) of KF, estimated glomerular filtration rate<15mL/min/1.73m 2 , or a 40% decrease in estimated glomerular filtration rate. Death from any cause was a secondary end point. After a median of 6.5 years of follow-up, 500 persons had experienced KF, 1,083 had experienced the CKE, and 680 had died., Analytical Approach: Time-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design with external validation., Results: 5,088 GCKD study participants were included in analyses of urine metabolites, and 5,144 were included in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with the CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (HR, 1.95; 95% CI, 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, the CKE, and death. External validation of the identified associations of metabolites with KF or the CKE revealed directional consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported., Limitations: Use of observational data and semiquantitative metabolite measurements at a single time point., Conclusions: The observed associations between metabolites and KF, the CKE, or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts., Plain-Language Summary: Incomplete understanding of the variability of chronic kidney disease (CKD) progression motivated the search for new biomarkers that would help identify people at increased risk. We explored metabolites in plasma and urine for their association with unfavorable kidney outcomes or death in persons with CKD. Metabolomic analyses revealed 182 metabolites significantly associated with CKD progression or death. Many of these associations confirmed previously reported findings or were validated by analysis in an external study population. Our comprehensive screen of the metabolome serves as a valuable foundation for future investigations into biomarkers associated with CKD progression., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Human T-cell leukemia virus type 1-associated myelopathy (HAM) is a chronic, progressive, inflammatory disease with unclear pathogenesis and no effective treatments. We aimed to investigate a novel mechanistic theory and treat HAM patients with rituximab, which can deplete CD20 + B lymphocytes in circulation., Methods: Single-cell RNA sequencing (scRNA-seq) data was analyzed to identify HTLV-1-associated B cells and their effect on T cells. An observational analysis of our HAM cohort was conducted to elucidate changes in the immunological microenvironment of these patients. Peripheral blood mononuclear cells (PBMC) from HAM patients were isolated to explore the efficacy of B cell depletion in vitro. To assess the effect of B-cell depletion on HAM patients, eligible participants in our cohort received rituximab therapy (NCT04004819)., Results: ScRNA-seq results suggest a significant effect of HTLV-1-associated B cells on T cells. Additionally, HTLV-1 was found to infect B cells and depletion of B cells inhibited the proliferation of T cells. Number of B cells in HAM patients had positive correlation with the proviral load and infected cell counts. Depletion of B cells led to a reduction in HTLV-1 proviral load in vitro. Furthermore, in clinical trial, 14 HAM patients were enrolled. Three patients (21.4%) who received rituximab failed to achieve remission, compared to 24 (85.7%) patients received any other therapy that failed to achieve remission. With a low level of circulating B cells, the proportion of Ki67-positive cells in CD4 + T cells fell., Interpretation: This study provided evidence that depleting B-lymphocytes is an innovative strategy for treating patients with HAM and broadens the understanding of the role of B cells in infectious immunity., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Aims/hypothesis: The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus, insulin resistance and the metabolic syndrome is well established. While zinc finger BED-type containing 3 (ZBED3) has been linked to type 2 diabetes mellitus and the metabolic syndrome, its role in MASLD remains unclear. In this study, we aimed to investigate the function of ZBED3 in the context of MASLD., Methods: Expression levels of ZBED3 were assessed in individuals with MASLD, as well as in cellular and animal models of MASLD. In vitro and in vivo analyses were conducted using a cellular model of MASLD induced by NEFA and an animal model of MASLD induced by a high-fat diet (HFD), respectively, to investigate the role of ZBED3 in MASLD. ZBED3 expression was increased by lentiviral infection or tail-vein injection of adeno-associated virus. RNA-seq and bioinformatics analysis were employed to examine the pathways through which ZBED3 modulates lipid accumulation. Findings from these next-generation transcriptome sequencing studies indicated that ZBED3 controls SREBP1c (also known as SREBF1; a gene involved in fatty acid de novo synthesis); thus, co-immunoprecipitation and LC-MS/MS were utilised to investigate the molecular mechanisms by which ZBED3 regulates the sterol regulatory element binding protein 1c (SREBP1c)., Results: In this study, we found that ZBED3 was significantly upregulated in the liver of individuals with MASLD and in MASLD animal models. ZBED3 overexpression promoted NEFA-induced triglyceride accumulation in hepatocytes in vitro. Furthermore, the hepatocyte-specific overexpression of Zbed3 promoted hepatic steatosis. Conversely, the hepatocyte-specific knockout of Zbed3 resulted in resistance of HFD-induced hepatic steatosis. Mechanistically, ZBED3 interacts directly with polypyrimidine tract-binding protein 1 (PTBP1) and affects its binding to the SREBP1c mRNA precursor to regulate SREBP1c mRNA stability and alternative splicing., Conclusions/interpretation: This study indicates that ZBED3 promotes hepatic steatosis and serves as a critical regulator of the progression of MASLD., Data Availability: RNA-seq data have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231875 ). MS proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository ( https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743 )., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The primary goal of this study is to evaluate the effect of the non-invasive radiofrequency hyperthermia (RFHT) device on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) rat model and investigate the underlying mechanism., Materials and Methods: In this study, Sprague-Dawley rats were randomly distributed into three groups: (1) normal control group, (2) CP/CPPS group, and (3) RFHT group. CP/CPPS rat models were induced by 17β-estradiol and dihydrotestosterone for 4 weeks and RFHT was administered for 5 weeks after model establishment. During RFHT administration, core body temperatures were continuously monitored with a rectal probe. After administering RFHT, we assessed pain index for all groups and collected prostate tissues for Western blot analysis, immunofluorescence, and immunohistochemistry. We also collected adjacent organs to the prostate including urinary bladder, testes, and rectum for safety assessment via H&E staining along with a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay., Results: After administering RFHT, pain in rats was significantly alleviated compared to the CP/CPPS group. RFHT reduced high-mobility group box 1 (HMGB1) expression and improved inflammation by downregulating subsequent proinflammatory cytokines through inhibition of the toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) pathway. In prostate-adjacent organs, no significant histological alteration or inflammatory infiltration was detected. The area of cell death also did not increase significantly after RFHT., Conclusions: In conclusion, RFHT demonstrated anti-inflammatory effects by inhibiting the HMGB1-TLR4-NF-κB pathway in CP/CPPS rat models. This suggests that RFHT could serve as a safe and promising therapeutic strategy for CP/CPPS., Competing Interests: The authors have nothing to disclose., (Copyright © 2024 Korean Society for Sexual Medicine and Andrology.)

Ethylene oxide (E.O) is an epoxide compound, and it has been utilized as a sterilizer or production of ether compounds in several industries. Although the toxic effects of E.O on bacteria and mammals have been reported, its effects on male reproductive toxicity during sperm capacitation are not fully understood. Therefore, this study was designed to evaluate the effects of E.O exposure during sperm capacitation. Boar spermatozoa were treated with various E.O concentrations (0, 0.1, 1, 10, and 100 μМ). After exposure, sperm motility, motion kinematics, capacitation status, intracellular ATP levels, cell viability, expression levels of protein kinase A (PKA) activation, and tyrosine phosphorylation were evaluated. Results revealed that E.O exposure significantly decreased sperm motility, motion kinematics, and intracellular ATP levels but significantly increased the capacitated spermatozoa. In addition, the PKA activation and tyrosine phosphorylation were abnormally changed. According to our results, E.O may cause toxic effects on sperm function during capacitation, which induces male reproductive toxicity. Consequently, we suggest that male reproductive toxicity should be considered when using E.O., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: There is a lack of effective biomarkers for predicting the distant metastasis in nasopharyngeal carcinoma (NPC). We aimed to explore the expression of FAP + Cancer-associated fibroblasts (CAFs) derived CXCL1 in NPC and its predictive values for distant metastasis and correlation with PD-L1 expression., Materials and Methods: A total of 345 patients with locoregionally advanced NPC were retrospectively enrolled (the training cohort: the validation cohort = 160:185). Co-expression of CXCL1 and FAP and the expression of PD-L1 were detected by multi-immunofluorescence staining and immunohistochemistry, respectively. The primary end-point was distant metastasis-free survival (DMFS). The Kaplan-Meier method was used to calculate the survival. The Cox proportional hazards model was used to assess prognostic risk factors., Results: A novel CXCL1 + &#95;FAP + phenotype in CAFs was identified in NPC and then used to divide patients into low and high risk groups. Both in the training cohort and validation cohort, patients in the high risk group had poorer DMFS, overall survival (OS), progression-free survival (PFS) and locoregional relapse-free survival (LRFS) than patients in the low risk group. Multivariate analysis revealed CXCL1 + &#95;FAP + phenotype was an independent prognostic factor for DMFS, OS, PFS and LRFS. Further results showed patients in the high risk group had higher PD-L1 expression than those in the low risk group., Conclusion: Our study showed CXCL1 + &#95;FAP + phenotype in CAFs could effectively classified locoregionally advanced NPC patients into different risk groups for distant metastasis and might be a potential biomarker for anti-PD-1/PD-L1 immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

FARS2-associated hereditary spastic paraplegia, later onset spastic paraplegia type 77, is a rarely neurodegenerative disease. Here, we reported two affected siblings in an autosomal recessive spastic paraplegia family with a pseudo-homozygous missense variant and Alu-mediated exon 5 deletion in FARS2. Both patients gradually developed altered gaits and weakness in both lower limbs. In our literature review, spastic paraplegia type 77 shows high heterogeneity in clinical manifestations. Our study broadens the scope of pathogenic mechanisms of SPG77 resulting from compound heterozygous mutations in FARS2 and provides strong evidence that deletion in FARS2 due to recombination event mediated by Alu element., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)